면역반응의 산화, 환원 생리학!! 2022년 nature review

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Redox regulation of the immune response

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• Review Article
• Open access
• Published: 02 September 2022

Redox regulation of the immune response

• Gerwyn Morris, 
• Maria Gevezova, 
• Victoria Sarafian & 
• Michael Maes 

Cellular & Molecular Immunology volume 19, pages1079–1101 (2022)Cite this article

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Abstract

The immune-inflammatory response is associated with increased nitro-oxidative stress. The aim of this mechanistic review is to examine:

(a) the role of redox-sensitive transcription factors and enzymes, ROS/RNS production, and the activity of cellular antioxidants in the activation and performance of macrophages, dendritic cells, neutrophils, T-cells, B-cells, and natural killer cells;

(b) the involvement of high-density lipoprotein (HDL), apolipoprotein A1 (ApoA1), paraoxonase-1 (PON1), and oxidized phospholipids in regulating the immune response; and

(c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response.

The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor-κB, HIF1α, the mechanistic target of rapamycin, the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, mitogen-activated protein kinases, 5' AMP-activated protein kinase, and peroxisome proliferator-activated receptor. The performance and survival of individual immune cells is under redox control and depends on intracellular and extracellular levels of ROS/RNS. They are heavily influenced by cellular antioxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2, and the HDL/ApoA1/PON1 complex.

Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.

면역-염증 반응은 

니트로 산화 스트레스 nitro-oxidative stress  증가와 관련이 있습니다. 

이 기계론적 검토의 목적은 다음을 검토하는 것입니다: 

(a) 대식세포, 수지상세포, 호중구, T세포, B세포, 자연살해세포의 활성화와 성능에 있어 

    산화 환원 민감성 전사인자 및 효소의 역할, ROS/RNS 생성, 세포 항산화제의 활성; 

(b) 고밀도 지단백질(HDL), 아포지단백질 A1(ApoA1), 파라옥소나제-1(PON1) 및 산화 인지질이 

    면역 반응을 조절하는 데 관여하며,

(c) 과질소산화 및 만성 질소 산화 스트레스가 면역 반응에 미치는 해로운 영향.

(a) the role of redox-sensitive transcription factors and enzymes, ROS/RNS production, and the activity of cellular antioxidants in the activation and performance of macrophages, dendritic cells, neutrophils, T-cells, B-cells, and natural killer cells;

(b) the involvement of high-density lipoprotein (HDL), apolipoprotein A1 (ApoA1), paraoxonase-1 (PON1), and oxidized phospholipids in regulating the immune response; and

(c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response.

면역 염증 반응 중

산화 환원 변화는

핵 인자-κB,

라파마이신의 기계적 표적인 HIF1α,

포스파티딜이노시톨 3-키나제/프로틴 키나제 B 신호 경로,

미토겐 활성화 단백질 키나제,

5' AMP 활성화 단백질 키나제,

퍼옥시좀 증식인자 활성화 수용체의 작용에 의해 조율됩니다.

nuclear factor-κB, HIF1α, the mechanistic target of rapamycin, the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, mitogen-activated protein kinases, 5' AMP-activated protein kinase, and peroxisome proliferator-activated receptor

개별 면역 세포의 성능과 생존은

산화 환원 제어하에 있으며

세포 내 및 세포 외 ROS/RNS 수준에 따라 달라집니다.

이들은

글루타티온 및 티오레독신 시스템,

핵 인자 적혈구 2 관련 인자 2,

HDL/ApoA1/PON1 복합체를 포함한

세포 항산화제의 영향을 많이 받습니다.

glutathione and thioredoxin systems,

nuclear factor erythroid 2-related factor 2, and the

HDL/ApoA1/PON1 complex.

만성적인 니트로 산화 스트레스와 과니트로실화는

이러한 항산화 시스템의 활성,

트리카르복실산 주기,

미토콘드리아 기능,

면역 세포의 대사를 억제합니다.

Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. 

결론적으로

산화 환원 관련 메커니즘은

면역 세포의 대사 재프로그래밍,

대식세포 및 T 헬퍼 세포 분극화,

식균 작용,

염증성 및 항염증성 사이토카인 생성,

면역 훈련 및 내성,

화학 작용,

병원체 감지,

항바이러스 및 항균 효과,

톨 유사 수용체 활성 및 내독소 내성을 조절합니다.

In conclusion, redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.

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Introduction

The instigation of the innate immune response commences as a result of the recognition of an invading pathogen by organ-specific resident macrophages, dendritic cells (DCs), fibroblasts, pericytes, and in many cases endothelial cells [1,2,3,4]. This recognition is accomplished by cytosolic or membrane-bound Toll-like or NOD-like pattern-recognition receptors (PRR) that leads to the activation of these sentinel cells and the release of cytokines and chemokines [3,4,5]. Once secreted these molecules activate endothelial cells that then express chemokines and adhesion factors [6, 7]. Recruitment, binding, and activation of neutrophils, monocytes, macrophages, and platelets follow these processes in turn allowing the migration of myeloid cells into tissues that reach the sites of infection [8,9,10].

The multiple phenotypical and functional roles of myeloid cells are enabled by metabolic reprogramming comprising of changes in levels of glycolysis, fatty acid oxidation (FAO), the tricarboxylic acid (TCA) cycle activity, involvement of the pentose phosphate pathway (PPP), and mitochondrial respiration [11,12,13]. This is also true for neutrophils, T-cell activation and differentiation into helper, effector, and cytotoxic subsets [14], B-cell activation, differentiation and antibody production [15], and the activation and cytotoxic properties of natural killer (NK) cells [16].

These metabolic and redox changes are orchestrated and regulated by the cooperative and/or antagonistic actions of nuclear factor (NF-κB), HIF1α, the mechanistic target of rapamycin (mTOR), and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Mitogen-activated protein (MAP) kinases, 5' AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR) are also implicated. All these factors lead to the increase in reactive oxygen species (ROS) produced by mitochondria and to the upregulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). These transcription factors and enzymes are all redox-sensitive as is the performance of mitochondria [17,18,19,20,21,22,23].

In addition, the functioning of individual immune cells is under redox control. It is sensitive to intracellular and extracellular levels of nitric oxide (NO) [24, 25] and ROS [26,27,28] and is also heavily influenced by the activity of nuclear factor erythroid 2-related factor 2 (Nrf-2) and cellular antioxidants [29,30,31]. The action of individual immune cells is regulated by oxidized phospholipids [32,33,34,35], high-density lipoprotein (HDL), apolipoprotein A1 (ApoA1), paraoxonase-1 (PON1) activity [36,37,38], and indoleamine 2, 3-dioxygenase (IDO) [39, 40]. The levels and immune functions of these molecular players are under redox control as well [41].

소개

선천성 면역 반응의 시작은

기관별 상주 대식세포,

수지상세포(DC),

섬유아세포,

혈관내피세포 및 많은 경우 내피세포가

침입 병원체를 인식한 결과로 시작됩니다[1,2,3,4].

이러한 인식은

세포질 또는 막에 결합된 톨 유사 또는

NOD 유사 패턴 인식 수용체(PRR)에 의해 이루어지며,

이러한 패턴 인식 수용체는

이러한 감시 세포의 활성화와

사이토카인 및

케모카인의 방출로 이어집니다[3,4,5].

분비된 분자는

내피 세포를 활성화하여

케모카인과 접착 인자를 발현합니다[6, 7].

호중구, 단핵구, 대식세포 및 혈소판의 모집,

결합 및 활성화는

이러한 과정을 거쳐

골수 세포가 감염 부위에 도달하는 조직으로 이동할 수 있게 합니다[8,9,10].

골수 세포의 다양한 표현형 및 기능적 역할은

해당 과정,

지방산 산화(FAO),

트리카르복실산(TCA) 주기 활성,

펜토스인산 경로(PPP)의 관여 및

미토콘드리아 호흡 수준의 변화로 구성된

대사 재프로그래밍을 통해 가능합니다 [11,12,13].

이는

호중구,

T세포 활성화 및 헬퍼, 이펙터, 세포 독성 하위 집합으로의 분화[14],

B세포 활성화, 분화 및 항체 생산[15],

자연 살해(NK) 세포의 활성화 및

세포 독성 특성[16]에도 해당됩니다.

이러한 대사 및 산화 환원 변화는

핵 인자(NF-κB),

HIF1α,

라파마이신(mTOR)의 기계적 표적,

포스파티딜이노시톨 3키나제(PI3K)/프로틴 키나제 B(AKT) 신호 경로의

협력적 또는 길항적 작용으로 조율되고 조절됩니다.

미토겐 활성화 단백질(MAP) 키나제,

5' AMP 활성화 단백질 키나제(AMPK),

퍼옥시좀 증식 인자 활성화 수용체(PPAR)도 관련되어 있습니다.

이러한 모든 인자는

미토콘드리아에서 생성되는

활성 산소 종(ROS)의 증가와

니코틴아미드 아데닌 디뉴클레오티드 인산염(NADPH) 산화 효소(NOX)의

상향 조절로 이어집니다.

이러한

전사 인자와 효소는 모두

미토콘드리아의 성능과 마찬가지로

산화 환원에 민감합니다[17,18,19,20,21,22,23].

또한

개별 면역 세포의 기능도

산화 환원 제어를 받습니다.

세포 내 및 세포 외 산화질소(NO) 수준[24, 25] 및

ROS[26,27,28]에 민감하며,

핵인자 적혈구 2 관련 인자 2(Nrf-2) 및

세포 항산화제의 활성에도 큰 영향을 받습니다[29,30,31].

개별 면역 세포의 작용은

산화 인지질[32,33,34,35],

고밀도 지단백질(HDL),

아포지단백질 A1(ApoA1),

파라옥소나제-1(PON1) 활성[36,37,38],

인돌아민 2, 3-다이옥소아제(IDO)[39, 40] 등에 의해 조절됩니다.

이러한

분자 플레이어의 수준과 면역 기능도

산화 환원 제어를 받습니다 [41].

Figure 1 shows the outcome of a STRING (STRING version 11.0; https://string-db.org) protein–protein network analysis performed on the aforementioned proteins and enzymes, which are discussed in detail in this review. The zero-order network consists of 16 nodes. The number of edges (n = 50) exceeds the expected number of edges (n = 13) with p-enrichment value of 2.22E–15, average node degree = 6.25 and average local clustering coefficient = 0.78.

Fig. 1

STRING protein–protein network analysis performed on the key proteins included in the present review. Nodes indicate proteins and edges indicate protein–protein interactions. Red colour of the nodes: reflects response to stress (p < 1.57E–05), blue node colour: small molecular metabolic process (p < 1.68E–05), green node colour: positive regulation of metabolic process (p < 2.17E–05), and yellow node colour: regulation of immune system process (p < 3.78E–05). Colours of the edges: see https://string-db.org for details. The figure displays the gene names and Table 1 specifies the names and functions of the proteins.

NFKB1 nuclear factor (NF)-κB (NF-κB),

HIF1A hypoxia-inducible factor 1-alpha (HIF1α),

MTOR the mechanistic target of rapamycin (mTOR),

PIK3CA phosphatidylinositol 3-kinase (PI3K),

AKT1 protein kinase B,

MAPK mitogen-activated protein kinases,

PRKAB1 AMP-activated protein kinase (AMPK),

PPARA peroxisome proliferator-activated receptor,

NOX NADPH oxidase,

NFE2L2 nuclear factor erythroid 2-related factor 2 (Nrf-2),

APOA1 apolipoprotein A1 (ApoA1),

PON1 paraoxonase-1,

IDO1 indoleamine 2, 3-dioxygenase (IDO),

TLR-4 Toll-like receptor-4

Full size image

Table 1 summarizes the functions of the proteins in this highly interconnected protein interaction network.

Table 1 Names and functions of the key proteins included in the present review

NF-κB

핵 인자 NF-카파-B

면역 활성화, 분화, 세포 성장 및 세포 사멸을 포함한 일련의 신호 전달 사건의 종말점이자 다발성 전사인자.

[42,43,44, 88, 89]

HIF1α

저산소증 유도 인자 1-알파

저산소증에 대한 반응의 전사 조절 인자. 해당 효소, 포도당 수송체, 혈관 내피 성장 인자, 산소 전달을 증가시키는 단백질 등 40개 이상의 유전자를 활성화합니다.

[47, 49, 54,55,56,57]

mTOR

라파마이신의 메커니즘적 표적

스트레스, 호르몬 및 에너지 신호에 반응하여 세포 대사, 생존 및 성장을 조절합니다.

[72,73,74,75,76,77,78, 180, 228]

PI3K

PI3-키나아제

포스파티딜이노시톨 4,5-비스포스페이트 3-키나아제 촉매 서브유닛 알파 이소형

포스파티딜 이노시톨 3- 키나제

증식, 분화, 생존, 운동성 및 형태를 포함한 세포 기능을 조절하는 신호 전달 효소 그룹

[45, 47,48,49, 130, 230, 231]

AKT1

RAC-알파 세린/트레오닌-단백질 키나아제

신진대사, 세포 생존, 증식 및 성장 조절

[22, 46, 48, 73, 331, 479]

MAPK1

미토겐 활성화 단백질 키나아제

전사 및 번역 과정과 세포 골격 재배열을 통해 접착, 세포 성장, 생존 및 분화를 매개합니다.

[435]

AMPK

5'-AMP 활성화 단백질 키나아제

ATP 감소에 대응하여 에너지 대사를 조절하고 에너지 소비 과정을 약화시킵니다. AMPK는 탄수화물, 지질 및 단백질 합성을 감소시킵니다.

[21, 133, 134, 293, 346, 448]

PPAR

퍼옥시솜 증식 인자 활성화 수용체

베타 산화 경로와 지질 대사를 조절합니다.

[41, 90, 138, 139]

NADPH 산화 효소(NOX)

니코틴아미드 아데닌 디뉴클레오티드 인산염 산화 효소

구성적으로 슈퍼옥사이드 생성 가능

[144, 216, 470, 472]

TLR-4

톨 유사 수용체-4

리포다당류에 대한 면역 반응을 매개합니다.

[85, 87]

Nrf-2

핵 인자 에리스로이드 2 관련 인자 2

(항산화) 표적 유전자의 프로모터 영역에서 항산화 반응 요소에 결합하는 전사 활성화제

[160, 195, 196, 436]

PON1

파라옥소나제/아릴에스테라아제 1

저밀도 지단백질을 산화적 변형 및 그에 따른 죽종 생성으로부터 보호합니다.

[525, 526]

IDO

인돌아민 2,3-다이옥소아제 1

트립토판이 키누레닌 및 기타 트립토판 이화산물로 전환되는 첫 번째 단계를 촉매합니다.

[535]

ApoA1

아포지단백질 A-I

레시틴 콜레스테롤 아실 트랜스퍼라제의 보조 인자로 작용하며 역 콜레스테롤 수송에 참여합니다.

This paper has three aims.

Firstly, to detail the role of redox-sensitive transcription factors and enzymes, ROS, and reactive nitrogen species (RNS) production and the effect of cellular antioxidants on the activation and performance of macrophages, DCs, neutrophils, T-cells, B-cells, and NK-cells.

Secondly, to explain the involvement of HDL, ApoA1, PON1, and oxidized phospholipids in regulating the immune-inflammatory response.

Thirdly, to clarify the detrimental effects of chronic oxidative and nitrosative stress on the performance of individual immune cells and the immune-inflammatory response as a whole. We will begin with a discussion of the effects of these factors on macrophage activation and function, which offers a vehicle to illustrate many of the principles involved in metabolic reprogramming and the effects of individual signaling molecules, thus avoiding unnecessary repetition in later sections of the paper.

이 논문은 세 가지 목표를 가지고 있습니다. 

첫째, 산화 환원 민감성 전사인자 및 효소, ROS, 반응성 질소 종(RNS) 생성의 역할과 

        세포 항산화제가 대식세포, DC, 호중구, T세포, B세포, NK세포의 활성화와 성능에 미치는 영향을

       자세히 설명하는 것입니다. 

redox-sensitive transcription factors and enzymes

둘째, 면역 염증 반응을 조절하는 데 있어 

        HDL, ApoA1, PON1 및 산화 인지질의 관여를 설명하기 위해서입니다. 

셋째, 만성 산화 및 질산화 스트레스가 

        개별 면역 세포의 성능과 면역 염증 반응 전체에 미치는 해로운 영향을 명확히하기 위해.

        이러한 요인들이 대식세포 활성화와 기능에 미치는 영향에 대한 논의로 시작하여

        대사 재프로그래밍과 관련된 많은 원리와 개별 신호 분자의 효과를 설명하는 수단을 제공하므로

         논문의 후반부에서 불필요한 반복을 피할 수 있습니다.

Metabolic reprogramming and redox factors involved in macrophage activation

Metabolic reprogramming in macrophages

Macrophages may be activated by cytokines, ROS, and PRR engagement by pathogen-associated molecular patterns, damage-associated molecular patterns, and commensal LPS leading to the activation of NF-κB [42,43,44] and the PI3K/AKT signaling pathway [45, 46]. Upregulated NF-κB results in increased transcription of proinflammatory cytokines and chemokines, inducible NO synthase (iNOS), and HIF1α [42,43,44]. Enhanced PI3K signaling also leads to the upregulation of mTOR [47,48,49] which in turn reinforces the upregulation of HIF1α [45, 46]. These signaling pathways, enzymes, and transcription factors play an essential role in maintaining macrophage activation and M1 polarization by driving metabolic reprogramming. It involves the downregulation of ATP production by mitochondrial oxidative phosphorylation (OXPHOS) and FAO [50, 51] to ATP production via aerobic glycolysis [52].

The shift to aerobic glycolysis is an indispensable metabolic event for M1 macrophages in terms of maintaining and increasing phagocytosis, production of ROS and proinflammatory cytokines and unsurprisingly, its inhibition may impair those functions [53,54,55]. Maintenance of this state is dependent on the activity of a range of transcription factors, most notably mTOR and HIF1α, with the latter playing a dominant role in enabling the continuance of glycolysis under normoxic conditions [49, 56].

HIF1α acts as a modulator of transcription by changing the methylation status of hypoxia-responsive elements in the promoter regions of target genes involved in the termination of OXPHOS and the instigation of aerobic glycolysis [57]. For example, HIF1α upregulation suppresses the activity of electron transport chain (ETC) enzymes [58, 59], decreases mitochondrial activity, and induces mitochondrial autophagy [60, 61]. Increased activity of this transcription factor also suppresses genes involved in FAO [62, 63]. HIF1α restrains metabolism by activating the gene for pyruvate dehydrogenase kinase 1, which in turn inhibits the TCA cycle [64] and inactivates pyruvate dehydrogenase [65]. In addition, HIF1α-regulated gene expression‎ reduces the production of acetyl-CoA and succinyl-CoA [66].

HIF1α intensifies glycolytic flux, thereby augmenting the expression‎ of glucose transporters (GLUT-1 and GLUT-3) [67]. Glycolysis is stimulated by the high levels of hexokinases [68], aldolase A, enolase 1 [69], and phosphoglycerate kinase 1 [70]. Finally, HIF1α also induces the transcription of lactate dehydrogenase A, which plays an indispensable role in maintaining a continuous supply of NAD+, thereby enabling the continuation of glycolysis [71]. HIF1α-regulated gene expression‎ prevents acetyl-CoA from being synthesized from glucose and fatty acid-derived carbons [66].

While the role of HIF1α in instigating and regulating the transition between OXPHOS and aerobic glycolysis is of paramount importance, it should be emphasized that the activation of mTOR is involved. Firstly, mTOR stabilizes and enhances the activity of HIF1α and, secondly, it increases the rate of glycolysis, AKT, forkhead box transcription factors (FoxO), hexokinase II, and Myc proto-oncogene [72,73,74]. Upregulated mTOR participates in further reducing OXPHOS by enhancing NO and interferon (IFN)-γ production, thus compromising the activity of the mitochondrial ETC [75]. In total, the actions of mTOR inhibit M2 polarization [76] and stimulate M1 polarization [77, 78].

The PPP main role is to utilize the energy released from the metabolism of glucose-6-phosphate into ribulose-5-phosphate to form NADPH. The latter is used in the production of NADPH oxidase and as a reducing equivalent enabling the function of the glutathione (GSH) and thioredoxin antioxidant systems [13, 79]. The activation of M1 polarized macrophages also results in several other aspects of metabolic reprogramming in order to maintain the inflammatory status and prolong survival. Most notable are the upregulation of the cytosolic PPP [50, 80], increased lipid synthesis, and decreased lipid catabolism [62, 81], altered glutamine and arginine metabolism [81, 82], and a “broken” TCA cycle [83, 84]. These parameters are discussed below commencing with the Toll-like Receptor (TLR) and proinflammatory cytokine-mediated reprogramming of the lipidome [85].

The synthesis of lipids is a key component in membrane remodeling. In M1 macrophages the process depends on the production of acetyl-CoA from citrate ATP-citrate lyase [86]. The activity of this enzyme rapidly increases in activated macrophages. Intracellular fatty acids can also be used to synthesize triglycerides for energy storage, and sphingolipids for membrane synthesis, as well as eicosanoids for signaling [81]. The increase in lipid synthesis is largely enabled and regulated by the high activity of sterol regulatory element binding protein-1 (SREBP-1) by TLR-4 and PI3K-activated mTOR [73, 87]. It is also controlled by the enhanced expression‎ of NF-κB and the presence of proinflammatory cytokines [88, 89]. SREBP-1 activation stimulates the synthesis of proinflammatory cytokines, ROS, and triggers the inflammasome [87,88,89]. M1 activation is accompanied by elevated iNOS, which induces the conversion of arginine to NO, so that the production of other RNS may be initiated [82, 90, 91].

M1 polarized macrophages accumulate cytosolic citrate stemming from the decreased activity of isocitrate dehydrogenase (IDH) [50] and the upregulation of the mitochondrial citrate carrier (CIC) [92, 93]. The increased activity of IDH is mediated by ADP levels [94]. CIC is upregulated by several inflammatory mediators such as tumor necrosis factor (TNF)-α, IFN-γ, or commensal LPS via the upregulation of NF-κB and or STAT-1 [92, 95]. In this scenario, citrate exerts a multiplicity of vital roles, enabling macrophage function and inflammatory status such as increasing NO, ROS, and prostaglandin E2 (PGE2) production [92, 96]. Cytosolic citrate can also act as a source of NADPH, either as a result of malate import into mitochondria via CIC, and the subsequent formation of pyruvate via malic enzyme, or the conversion of citrate into alpha-ketoglutarate via the action of cytosolic IDH [97, 98]. Cytosolic citrate is also a substrate of ACLY, producing acetyl-CoA and oxaloacetate and upregulating acetyl-CoA carboxylase (ACC) stimulating lipid synthesis [99].

Activated M1 polarized macrophages are characterized by high levels of cytosolic itaconate from cis-aconitate drawn from the Krebs cycle via a significant inflammation-mediated upregulation of macrophage aconitate decarboxylase 1 [100, 101]. Itaconate is involved in tolerance and suppression of inflammation [102, 103], inhibits mitochondrial respiration, stabilizes HIF1α, and activates Nrf-2 via alkylation of KEAP-1 [84, 104]. Finally, itaconate accumulation leads to the inhibition of succinate dehydrogenase, directing the accumulation of succinate and leading to numerous proinflammatory and prooxidative consequences [103, 105, 106]. For example, elevated succinate oxidation in a cellular environment of few or no ATP generation induces a phenomenon described as reverse electron transport whereby electrons flow “backwards” along the ETC to complex I. As a result, large increases in the genesis and release of ROS follow [107, 108]. High levels of cytosolic succinate may induce an increase in lysine group succinylation in the cellular proteome, which many influence protein activity via changes in charge and conformation [109]. The mechanisms involved are beyond the scope of this review, but it is important to note that this post-translational modification offers another route relaying subtle redox-mediated metabolic changes to protein function [110]. Finally, once externalized, succinate can bind to the G protein-coupled succinate receptor 1 (SUCNR1) that is expressed on the surface of activated M1 polarized macrophages [111, 112]. This is a mechanism involved in sustaining and amplifying their inflammatory effects [12, 113].

대식세포의 대사 재프로그래밍

대식세포는

병원체 관련 분자 패턴,

손상 관련 분자 패턴 및

공생 LPS에 의한 사이토카인,

ROS 및 PRR 결합에 의해 활성화되어

NF-κB [42,43,44] 및 PI3K/AKT 신호 경로 [45, 46]의 활성화로

이어질 수 있습니다.

상향 조절된 NF-κB는

염증성 사이토카인과 케모카인,

유도성 NO 합성효소(iNOS),

HIF1α의 전사를 증가시킵니다[42,43,44].

강화된 PI3K 신호는 또한

mTOR의 상향 조절로 이어지며[47,48,49],

이는 다시 HIF1α의 상향 조절을 강화합니다[45, 46].

이러한

신호 경로,

효소 및 전사인자는

대사 재프로그래밍을 유도하여

대식세포 활성화와 M1 분극화를 유지하는 데

필수적인 역할을 합니다.

여기에는

미토콘드리아 산화적 인산화(OXPHOS)와

FAO[50, 51]에 의한 ATP 생산의 하향 조절에서

호기성 해당작용을 통한 ATP 생산[52]으로의 전환이 포함됩니다.

유산소 해당 과정으로의 전환은

식세포 작용,

ROS 및 염증성 사이토카인 생산의 유지 및 증가 측면에서

M1 대식세포에 필수적인 대사 작용이며,

이를 억제하면 당연히 이러한 기능이 손상될 수 있습니다[53,54,55].

이 상태의 유지는

다양한 전사인자,

특히 mTOR와 HIF1α의 활성에 의존하며,

후자는 정상 산소 조건에서 해당 작용이 지속될 수 있도록 하는 데

지배적인 역할을 합니다[49, 56].

HIF1α는

OXPHOS의 종결 및 유산소성 해당 작용의 유발에 관여하는 표적 유전자의 프로모터 영역에서

저산소 반응 요소의 메틸화 상태를 변경하여

전사의 조절자 역할을 합니다 [57].

예를 들어,

HIF1α 상향 조절은

전자 수송 사슬(ETC) 효소의 활성을 억제하고[58, 59],

미토콘드리아 활성을 감소시키며,

미토콘드리아 자가포식을 유도합니다[60, 61].

이 전사 인자의 활성 증가는 또한

FAO에 관여하는 유전자를 억제합니다 [62, 63].

HIF1α는

피루베이트 탈수소효소 키나제 1 유전자를 활성화하여 대사를 억제하고,

이는 다시 TCA 사이클을 억제하고[64]

피루베이트 탈수소효소를 비활성화합니다[65].

또한,

HIF1α 조절 유전자 발현은

아세틸-CoA 및 숙시닐-CoA의 생성을 감소시킵니다 [66].

HIF1α는 해당 작용 플럭스를 강화하여 포도당 수송체(GLUT-1 및 GLUT-3)의 발현을 증가시킵니다 [67]. 해당 작용은 높은 수준의 헥소키나제[68], 알돌라제 A, 에놀라제 1[69], 포스포글리세레이트 키나아제 1[70]에 의해 자극됩니다. 마지막으로, HIF1α는 또한 젖산 탈수소효소 A의 전사를 유도하는데, 이는 NAD+의 지속적인 공급을 유지하는 데 필수적인 역할을 하여 해당 작용을 지속할 수 있게 합니다 [71]. HIF1α 조절 유전자 발현은 포도당과 지방산 유래 탄소로부터 아세틸-CoA가 합성되는 것을 방지합니다 [66].
옥스포스와 유산소 해당 과정 사이의 전환을 유도하고 조절하는 데 있어 HIF1α의 역할이 가장 중요하지만, mTOR의 활성화도 관련되어 있다는 점을 강조해야 합니다. 첫째, mTOR는 HIF1α의 활성을 안정화하고 강화하며, 둘째, 해당 과정, AKT, 포크헤드 박스 전사인자(FoxO), 헥소키나제 II 및 Myc 원시 종양 유전자의 속도를 증가시킵니다[72,73,74]. 상향 조절된 mTOR는 NO 및 인터페론(IFN)-γ 생산을 강화하여 미토콘드리아 ETC의 활성을 손상시킴으로써 OXPHOS를 더욱 감소시키는 데 관여합니다[75].

전체적으로

mTOR의 작용은

M2 분극을 억제하고[76]

M1 분극을 자극합니다[77, 78].

PPP의 주요 역할은 포도당-6-인산염의 대사에서 리불로스-5-인산염으로 방출되는 에너지를 활용하여 NADPH를 형성하는 것입니다. 후자는 NADPH 산화 효소의 생산에 사용되며 글루타티온 (GSH) 및 티오레독신 항산화 시스템의 기능을 가능하게하는 환원 등가물로 사용됩니다 [13, 79]. M1 편광 대식세포의 활성화는 또한 염증 상태를 유지하고 생존을 연장하기 위해 대사 재프로그래밍의 여러 다른 측면을 초래합니다. 가장 주목할 만한 것은 세포질 PPP의 상향 조절[50, 80], 지질 합성 증가 및 지질 이화 작용 감소[62, 81], 글루타민 및 아르기닌 대사 변화[81, 82], TCA 주기 "중단"[83, 84] 등이 있습니다. 이러한 매개변수는 아래에서 톨유사수용체(TLR) 및 염증성 사이토카인 매개 리프로그래밍으로 시작하여 설명합니다[85].

지질 합성은 막 리모델링의 핵심 구성 요소입니다. M1 대식세포에서 이 과정은 구연산염 ATP-구연산염 리아제에서 아세틸-CoA를 생성하는 데 의존합니다 [86]. 이 효소의 활성은 활성화된 대식세포에서 빠르게 증가합니다. 세포 내 지방산은 또한 에너지 저장을위한 트리글리세리드, 막 합성을위한 스핑고 지질, 신호 전달을위한 에이코 사 노이드를 합성하는 데 사용될 수 있습니다 [81]. 지질 합성의 증가는 주로 TLR-4 및 PI3K 활성화 mTOR에 의한 스테롤 조절 요소 결합 단백질-1(SREBP-1)의 높은 활성에 의해 활성화되고 조절됩니다 [73, 87]. 또한 NF-κB의 발현 증가와 염증성 사이토카인의 존재에 의해 조절됩니다 [88, 89]. SREBP-1 활성화는 염증성 사이토카인, ROS의 합성을 자극하고 인플라마좀을 촉발합니다 [87,88,89]. M1 활성화는 아르기닌이 NO로 전환되도록 유도하는 iNOS의 상승을 동반하여 다른 RNS의 생성이 시작될 수 있습니다 [82, 90, 91].

M1 편광 대식세포는 이소시트레이트 탈수소효소(IDH)의 활성 감소[50] 및 미토콘드리아 구연산염 운반체(CIC)의 상향 조절[92, 93]로 인해 세포질 구연산염을 축적합니다. IDH의 활성 증가는 ADP 수준에 의해 매개됩니다 [94]. CIC는 종양 괴사인자(TNF)-α, IFN-γ 또는 공생 LPS와 같은 여러 염증 매개체에 의해 NF-κB 및/또는 STAT-1의 상향 조절을 통해 상향 조절됩니다 [92, 95]. 이 시나리오에서 구연산염은 여러 가지 중요한 역할을 수행하여 대식세포 기능과 NO, ROS 및 프로스타글란딘 E2(PGE2) 생성을 증가시키는 등 염증 상태를 활성화합니다[92, 96]. 세포질 구연산염은 또한 CIC를 통해 미토콘드리아로 말산염이 유입되고 이후 말산 효소를 통해 피루브산이 형성되거나 세포질 IDH의 작용으로 구연산염이 알파-케토글루타레이트로 전환되어 NADPH의 원천으로 작용할 수 있습니다 [97, 98]. 세포질 구연산염은 또한 ACLY의 기질로서 아세틸-CoA와 옥살로아세테이트를 생성하고 지질 합성을 자극하는 아세틸-CoA 카르복실라제(ACC)를 상향 조절합니다[99].

활성화된 M1 편광 대식세포는 대식세포 아코니테이트 탈카르복실효소 1의 중요한 염증 매개 상향 조절을 통해 크렙스 주기에서 추출한 시스-아코니테이트에서 높은 수준의 세포질 이타코네이트를 생성하는 것이 특징입니다 [100, 101]. 이타코네이트는 염증의 내성 및 억제에 관여하고[102, 103], 미토콘드리아 호흡을 억제하고, HIF1α를 안정화하며, KEAP-1의 알킬화를 통해 Nrf-2를 활성화합니다[84, 104]. 마지막으로, 이타코네이트 축적은 숙시네이트 탈수소효소의 억제를 유도하여 숙시네이트의 축적을 유도하고 수많은 염증 및 항산화 결과를 초래합니다[103, 105, 106]. 예를 들어, ATP 생성이 거의 또는 전혀 없는 세포 환경에서 숙시네이트 산화가 증가하면 전자가 ETC를 따라 복합체 I로 "역방향"으로 흐르는 역전자 수송 현상을 유도합니다. 그 결과 ROS의 생성과 방출이 크게 증가합니다[107, 108]. 높은 수준의 세포질 숙시네이트는 세포 단백질체에서 라이신 그룹 숙시닐화의 증가를 유도할 수 있으며, 이는 전하 및 형태 변화를 통해 단백질 활성에 많은 영향을 미칩니다 [109]. 관련된 메커니즘은 이 리뷰의 범위를 벗어나지만, 이러한 번역 후 변형이 단백질 기능에 대한 미묘한 산화 환원 매개 대사 변화를 전달하는 또 다른 경로를 제공한다는 점에 유의하는 것이 중요합니다 [110]. 마지막으로, 일단 외부화되면 숙시네이트는 활성화된 M1 편광 대식세포의 표면에서 발현되는 G 단백질 결합 숙시네이트 수용체 1(SUCNR1)에 결합할 수 있습니다[111, 112]. 이는 염증 효과를 지속하고 증폭하는 데 관여하는 메커니즘입니다[12, 113].

M2 polarized macrophages

In an environment of elevated IL-4 and or IL-13, activated M1 polarized macrophages may ultimately be driven toward a range of anti-inflammatory and tissue healing phenotypes classified as M2a, M2b, M2c, and M2d that for the purposes of this paper may be usefully described as “M2” [114,115,116]. Tyrosine phosphorylation and activation of the signal transducer/transcription activator 6 (STAT-6) are required for macrophage M2 polarization [117, 118]. The latter then triggers a wide range of M2-associated genes including GATA binding protein 3 (GATA3), CD36, arginase-1 (Arg1), matrix metalloproteases (MMPs), FIZZ1, and PPARγ [119, 120]. IL-4 and IL-13 also upregulate the activity of transforming growth factor (TGF)-β, suppressor of cytokine signaling 1 (SOCS-1), and insulin-like growth factor 1 (IGF-1) that act to suppress the production of proinflammatory cytokines and promotes tissue repair [114, 115, 121]. Unlike M1 polarization, M2 polarization is associated with a return to OXPHOS and increased FAO [114, 115]. In addition, M2 polarized macrophages possess an intact TCA cycle [114, 115].

M2 macrophages are also characterized by activation of the nuclear liver X receptor (LXR) thereby regulating lipid synthesis and cholesterol homeostasis [122]. Overexpression‎ of LXR inhibits NF-κB and activator protein-1 (AP-1) to reduce M1 responses and inflammation [123, 124]. One major element reinforcing the transition from M1 to M2 polarization is the change in the metabolism of arginine. In M1 polarized macrophages, elevated activity of iNOS leads to the metabolism of arginine to produce citrulline and NO. The latter is a major element in maintaining the switch toward aerobic glycolysis as explained above [84]. However, in M2 polarized macrophages, the increased transcription of arginase-1 metabolizes arginine to ornithine and urea. They both play a vital role in M2 macrophage survival, proliferation, and tissue repair [120, 125]. Glutamine metabolism is also of particular importance in M2 macrophages for two main reasons. Firstly, oxidation of this amino acid is an essential source of acetyl-CoA in an inflammatory environment leading to depleted extracellular glucose levels thereby maintaining TCA activity [126,127,128]. Secondly, glutaminolysis-mediated increase in α-ketoglutarate and the activation of the glutamine–UDP-N-acetylglucosamine (GlcNAc) pathway reinforce M2 polarization [126].

There are major differences in the regulation of the metabolic bioenergetic pathways involved in the transition to M2 polarization compared to those governing M1 polarization. In the case of M2 polarization the main players are AMPK and PPARγ whose activities are briefly described below. AMPK stimulates OXPHOS and FAO while inhibiting NF-κB and mTOR. This, in turn, decreases inflammation, reduces the levels of HIF1α, and terminates aerobic glycolysis [129,130,131,132]. AMPK inhibits ACC, increases glycolytic flux, mitogenesis, lipases, autophagy, and lysosomal degradation [133, 134]. PPAR-γ upregulates FAO, maintains mitochondrial membrane potential, mitochondrial citrate synthase, and regulates numerous genes involved in mitochondrial function including transcription factor A (TFAM), and peroxisome proliferator-activated receptor-gamma (PGC)-1α [135,136,137,138]. It also downregulates NF-κB and upregulates Nrf-2 [135,136,137]. PPAR stimulates the activity of LXR [139], which controls cholesterol and lipid homeostasis. Thus, inflammation is reduced and glycolysis is blocked via the inhibition of NF-κB [123, 124]. Finally, PPAR-γ promotes the oxidation of glutamine [126] whose importance in M2 polarization has been discussed above [140].

M2 편광 대식세포

IL-4 및/또는 IL-13이 증가된 환경에서 활성화된 M1 편광 대식세포는 궁극적으로 M2a, M2b, M2c 및 M2d로 분류되는 다양한 항염증 및 조직 치유 표현형으로 유도될 수 있으며, 이 백서의 목적상 "M2"로 유용하게 설명할 수 있습니다[114,115,116]. 대식세포 M2 분극에는 티로신 인산화와 신호 전달자/전사 활성화제 6(STAT-6)의 활성화가 필요합니다[117, 118]. 그런 다음 GATA 결합 단백질 3(GATA3), CD36, 아르기나제-1(Arg1), 매트릭스 메탈로프로테아제(MMP), FIZZ1, PPARγ 등 광범위한 M2 관련 유전자가 활성화됩니다[119, 120]. IL-4와 IL-13은 또한 전 염증성 사이토카인의 생성을 억제하고 조직 회복을 촉진하는 역할을 하는 형질 전환 성장 인자(TGF)-β, 사이토카인 신호 전달 억제제 1(SOCS-1), 인슐린 유사 성장 인자 1(IGF-1)의 활성을 상향 조절합니다[114, 115, 121]. M1 편광과 달리 M2 편광은 옥시포스로의 복귀 및 FAO 증가와 관련이 있습니다 [114, 115]. 또한 M2 편광 대식세포는 온전한 TCA 주기를 가지고 있습니다 [114, 115].

M2 대식세포는 또한 핵 간 X 수용체(LXR)를 활성화하여 지질 합성과 콜레스테롤 항상성을 조절하는 특징이 있습니다[122]. LXR의 과발현은 NF-κB와 활성화 단백질-1(AP-1)을 억제하여 M1 반응과 염증을 감소시킵니다[123, 124]. M1에서 M2 분극으로의 전환을 강화하는 한 가지 주요 요소는 아르기닌 대사의 변화입니다. M1 분극화된 대식세포에서 iNOS의 활성이 증가하면 아르기닌의 대사가 시트룰린과 NO를 생성하게 됩니다. 후자는 위에서 설명한 것처럼 유산소 해당 작용으로의 전환을 유지하는 데 중요한 요소입니다 [84]. 그러나 M2 분극성 대식세포에서는 아르기나제-1의 전사 증가로 아르기닌이 오르니틴과 요소로 대사됩니다. 이 둘은 M2 대식세포의 생존, 증식, 조직 복구에 중요한 역할을 합니다 [120, 125]. M2 대식세포에서 글루타민 대사가 특히 중요한 이유는 크게 두 가지입니다. 첫째, 이 아미노산의 산화는 염증 환경에서 아세틸-CoA의 필수 공급원으로 세포 외 포도당 수치를 고갈시켜 TCA 활성을 유지합니다[126,127,128]. 둘째, 글루타민 분해에 의한 α-케토글루타레이트의 증가와 글루타민-UDP-N-아세틸글루코사민(GlcNAc) 경로의 활성화는 M2 분극화를 강화합니다[126].

M2 분극으로의 전환에 관여하는 대사 생체 에너지 경로의 조절에는 M1 분극을 관장하는 경로와 비교하여 큰 차이가 있습니다. M2 분극화의 경우 주요 역할을 하는 것은 AMPK와 PPARγ이며, 이들의 활동은 아래에 간략히 설명되어 있습니다. AMPK는 OXPHOS와 FAO를 자극하는 동시에 NF-κB와 mTOR를 억제합니다. 이는 차례로 염증을 감소시키고, HIF1α의 수치를 낮추며, 유산소성 해당 작용을 종료합니다[129,130,131,132]. AMPK는 ACC를 억제하고 해당 작용, 유사 분열, 리파아제, 자가포식 및 리소좀 분해를 증가시킵니다[133, 134]. PPAR-γ는 FAO를 상향 조절하고, 미토콘드리아 막 전위, 미토콘드리아 구연산염 합성 효소를 유지하며, 전사인자 A(TFAM), 퍼옥시좀 증식인자 활성화 수용체 감마(PGC)-1α 등 미토콘드리아 기능에 관여하는 수많은 유전자를 조절합니다 [135,136,137,138]. 또한 NF-κB를 하향 조절하고 Nrf-2를 상향 조절합니다[135,136,137]. PPAR은 콜레스테롤과 지질 항상성을 조절하는 LXR [139]의 활동을 자극합니다. 따라서 NF-κB의 억제를 통해 염증이 감소하고 해당 작용이 차단됩니다 [123, 124]. 마지막으로, PPAR-γ는 M2 분극에서 중요성이 위에서 논의된 글루타민의 산화를 촉진합니다[126][140].

Redox regulation of macrophage activation functions and survival

Macrophage ROS levels affect the activity of STAT-1, MAPKs, and NF-κB and lead to an overall increase in inflammatory signaling [141]. ROS levels also affect the assembly of NADPH oxidase subunits and regulate the formation of corrosive RNS species such as peroxynitrite, thereby influencing H2O2-mediated intracellular signaling and macromolecule damage [142]. Continually high ROS or NO levels are accompanied by the development of macrophage senescence [143,144,145]. The mechanisms driving this phenomenon appear to involve the persistent expression‎ of NF-κB, STAT-3, IL-10, and TGF-β, and potentially the upregulation of PD-1 [144, 146, 147].

There is also ample evidence that macrophage functions and polarization patterns are influenced by GSH levels and the overall activity of the GSH system [148, 149]. For example, increased GSH oxidation compromises phagocytosis and macrophage survival [150, 151]. The GSH system also plays a key role in regulating M1 inflammatory status and the production of PGE2 and NO, while protecting macromolecules from oxidative damage [152, 153]. The antiviral responses initiated following M1 macrophage activation such as increased expression‎ of STAT-1, Irf7, and Irf9 are also dependent on an optimally functioning GSH system and are compromised by GSH depletion [154].

Thioredoxin (TRX)-1 affects the inflammatory status of macrophages by modulating the activity of macrophage receptors, and the macrophage migration inhibiting factor (MIF) [155]. The latter effect reduces the proinflammatory status of M1 macrophages and encourages M2 polarization by lowering TNF-α and monocyte-chemoattractant protein (MCP)-1 production [156,157,158,159].

Nrf-2 upregulation also exerts an anti-inflammatory effect in activated macrophages by attenuating the activity of IL-1β and IL-6 [160, 161]. The mechanism involves Nrf-2 binding at the relevant gene promoter sites resulting in inhibition of the recruitment of RNA Polymerase II complex [162]. Nrf-2 upregulation also rises the expression‎ of CD163 and Arg1 [161, 163]. It affects the transcription of a multitude of genes involved in the switch between M1 and M2 polarization [160, 161].

The metabolic reprogramming in macrophages is presented in Fig. 2 and Table 2 summarizes the effects of redox mechanisms on macrophage functions.

대식세포 활성화 기능 및 생존의 산화 환원 조절

대식세포 ROS 수치는 STAT-1, MAPK 및 NF-κB의 활성에 영향을 미치고 염증 신호의 전반적인 증가로 이어집니다 [141]. ROS 수준은 또한 NADPH 산화효소 서브유닛의 조립에 영향을 미치고 과산화아질산염과 같은 부식성 RNS 종의 형성을 조절하여 H2O2 매개 세포 내 신호 및 거대 분자 손상에 영향을 미칩니다[142]. 지속적으로 높은 ROS 또는 NO 수준은 대식세포 노화의 진행을 동반합니다[143,144,145]. 이러한 현상을 일으키는 메커니즘은 NF-κB, STAT-3, IL-10, TGF-β의 지속적인 발현과 잠재적으로 PD-1의 상향 조절을 포함하는 것으로 보입니다 [144, 146, 147].
또한 대식세포의 기능과 분극화 패턴이 GSH 수치와 GSH 시스템의 전반적인 활성에 영향을 받는다는 충분한 증거가 있습니다[148, 149]. 예를 들어, GSH 산화가 증가하면 식세포 작용과 대식세포 생존이 저하됩니다 [150, 151]. 또한 GSH 시스템은 산화적 손상으로부터 거대 분자를 보호하면서 M1 염증 상태와 PGE2 및 NO의 생성을 조절하는 데 중요한 역할을 합니다 [152, 153]. STAT-1, Irf7, Irf9의 발현 증가와 같은 M1 대식세포 활성화에 따라 시작되는 항바이러스 반응도 최적의 기능을 하는 GSH 시스템에 의존하며 GSH 고갈로 인해 손상됩니다[154].
티오레독신(TRX)-1은 대식세포 수용체와 대식세포 이동 억제 인자(MIF)의 활성을 조절하여 대식세포의 염증 상태에 영향을 미칩니다[155]. 후자의 효과는 M1 대식세포의 염증 상태를 감소시키고 TNF-α 및 단핵구-화학 유인 단백질(MCP)-1 생산을 낮추어 M2 분극화를 촉진합니다[156,157,158,159].
Nrf-2 상향 조절은 또한 활성화된 대식세포에서 IL-1β 및 IL-6의 활성을 약화시켜 항염증 효과를 발휘합니다[160, 161]. 이 메커니즘은 관련 유전자 프로모터 부위에서 Nrf-2가 결합하여 RNA 중합효소 II 복합체의 모집을 억제하는 것을 포함합니다 [162]. Nrf-2 상향 조절은 또한 CD163 및 Arg1의 발현을 증가시킵니다 [161, 163]. 이는 M1과 M2 양극화 사이의 전환에 관여하는 여러 유전자의 전사에 영향을 미칩니다 [160, 161].
대식세포의 대사 재프로그래밍은 그림 2에 표시되어 있으며 표 2에는 산화 환원 메커니즘이 대식세포 기능에 미치는 영향이 요약되어 있습니다.

Fig. 2

Metabolic reprogramming in macrophages (Maf).

DAMPs damage-associated molecular patterns, PAMPs pathogen-associated molecular patterns, ROS reactive oxygen species, LPS lipopolysaccharide, STAT-6 signal transducer/transcription activator 6, GATA3 GATA binding protein 3, Arg1 Arginase-1, LXR liver X receptor, PPARγ peroxisome proliferator-activated receptor, AMPK AMP-activated protein kinase, iNOS inducible nitric oxide synthase, NO nitric oxide, PGE2 prostaglandin E2, OXPHOS oxidative phosphorylation, TCA tricarboxylic acid cycle, FA fatty acid, NF-kB nuclear factor NF-kappa-B, PI3K phosphatidylinositol 3-kinase, mTOR mechanistic target of rapamycin, STAT-1 signal transducer and activator оf transcription 1, HIF1α hypoxia-inducible factor 1-alpha

대식세포의 대사 재프로그래밍(Maf). D

AMPs 손상 관련 분자 패턴, PAMPs 병원체 관련 분자 패턴, ROS 활성 산소 종, LPS 지질 다당류, STAT-6 신호 전달자/전사 활성화제 6, GATA3 GATA 결합 단백질 3, Arg1 아르기나제-1, LXR 간 X 수용체, PPARγ 퍼옥시솜 증식 인자 활성화 수용체, AMPK AMP 활성화 단백질 키나아제, iNOS 유도성 산화질소 합성 효소, NO 산화질소, PGE2 프로스타글란딘 E2, OXPHOS 산화 인산화, TCA 트리카르복실산 주기, FA 지방산, NF-kB 핵 인자 NF-kappa-B, PI3K 포스파티딜이노시톨 3-kinase, 라파마이신의 mTOR 메커니즘 타겟, STAT-1 신호 전달자 및 활성화제 оf 전사인자 1, HIF1α 저산소증 유도 인자 1-alpha.

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Table 2 Redox mechanisms influencing macrophage functions

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Metabolic reprogramming and redox factors involved in Dendritic cells activation

Metabolic reprogramming of DCs

DCs are archetypal antigen presenting cells (APCs) and play a dominant role in linking innate and humoral immunity [164]. In physiological conditions, tissue-resident DCs drain to the lymph nodes and, thereafter, present self-antigens to T-cells, thereby maintaining immune tolerance [165]. However, after pathogen invasion, TLR- mediated activation of DCs is followed by numerous changes in function and phenotype resulting in their active migration to lymph nodes and cytokine production [166].

Resting-state DCs rely on OXPHOS-driven TCA cycle activity fueled by glutaminolysis and FAO to meet their energy needs [167, 168]. Their overall metabolism is regulated by AMPK [168]. However, following pathogen recognition, TLR engagement results in activation of NF-κB, PI3K/AKT signaling, mTOR, and PPAR-γ and in a rapid shift to aerobic glycolysis and lactate production in a similar manner to M1 polarized macrophages discussed above [169, 170]. In addition, glycolytic intermediates are shunted into the PPP while increased NO production inhibits the ETC. Moreover, citrate is withdrawn from the TCA acting as a crucial player in FA synthesis that maintains and increases inflammatory cytokines, NO, and ROS production [171, 172]. The acute switch to glycolytic metabolism is facilitated by PI3K /AKT signaling [173]. However, chronic aerobic glycolysis is enabled and regulated by mTOR and HIF1α activation [174, 175]. In addition, upregulation of mTOR and the subsequent increase in HIF1α activity induces the transcription of iNOS [176, 177] leading to NO-mediated suppression of mitochondrial OXPHOS via reversible inhibition of ETC complex I, III, and IV [17, 178, 179]. mTOR activation initiates and controls lipid synthesis and mitochondrial biogenesis via the downstream upregulation of SREBPs and PPAR. It stimulates IL-6, IL-1, and TNF-α production, via the upregulation of AKT, FOXO3, and Myc [180]. mTOR activation serves as the enabler and master regulator of DC migration, maturation, and endocytosis [180].

DC의 대사적 재프로그래밍
DC는 전형적인 항원 제시 세포(APC)이며 선천성 면역과 체액성 면역을 연결하는 데 지배적인 역할을 합니다[164]. 생리적 조건에서 조직 상주 DC는 림프절로 배출되고, 이후 T세포에 자가 항원을 제시하여 면역 관용을 유지합니다[165]. 그러나 병원체 침입 후 TLR을 매개로 한 DC의 활성화는 기능과 표현형에 많은 변화를 가져와 림프절로의 활발한 이동과 사이토카인 생산으로 이어집니다 [166].

휴식 상태의 DC는 글루타민 분해 및 FAO에 의해 연료가 공급되는 OXPHOS 기반 TCA 사이클 활동에 의존하여 에너지 요구를 충족합니다 [167, 168]. 이들의 전반적인 신진대사는 AMPK에 의해 조절됩니다 [168]. 그러나 병원체 인식 후 TLR의 관여는 위에서 설명한 M1 편광 대식세포와 유사한 방식으로 NF-κB, PI3K/AKT 신호, mTOR 및 PPAR-γ를 활성화하고 유산성 해당 작용 및 젖산염 생산으로의 빠른 전환을 초래합니다 [169, 170]. 또한, 해당과정 중간체는 PPP로 전환되는 반면 NO 생성 증가는 ETC를 억제합니다. 또한 구연산염은 염증성 사이토카인, NO 및 ROS 생성을 유지하고 증가시키는 FA 합성의 중요한 역할을 하는 TCA에서 제거됩니다 [171, 172]. 해당 대사로의 급성 전환은 PI3K /AKT 신호에 의해 촉진됩니다 [173]. 그러나 만성 유산소 해당 작용은 mTOR 및 HIF1α 활성화에 의해 활성화되고 조절됩니다 [174, 175]. 또한, mTOR의 상향 조절과 그에 따른 HIF1α 활성의 증가는 iNOS의 전사를 유도하여 [176, 177] ETC 복합체 I, III, IV의 가역적 억제를 통해 미토콘드리아 OXPHOS의 NO 매개 억제로 이어집니다 [17, 178, 179]. mTOR 활성화는 SREBP 및 PPAR의 하향 상향 조절을 통해 지질 합성 및 미토콘드리아 생성을 시작하고 제어합니다. mTOR 활성화는 AKT, FOXO3, Myc의 상향 조절을 통해 IL-6, IL-1, TNF-α 생성을 자극합니다 [180]. mTOR 활성화는 DC 이동, 성숙, 내세포증식의 조력자이자 마스터 조절자 역할을 합니다 [180].

Redox regulation of DC activation and function

Phagosomal ROS levels are involved in MH1-mediated presentation of digested antigens to CD8 T cells [181, 182]. In this context, it is noteworthy that the activation of CD8 T cells requires upregulation of mitochondrial reactive oxygen species (mtROS) production [183]. DC production of ROS following TLR activation also plays a major role in the maturation and priming of CD4 T cells [184, 185]. Many aspects of DC function are influenced by the GSH system activity. For example, GSH levels regulate DC differentiation and function as APCs [186]. DC GSH levels also determine T-cell polarization patterns by affecting IL-27 and IL-12 production [187, 188]. GSH depletion is associated with the differentiation of naive T cells [188] and inhibits DC maturation and inflammatory cytokine production leading to profound cellular dysfunction [189]. Moreover, DCs directly influence the redox state of activated T cells via the transfer of thioredoxin [190].

Redox homeostasis within activated DCs is regulated by Nrf-2 which acts to restrain T-cell proliferation by repressing IL-12 production and upregulating IL-10 [191, 192]. Conversely, DCs that lack Nrf-2 generate increased numbers of activated T helper (Th) cells and reduced numbers of T regulatory (Treg) cells [193]. Moreover, Nrf-2 depletion and the resultant prooxidative state in DCs encourage a Th-2 pattern of differentiation in naive T cells [194, 195]. Finally, Nrf-2 also plays an important role in the transition between glycolysis and OXPHOS in tolerogenic DCs that enables their long-term survival [196].

There is considerable evidence of DC dysfunction in diseases underpinned by chronic inflammation and oxidative stress [197, 198]. Such dysfunction may be directly or indirectly driven by increased inflammatory cytokines, RNS, and ROS. Direct effects involve damage to functional macromolecules and increased activation of apoptotic pathways [199, 200]. Indirect effects include enhanced Wnt signaling [90], epigenetic dysregulation, and compromised TLR activity [166, 201,202,203].

The metabolic reprogramming of DCs is shown in Fig. 3 and Table 3 summarizes the effects of redox mechanisms on DC functions.

DC 활성화 및 기능의 산화 환원 조절

포식체 ROS 수준은 MH1을 매개로 소화된 항원을 CD8 T 세포에 전달하는 데 관여합니다[181, 182]. 이러한 맥락에서 CD8 T 세포의 활성화에는 미토콘드리아 활성 산소 종(mtROS) 생성의 상향 조절이 필요하다는 점이 주목할 만합니다 [183]. TLR 활성화에 따른 ROS의 DC 생성도 CD4 T 세포의 성숙과 프라이밍에 중요한 역할을 합니다 [184, 185]. DC 기능의 많은 측면은 GSH 시스템 활동의 영향을 받습니다. 예를 들어, GSH 수치는 DC 분화 및 APC로서의 기능을 조절합니다 [186]. 또한 DC GSH 수치는 IL-27 및 IL-12 생산에 영향을 미쳐 T세포 분극 패턴을 결정합니다[187, 188]. GSH 고갈은 순진한 T 세포의 분화와 관련이 있으며[188], DC 성숙과 염증성 사이토카인 생성을 억제하여 심각한 세포 기능 장애를 유발합니다[189]. 또한 DC는 티오레독신의 전달을 통해 활성화된 T 세포의 산화 환원 상태에 직접적인 영향을 미칩니다 [190].

활성화된 DC 내의 산화 환원 항상성은 IL-12 생성을 억제하고 IL-10을 상향 조절하여 T세포 증식을 억제하는 역할을 하는 Nrf-2에 의해 조절됩니다 [191, 192]. 반대로, Nrf-2가 부족한 DC는 활성화된 T 헬퍼(Th) 세포의 수가 증가하고 T 조절(Treg) 세포의 수가 감소합니다 [193]. 또한, DC의 Nrf-2 고갈과 그에 따른 과산화 상태는 순진한 T 세포에서 Th-2 분화 패턴을 촉진합니다 [194, 195]. 마지막으로, Nrf-2는 또한 내관성 DC에서 해당 작용과 옥시포스 사이의 전환에 중요한 역할을 하여 장기 생존을 가능하게 합니다 [196].

만성 염증과 산화 스트레스에 의해 뒷받침되는 질병에서 DC 기능 장애에 대한 상당한 증거가 있습니다 [197, 198]. 이러한 기능 장애는 염증성 사이토카인, RNS 및 ROS의 증가에 의해 직간접적으로 유발될 수 있습니다. 직접적인 영향으로는 기능적 거대 분자의 손상과 세포 사멸 경로의 활성화 증가가 있습니다[199, 200]. 간접적인 영향으로는 Wnt 신호 강화[90], 후성유전학적 조절 장애, TLR 활성 저하 등이 있습니다[166, 201,202,203].

DC의 대사적 재프로그래밍은 그림 3에 표시되어 있으며 표 3에는 산화 환원 메커니즘이 DC 기능에 미치는 영향이 요약되어 있습니다.

Fig. 3

Metabolic reprogramming of dendritic cells (DCs). OXPHOS oxidative phosphorylation, TCA tricarboxylic acid cycle, FA fatty acid, NF-kB nuclear factor NF-kappa-B, mTOR mechanistic target of rapamycin, HIF1α hypoxia-inducible factor 1-alpha, PPARγ peroxisome proliferator-activated receptor, ROS reactive oxygen species, NO nitric oxide

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Table 3 Redox mechanisms influencing dendritic cell and neutrophil functions

Full size table

Metabolic reprogramming and redox regulation of neutrophil activation

Metabolic reprogramming of neutrophils

Neutrophils are the first line responders of the innate immune system, which play a key role in the destruction of invading pathogens. However, these leucocytes also participate in humoral immunity via a sophisticated cross-talk with other immune cells [204,205,206]. Importantly, these regulatory functions extend beyond modulation of the activity of myeloid cells and also involve modifying the function of T-cells, marginal zone B-cells, and NK-cell homeostasis [204,205,206]. There is also considerable evidence of functionally distinct subsets and extensive cellular plasticity enabling a range of roles depending on cellular location and inflammatory status [207, 208]. These immune cells may be activated and/or primed by multiple stimuli such as inflammatory cytokines, chemokines, growth factors, PRRs (mainly c-type lectin receptors), opsonins (C3a and IgG), and G protein-coupled receptors [209, 210].

Glycolysis is the primary energy source for activated neutrophils under physiological conditions [211]. This is also true for inflammatory environments [212]. However, neutrophils adjust their metabolism to carry out their various effector functions such as phagocytosis, degranulation, oxidative burst, neutrophil extracellular traps (NET) formation, and chemotaxis [213]. The weight of evidence suggests that NET formation is reliant on glycolysis, with extensive involvement of lactate synthesis, the PPP, and glutamine metabolism as sources of NADPH [214, 215]. This metabolic reprogramming also supplies superoxide production, and induces ROS and hypochlorous acid, used in the neutrophil oxidative burst following phagocytosis of invading pathogens [211, 216,217,218]. The metabolic changes underpinning chemotaxis are somewhat more complicated, however, and involve mitochondrial contributions in addition to upregulated glycolysis [219,220,221]. This activity supplies ATP which activates membrane-bound P2Y2 receptors following the receipt of chemotactic stimuli (2019–2021). Mitochondrial activity provides the ATP required for neutrophil activity in regions of profound glucose deprivation. It occurs in an environment of extreme inflammation and also plays a dominant role in neutrophil autophagy and survival via FAO (2011) [222].

These metabolic changes underpinning neutrophil activity in inflammatory environments are primarily regulated by the cooperative action of NF-κB [43, 223], HIF1α [224, 225], and mTOR [211, 226]. The multiple and arguably pivotal roles of the latter include the regulation of NET production, autophagy, oxidative burst, phosphorylation, and stabilization of NOX and HIF1α [226, 227]. mTOR also increases the surface expression‎ of GLUT-1 and intensifies mitochondrial biogenesis and FAO via the upregulation of PPARγ and SREBPs [72]. Elevated mTOR activity increases the production of leukotrienes, prostaglandins, resolving, and proinflammatory cytokines via phosphorylation of AKT [228]. mTORC1 also exerts an inhibitory effect on OXPHOS by upregulation of IFN-γ and NO which inhibits the activity of enzymes in the ETC [229].

While mTOR upregulation plays a key role in the optimal function of activated neutrophils, it should be stressed that other enzymes and transcription factors are also important regulatory elements enabling pathogen destruction. This in turn restrains extreme inflammation and prevents excessive survival. For example, PI3K enables chemotaxis and endothelial crawling via an intricate pattern of “cross-talk” with the Rho family GTPases [230, 231]. On the other hand, AMPK regulates and restrains NF-κB and the production of proinflammatory cytokines, limiting tissue inflammation and destruction while optimizing chemotaxis and phagocytosis [232, 233]. Finally, PPAR-γ also regulates migration and restrains inflammation by inhibiting NF-κB while stimulating IL-10 production [211, 234].

호중구 활성화의 대사 재프로그래밍 및 산화 환원 조절

호중구의 대사 재프로그래밍

호중구는 침입한 병원균을 파괴하는 데 핵심적인 역할을 하는 선천 면역 체계의 일차 반응자입니다. 그러나 이러한 백혈구는 다른 면역 세포와의 정교한 상호 작용을 통해 체액성 면역에도 참여합니다[204,205,206]. 중요한 것은 이러한 조절 기능이 골수 세포의 활성 조절을 넘어 T 세포, 주변 영역 B 세포 및 NK 세포 항상성 조절에도 관여한다는 점입니다[204,205,206]. 또한 기능적으로 뚜렷한 하위 집합과 광범위한 세포 가소성에 대한 상당한 증거가 있어 세포 위치와 염증 상태에 따라 다양한 역할을 수행할 수 있습니다[207, 208]. 이러한 면역 세포는 염증성 사이토카인, 케모카인, 성장 인자, PRR(주로 c형 렉틴 수용체), 옵소닌(C3a 및 IgG), G 단백질 결합 수용체와 같은 여러 자극에 의해 활성화되거나 프라이밍될 수 있습니다[209, 210].

해당 작용은 생리적 조건에서 활성화된 호중구의 주요 에너지원입니다[211]. 이는 염증 환경에서도 마찬가지입니다 [212]. 그러나 호중구는 대사를 조절하여 식균작용, 탈과립, 산화적 폭발, 호중구 세포 외 트랩(NET) 형성, 화학 주성 등 다양한 이펙터 기능을 수행합니다[213]. 여러 증거에 따르면 NET 형성은 해당 작용에 의존하며 젖산염 합성, PPP, 글루타민 대사가 NADPH의 공급원으로서 광범위하게 관여합니다[214, 215]. 이러한 대사 재프로그래밍은 또한 슈퍼옥사이드 생성을 공급하고 침입 병원균의 식균 작용 후 호중구 산화 폭발에 사용되는 ROS와 차아염소산을 유도합니다[211, 216,217,218]. 그러나 화학작용을 뒷받침하는 대사 변화는 다소 복잡하며, 상향 조절된 해당 작용 외에도 미토콘드리아의 기여를 포함합니다[219,220,221]. 이 활동은 화학적 자극을 받은 후 막에 결합된 P2Y2 수용체를 활성화하는 ATP를 공급합니다(2019-2021). 미토콘드리아 활동은 포도당이 극도로 부족한 지역에서 호중구 활동에 필요한 ATP를 제공합니다. 이는 극심한 염증 환경에서 발생하며 FAO(2011)[222]를 통해 호중구 자가포식 및 생존에 지배적인 역할을 합니다.

염증 환경에서 호중구 활동을 뒷받침하는 이러한 대사 변화는 주로 NF-κB [43, 223], HIF1α [224, 225] 및 mTOR [211, 226]의 협력 작용에 의해 조절됩니다. 후자의 여러 가지 중추적인 역할에는 NET 생성, 자가포식, 산화적 폭발, 인산화, NOX 및 HIF1α의 안정화 조절이 포함됩니다 [226, 227]. mTOR는 또한 GLUT-1의 표면 발현을 증가시키고 PPARγ 및 SREBP의 상향 조절을 통해 미토콘드리아 생물 생성 및 FAO를 강화합니다 [72]. mTOR 활성 증가는 AKT의 인산화를 통해 류코트리엔, 프로스타글란딘, 해결 및 염증성 사이토카인의 생성을 증가시킵니다 [228]. mTORC1은 또한 IFN-γ 및 NO의 상향 조절을 통해 OXPHOS에 억제 효과를 발휘하여 ETC에서 효소의 활성을 억제합니다 [229].

활성화된 호중구의 최적 기능에는 mTOR 상향 조절이 핵심적인 역할을 하지만, 다른 효소와 전사인자 역시 병원체 파괴를 가능하게 하는 중요한 조절 요소라는 점을 강조해야 합니다. 이는 결국 극단적인 염증을 억제하고 과도한 생존을 방지합니다. 예를 들어, PI3K는 Rho 계열 GTPase와의 복잡한 "크로스 토크" 패턴을 통해 화학 주성 및 내피 크롤링을 가능하게 합니다[230, 231]. 반면에 AMPK는 NF-κB와 염증성 사이토카인의 생성을 조절하고 억제하여 조직 염증과 파괴를 제한하는 동시에 화학 주성과 식세포 작용을 최적화합니다 [232, 233]. 마지막으로, PPAR-γ는 또한 IL-10 생성을 자극하면서 NF-κB를 억제하여 이동을 조절하고 염증을 억제합니다 [211, 234].

Redox regulation of neutrophil activation and function

The function of individual neutrophils is heavily influenced by cellular redox status in terms of cellular antioxidant system activity and or ROS/RNS production. For example, excessive ROS fabrication may compromise the initiation and outcome of phagocytosis [235], resulting in a dysregulated or decreased oxidative burst [236] and production of NETs [237]. In addition, intracellular and extracellular levels of ROS play a role in neutrophil “sensing “ of pathogens and consequent activation of the NLRP3 inflammasome and cytokine synthesis [238, 239]. Chronically upregulated ROS and cytokine production may also result in the internalization of membrane chemokine receptors, most notably CXCR2 [240], thereby decreasing neutrophil migration.

Upregulated NO inhibits neutrophil migration, crawling, and adhesion [241,242,243]. Mechanistically, this is achieved via the downregulation of adhesion factors such as E-selectin, P-selectin, ICAM-1, and VCAM-1. As a result, neutrophil binding to the endothelium is compromised, and subsequent crawling and transmigration to inflammatory centers are damaged [244]. Neutrophil migration may also be hampered by increased production of peroxynitrite due to the combination of NO and superoxide cations [245,246,247,248]. There is evidence suggesting that the tyrosine nitration mediates inhibition of P-selectins [245,246,247] and upregulation of haem oxygenase (HO-1)-1 [249].

A multitude of neutrophil functions is heavily affected by the cellular antioxidant system. For example, Nrf-2 activity influences the efficiency of neutrophil phagocytosis [250], recruitment to inflammatory sites [251], and prolonged survival [252]. The glutathione system regulates various functions displayed by activated neutrophils most notably the stimulation of glutathione reductase. It sustains the neutrophil respiratory burst and NET production [253, 254] influencing optimal phagocytic activity [255, 256]. It is noteworthy that the basal activity of the GSH system in neutrophils appears to be lower than that found in myeloid cells [257], rendering these immune cells vulnerable to depleted GSH levels [257]. This may result in compromised cytoskeletal reorganization, affecting chemotaxis and transmigration and leading to reduced recruitment to sites of inflammation, impaired degranulation, and early apoptosis [258, 259]. In this context, it should be noted that prolonged neutrophil activity depletes levels of GSH, likely due to excessive production of myeloperoxidase (MPO) during chronic nitro-oxidative stress and inflammation [260,261,262].

TRX plays an important role in the regulation of neutrophil chemotaxis as a result of its release from infected cells and/or inflamed tissues [263, 264]. This effect appears to be a result of the desensitization of neutrophils toward MCP-1 [264, 265], thereby restraining neutrophil recruitment into inflammatory tissues [266]. The mechanisms involved are not fully understood, but they appear to rely at least in part on the oxidation state of functional cysteine residues within the TRX protein [264].

Table 3 summarizes the redox mechanisms that affect neutrophil functions, and the metabolic reprogramming of neutrophils is presented in Fig. 4.

호중구 활성화 및 기능의 산화 환원 조절

개별 호중구의 기능은 세포 항산화 시스템 활성 및 ROS/RNS 생성 측면에서 세포 산화 환원 상태에 의해 크게 영향을 받습니다. 예를 들어, 과도한 ROS 생성은 식균 작용의 시작과 결과를 손상시켜[235], 조절 장애를 초래하거나 산화적 폭발[236] 및 NET 생성[237]의 감소를 초래할 수 있습니다. 또한 세포 내 및 세포 외 수준의 ROS는 병원균의 호중구 "감지"와 그에 따른 NLRP3 인플라마좀 및 사이토카인 합성의 활성화에 중요한 역할을 합니다 [238, 239]. 만성적으로 상향 조절된 ROS와 사이토카인 생산은 막 케모카인 수용체, 특히 CXCR2 [240]의 내재화를 초래하여 호중구 이동을 감소시킬 수 있습니다.

상향 조절된 NO는 호중구의 이동, 크롤링 및 부착을 억제합니다[241,242,243]. 이는 기계적으로 E-셀렉틴, P-셀렉틴, ICAM-1, VCAM-1과 같은 접착 인자의 하향 조절을 통해 이루어집니다. 그 결과 내피에 대한 호중구의 결합이 손상되고 이후 염증 센터로의 크롤링 및 이동이 손상됩니다[244]. 호중구 이동은 NO와 슈퍼옥사이드 양이온의 결합으로 인한 과산화아질산염의 생성 증가로 인해 방해받을 수도 있습니다[245,246,247,248]. 티로신 질화가 P-셀렉틴의 억제[245,246,247]와 헤모글로빈 산소화 효소(HO-1)-1의 상향 조절을 매개한다는 증거가 있습니다[249].

다양한 호중구 기능은 세포 항산화 시스템에 의해 크게 영향을 받습니다. 예를 들어, Nrf-2 활성은 호중구 식균 작용의 효율성[250], 염증 부위로의 모집[251], 생존 기간 연장[252]에 영향을 미칩니다. 글루타치온 시스템은 활성화된 호중구가 나타내는 다양한 기능, 특히 글루타치온 환원효소의 자극을 조절합니다. 글루타치온은 호중구 호흡 폭발과 NET 생산[253, 254]을 유지하여 최적의 식세포 활동에 영향을 미칩니다[255, 256]. 호중구에서 GSH 시스템의 기본 활동은 골수 세포에서 발견되는 것보다 낮은 것으로 보이며[257], 이러한 면역 세포는 고갈된 GSH 수준에 취약한 것으로 나타났습니다[257]. 이로 인해 세포 골격 재편성이 손상되어 화학 주성 및 이동에 영향을 미치고 염증 부위로의 모집 감소, 탈과립화 장애 및 조기 세포 사멸로 이어질 수 있습니다 [258, 259]. 이러한 맥락에서 장기간의 호중구 활동은 만성 질소 산화 스트레스와 염증 동안 미엘로퍼옥시다제(MPO)의 과도한 생산으로 인해 GSH 수치를 떨어뜨린다는 점에 유의해야 합니다[260,261,262].

TRX는 감염된 세포 및/또는 염증 조직에서 방출되어 호중구 화학 주성 조절에 중요한 역할을 합니다[263, 264]. 이 효과는 MCP-1에 대한 호중구의 탈감작으로 인한 것으로 보이며[264, 265], 염증 조직으로의 호중구 모집을 억제합니다[266]. 관련된 메커니즘은 완전히 이해되지는 않았지만 적어도 부분적으로는 TRX 단백질 내의 기능성 시스테인 잔기의 산화 상태에 의존하는 것으로 보입니다 [264].

표 3에는 호중구 기능에 영향을 미치는 산화 환원 메커니즘이 요약되어 있으며, 호중구의 대사 재프로그래밍은 그림 4에 나와 있습니다.

Fig. 4

Мodulation of effector functions of neutrophils. PRRs pattern-recognition receptors, GPCRs G protein-coupled receptors, NET neutrophil extracellular traps, ROS reactive oxygen species, PPP pentose phosphate pathway, FA fatty acid, ATP adenosine triphosphate, NF-kB nuclear factor NF-kappa-B, HIF1α hypoxia-inducible factor 1-alpha, mTOR mechanistic target of rapamycin, PI3K phosphatidylinositol 3-kinase, AMPK AMP-activated protein kinase, PPARγ peroxisome proliferator-activated receptor

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Metabolic reprogramming and redox regulation of T-cell activation

Metabolic reprogramming of T-cells

Activation of T-cells follows the ligation of the T-cell receptor (TCR) and the major histocompatibility complex molecules by APC. Nuclear factor of activated T cell 1 (NFAT1), activation protein-1 (AP)-1, and NF-κB are triggered as a result of this signaling cascade [267]. When TCRs are ligated, ROS production increases by mitochondria and NOXs [268], which in turn regulates the signaling pathways required to enable and modulate T-cell activation, proliferation, and differentiation [268].

Unsurprisingly, T-cell activation and differentiation require extensive metabolic reprogramming [269,270,271,272,273]. In general, such reprogramming is regulated by the collaborative activity of PI3K/AKT, mTOR, HIF1α, and c-Myc [274,275,276]. However, it should be stressed that the metabolic reprogramming pathways of various T-cell subsets display important differences [277,278,279]. The metabolic needs of naive and memory T and Treg cells are relatively modest and are met by reliance on OXPHOS and FAO [274, 277, 279]. However, the differentiation and various effector functions of effector CD4 and CD8 cells require ATP obtained from aerobic glycolysis and NADPH. They are supplied by increased activity of the PPP and glutaminolysis, which is largely mediated by high levels of HIF1α and mTOR [278, 280,281,282,283,284].

Important differences exist between subsets when it comes to FA metabolism and T-cell activation and differentiation. For example, effector T-cell activity relies on FA uptake and FAS while T memory cells utilize stored FA [285, 286]. Uniquely, the relative reliance on FA uptake versus FA synthesis exerts a major influence on the differentiation of naive T cells into Tregs or Th-17 cells [286, 287]. In particular, uptake of environmental FA is a characteristic feature of Treg development, while Th-17 differentiation counts on ACC-mediated FA synthesis [276, 287].

TCR signaling also leads to the upregulation of amino acid transporters, facilitating the uptake of branch chain amino acids such as alanine, cysteine, leucine, glycine, and glutamine [288,289,290]. These amino acids, in combination with high PPP activity, promote the rapid increase of GSH needed for T-cell survival and function [284]. Augmented glutamine catabolism following T-cell activation, mediated by mitochondria-dependent oxidation, is of particular importance as the resultant increase in α-ketoglutarate production stimulates TCA activity and fuels increased OXPHOS [268, 291]. TCR-dependent uptake of glutamine, valine, and leucine is implicated in inflammatory T-cell responses, the differentiation of Th-1 and Th-17 cells, and the development of effector and memory CD8 cells [292,293,294,295].

Redox regulation of T-cells

ROS levels rise rapidly after TCR engagement and are critical in driving T-cell activation, proliferation, and differentiation [268, 291, 296, 297]. Unsurprisingly, given the information discussed above, ROS influences the differentiation patterns and the disparate effector functions of various T lymphocytes. For example, the Th-2 polarized phenotype is encouraged by excessive microenvironmental ROS [298]. Conversely, Th-1 and Th-17 polarizations occur at low microenvironmental levels of ROS [299]. Excessive ROS resulting from either high production or damaged cellular antioxidant defenses may lead to mitochondrial membrane polarization with fatal consequences for T-cell activation and survival following TCR engagement [300]. Similarly, prolonged or chronic ROS upregulation may result in T-cell hyperresponsiveness, exhaustion, and anergy [301,302,303,304,305]. Several mechanisms appear to underpin this phenomenon including compromised mitochondrial ETC activity and dynamics [302, 306], upregulation of PD-1 [307, 308], dysregulated NF-κB signaling, chronic IKKβ signaling [309,310,311], and oxidation of functional cysteine groups in proteins [312,313,314]. Finally, excessive ROS production may lead to dysregulated T-cell homeostasis by differential modulation of T-cell homeostasis as effector T cells are more susceptible to ROS-mediated cell death than Tregs [201, 315, 316].

Nrf-2 transcription is upregulated following TCR engagement on naive T cells and restrains inflammatory T-cell activity. Thus, a Th-2 pattern is activated following TCR stimulation [317, 318]. Animal studies show that the upregulation of Nrf-2 increases the proliferation of Tregs [319] and amplifies their immunosuppressive and cytotoxic functions [320].

As previously discussed, GSH synthesis rapidly escalates following TCR activation and affects T-cell survival and function [284]. Increased de novo GSH synthesis also suppresses Th-17 differentiation while encouraging the production of Tregs. Conversely, GSH depletion or loss of de novo GSH synthesis in a state of chronic nitro-oxidative stress [321] compromises mTOR, NFAT, and N-Myc function. Thus, the metabolic reprogramming is abrogated enabling the maintenance of aerobic glycolysis and leading to the termination of T-cell activation [322,323,324]. Tregs also appear to exert at least some of their cytotoxic and immunosuppressive functions on effector T cells by decreasing GSH synthesis [325].

The TRX system activity exerts a range of influences on T-cell proliferation and activation via increased TRX-1 production. This restrains their stimulation and encourages the development of Tregs from naive T cells, decreasing their differentiation down the Th-1 and Th-17 pathways [326]. TRX-1 upregulation is important in enabling T effector and Treg cell survival and function during chronic nitro-oxidative stress by protecting membrane protein thiols from oxidation [327, 328]. Increased TRX-1 activity is needed to maintain the production of IL-2 [329] and Th-mediated activation of B cells [330].

The metabolic reprogramming of T cells is depicted in Fig. 5 and Table 4 summarizes the redox mechanisms that affect T-cell functions.

Fig. 5

Metabolic reprogramming of T and B cells. Tm cells memory T cells, Treg cells regulatory T cells, OXPHOS oxidative phosphorylation, FA fatty acid, PPP pentose phosphate pathway, GSH glutathione, PI3K phosphatidylinositol 3-kinase, mTOR mechanistic target of rapamycin, HIF1α hypoxia-inducible factor 1-alpha, c-Myc Myc proto-oncogenes, Pl cells plasma cells, Bm cells memory B cells, B1/B2 subclass of B-cells

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Table 4 Redox mechanisms influencing T-, B-, and NK-cell functions

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Metabolic reprogramming and redox regulation of B-cell activation

Metabolic reprogramming of B-cells

B-cell receptor (BCR) or cytokine-associated activation of naive B cells results in PI3K phospholipase C gamma 1 expression‎, leading to calcium mobilization and NF-κB activation and upregulation of c-Myc, HIF1α, AKT, mTOR, and STAT-6 [331]. Once activated, these lymphocytes migrate to germinal centers and display high rates of glycolysis and OXPHOS [332,333,334]. The short-term metabolic reprogramming and increased glycolysis are controlled by PI3K, HIF1α, AKT, and STAT-6 signaling [332,333,334]. The role of mTOR appears to be confined to the upregulation of GLUT-1 [335]. It is noteworthy that GSK-3 has a key role in regulating glycolysis in activated B cells and may also adjust ROS production and changes in mitochondrial dynamics [335, 336]. However, while mTOR may not be the primary player in the regulation of glycolysis, sustained germinal center B-cell BCR signaling requires activation of mTOR [337, 338]. mTOR is also involved in somatic hypermutation and in the formation of memory B cells [339,340,341].

The relative levels of OXPHOS and glycolysis differ in plasmablasts and memory B cells, with glycolysis being dominant in the former and OXPHOS being dominant in the latter to enable their long-term survival [342]. B1 and B2 subsets appear to display differing metabolic profiles, with PPP, FAO, and aerobic glycolysis being more active in B1 compared to B2 cells [342]. The production of high-affinity antibodies by plasmablasts is an energetically demanding process and requires rapid increases in glucose consumption and mitochondrial mass accompanied by significant changes in mitochondrial dynamics [336, 343, 344], reviewed in [342]. Unsurprisingly, functional mitochondria are an indispensable element in B-cell differentiation and effector functions [345]. The process of antibody synthesis is also regulated by AMPK, which enables memory B-cell formation and survival in part by regulating mitochondrial dynamics and suppressing the activation of mTOR [133, 346, 347].

Redox regulation of B-cell activation and function

High levels of hydrogen peroxide are required to initiate and maintain BCR signaling [348, 349]. This is primarily provided by the activity of NOX-2 [350], but in the longer term, the source of hydrogen peroxide is mtROS [348, 349]. In addition, the cellular redox state and mtROS release play a major role in B-cell survival and differentiation and IgM synthesis [351, 352]. However, excessive mitochondrial mtROS synthesis may inhibit B-cell activation and the differentiation of B cells into antibody-producing plasmablasts [353]. Increased  concentrations of mtROS may also inhibit the production of antibodies by downregulating CD19 expression‎ [354]. Finally, chronically upregulated ROS can upregulate the consumption of IgM antibodies [355, 356].

In this context, it is noteworthy that B-cell activation is accompanied by a concomitant stimulation of the TRX and GSH system, with the latter involving triggering of the cystine transporter xCT and higher uptake of cysteine [352]. Upregulation of GSH/TRX systems by activated B cells enables their medium-term survival [357]. The intensive function of both systems correlates with elevated production of IgM [352]. Finally, there is evidence associating increased Nrf-2 expression‎ in activated B cells with prolonged survival and resistance to ROS-mediated apoptosis [358,359,360].

Table 4 summarizes the redox mechanisms that affect B-cell functions, and the metabolic reprogramming of B cells is depicted in Fig. 5.

Metabolic reprogramming and redox regulation of NK-cell activation

Metabolic reprogramming in NK-cells

The signaling mechanisms involved in NK-cell activation [361, 362] entail the engagement of multiple activation receptors such as natural cytotoxicity receptors [363,364,365] leading to the stimulation of AP-1, NFAT, and NF-κB [361, 366]. Cytoskeletal reorganization and release of chemokines, inflammatory cytokines, and lytic granules containing granzyme A, B, and perforin follows [367,368,369]. Unsurprisingly, the various effector and regulatory functions of activated NK-cells are enabled by metabolic programming, which is underpinned by the upregulation of glucose-driven glycolysis, OXPHOS, increased FA synthesis, and glutamine metabolism [370,371,372,373]. Metabolic reprogramming, glycolysis, and mitochondrial activity are controlled by mTOR that is upregulated in NK cells following stimulation by IL-15 and IL-3 [372, 374, 375]. The high expression‎ of this kinase is also responsible for increased FA synthesis and glutamine metabolism by activated NK cells via the upregulation of SREBPs and N-Myc [370, 376].

In inflammatory conditions, PI3K/mTOR signaling, along with NF-κB and STAT-3 transcriptional activity, is responsible for triggering HIF1 protein synthesis [377, 378]. The importance of mTOR and HIF1α in NK-cell proliferation and function is difficult to overemphasize as reduced HIF1α and mTOR activity are associated with loss of cytotoxic effects. It is evidenced by decreased production of perforin and granzyme B, and premature apoptosis [372, 379, 380].

Redox regulation of NK-cell activation and function

Increased ROS production enables NK-cell-mediated cytolysis by promoting the release of perforin and granzyme B [381] and NK-cell division and proliferation after pathogen invasion [382]. Nrf-2 activation serves as an immunological checkpoint following NK-cell activation [383, 384].

The upregulation of GSH synthesis may enable the proliferation and cytotoxic functions of NK-cells and, conversely, GSH downregulation results in compromised functions and recruitment to sites of inflammation [385,386,387]. In an inflammatory environment, the upregulation of TRX-1 plays a role in NK-cell survival by maintaining membrane cytoprotective sulfhydryl residues in a reduced state [388, 389]. This phenomenon may protect those cells from hydrogen peroxide-mediated NK-cell dysfunctions [388, 389]. However, this level of protection is clearly limited as chronic nitro-oxidative stress may result in NK-cell hypofunction and loss of cytotoxic activity [390,391,392,393]. There is evidence suggesting that this is due to compromised hydrogen peroxide signaling following NOX-2 hyperactivity [390]. However, there is also proof that NK-cell function may be impaired by excessive production of NO [392].

Table 4 summarizes the redox mechanisms that affect NK-cell functions, while Fig. 6 shows the metabolic reprogramming in NK-cells.

Fig. 6

Metabolic reprograming in NK-cells. AP-1 activator protein-1, NFAT nuclear factor of activated T cell, NF-kB nuclear factor NF-kappa-B, OXPHOS oxidative phosphorylation, FA fatty acid

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Role of the HDL complex and oxidized phospholipids in the immune response

Role of HDL, ApoA1, and PON1 in the regulation of the immune response

Previously, we have reviewed the important role of the HDL/ApoA1/PON1 complex in regulating immune responses [13, 41, 79, 90, 394]. In brief, HDL attenuates the activation of TLR-4 by stimulating cholesterol efflux from membrane lipid rafts (MLR), NF-κB activity, DC maturation and activation, and antigen presentation to T lymphocytes. It also affects Th-1 and Th-17 differentiation, T-cell and BCR activation, the complement system, and monocyte and macrophage chemotaxis [13, 41, 79, 90, 394]. HDL-mediated MLR disruption underpins anti-inflammatory and immunosuppressive effects. HDL exerts a unique immunoregulatory role by activating pentraxin 3, an immunosensory molecule. ApoA1 regulates the balance between Th-17 and Tregs, improves mitochondrial functions, increases the activity of the ETC, and stabilizes PON1 within the HDL particle, thereby maintaining PON1 activity. The latter protects against immune cell membrane lipid peroxidation, circulating oxidized lipoproteins, and oxidative damage to mitochondria. It positively affects glucose metabolism, PPP, FAO, PPAR-γ activity, and aerobic glycolysis via upregulation of GLUT-1 [41, 90].

Role of oxidized phospholipids in the regulation of the immune response

Evidence suggests that the bulk of oxidized phospholipids present in the circulation exists as immune complexes with natural IgM and IgG due to their status as oxidation-specific epitopes or neoantigens [395, 396]. It is also proposed that oxidized phospholipid complexes are proinflammatory [397, 398] using several routes, which include recruitment of the complement cascade [399] and production of inflammatory responses in human macrophages largely by engagement of the Fc gamma receptor 1 [400, 401]. These complexes may activate mature DCs leading to a primed inflammasome thereby exaggerating IFN-γ and IL-1 production [402,403,404]. Moreover, DCs activated and primed via this mechanism may trigger naive T cells and induce Th-17 polarization [404,405,406].

As a result of activating neutrophil PRR, oxidized phospholipids contribute significantly to inflammation and oxidative stress and the formation of NETs [407, 408]. In addition, oxidized phospholipid engagement with monocytes, macrophages, DCs, and NK cells may induce epigenetic and metabolic reprogramming leading to “immune training”. The process effectively endows these leucocytes with a de facto memory, resulting in an amplified inflammatory or anergic response to future antigenic challenges [409, 410]. The mechanisms driving the metabolic and epigenetic changes described above appear to depend, at least in part, on mTOR-induced assembly of NADPH oxidase and subsequent increases in ROS-mediated signaling [410, 411].

The final part of this review deals with the detrimental effects of chronic oxidative and nitrosative stress on the immune response as a whole. In physiological conditions, NOX-derived cytosolic hydrogen peroxide regulates redox-sensitive intracellular signaling pathways [412,413,414,415,416]. However, in conditions of excessive ROS production, hyperoxidation of thiolate anions to sulfonic acid essentially incapacitates reversible cysteine oxidation. It is an effective signaling mechanism, locking functional cysteines in the oxidized mode [90, 417].

The other signaling system involved in regulating the activity of redox-sensitive proteins and enzymes is reversible S-nitrosylation [17, 418]. However, pathological levels of ROS disable the mechanisms responsible for maintaining the reversibility of S-nitrosylation inducing a cellular state described as protein hypernitrosylation [202]. Hyperoxidation and S-nitrosylation can result in impaired function of the redox-sensitive transcription factors and enzymes regulating metabolic reprogramming in immune cells. Compromised mitochondrial functions and seriously suppressed immune cell activation and function may follow. Chronic nitro-oxidative stress also affects the activity of HDL, apoA1, and PON1 whilst increasing the density of oxidized phospholipids further dysregulates the immune response [41]. Finally, chronic nitro-oxidative stress and inflammation also stimulate IDO that may result in a state of profound immune suppression [419]. The section below deals with these processes, beginning with the effects of hypernitrosylation and hyperoxidation on transcription factors and enzymes.

The detrimental effects of chronic nitro-oxidative stress on the immune response

Chronic nitro-oxidative stress on transcription factors and enzymes

S-nitrosylation exerts a significant inhibition of NF-κB function by reducing the binding of its subunits to DNA thereby decreasing the activity of the complex as a transcription factor [420,421,422], as well as the expression‎ of target effector genes [420, 423]. This consequence is largely due to S-nitrosylation-mediated conformational changes to crucial functional cysteine residues located on the p65 subunit of p50/p65 abrogating NF-κB DNA-binding capacity [420, 424]. The outcomes involve decreased levels of IL-12 [425], IL-1β [426], IL-6, IL-8, and iNOS [427, 428]. Moreover, S-nitrosylation may inhibit TLR-4 [429, 430] and TLR-2 signaling [431].

There is also in vivo evidence that S-nitrosylation leads to the inhibition of numerous MAPKs, most notably p38/MAPK [432, 433], Janus kinase [432, 434], and consequent STAT-3 and NF-κB activation [435]. S-nitrosylation is additionally involved in Nrf-2 triggering, which appears to be affected via the conformational modification of crucial thiol groups [436,437,438]. Hypernitrosylation is also accompanied by chronic activation of HIF1α via upregulation and/or stabilization of HIF1α [439,440,441]. In addition, irreversible nitrosylation of functional cysteine thiols may cause chronic upregulation of PI3K/AKT and mTOR signaling [442,443,444,445] thereby decreasing the capacity of immune cells to adapt to environmental conditions or changing metabolic needs. Moreover, mTOR may be directly activated following S-nitrosylation of the tuberous sclerosis complex 2 [445] and the nitrosylation of small GTPases [446]. Prolonged nitrosylation may also compromise immune cells via the chronic upregulation of GSK-3 [202]. Finally, by inhibiting AMPK activity, nitrosylation-mediated upregulation of PI3K/AKT and GSK-3 may introduce a further dimension of metabolic disorders [447, 448]. In addition, in an environment of chronic nitro-oxidative stress, mTOR may be inactivated by oxidation of Cys1483 [449] and AMPK activation [450, 451]. In an environment of increased ROS, several enzymes involved in regulating metabolic reprogramming in immune cells are triggered most notably via PPAR-γ [452, 453].

Detrimental effects on immune cells due to nitro-oxidative stress-mediated mitochondrial dysfunction

Chronically elevated ROS/RNS can impair mitochondrial structure and functions by injuring DNA, proteins, and lipids. The most prominent results are damage to the enzymes of the ETC [248, 454,455,456] and a range of structural and functional phospholipids, basically cardiolipin [457,458,459]. This ultimately leads to altered ATP production and accelerated ROS, provoking further impairement of macromolecules, forming the basis of self-amplifying pathology [248, 454,455,456]. Increased NO production by mitochondria in an environment of nitrosative stress may also be a source of dysfunction and damage [460,461,462]. In essence, two pathways are implicated. The first involves reversible inhibition of ETC enzymes by NO-mediated S-nitrosylation [17, 463, 464]. The second comprises irreversible nitration of functional enzymes and structural proteins by ONOO- [248, 465]. This pattern of pathology leads to a vicious circle of bioenergetic failure and elevated mtROS production [466,467,468,469].

Clearly compromised mitochondrial function has many direct adverse effects on the activity of immune cells, as discussed above. However, mitochondrial dysfunction may also lead to numerous indirect negative consequences related to depleted levels of NADPH, which results from the distorted activity of this organelle [470,471,472]. This is a significant source of metabolic dysfunction in immune cells as the GSH/TRX systems are wholly dependent on the presence of adequate levels of NADPH, which acts as an indispensable source of reducing equivalents [473,474,475,476]. The synthesis of NADPH from NADP [477, 478] and NAD+ kinases, which catalyze the production of NADP from NAD+ [479, 480], is dependent on mitochondrial respiration and on an adequate supply of ATP [470, 471, 481]. Mitochondrial dysfunction is associated with depleted levels of NAD+ [13] due to the fact that the enzyme nicotinamide mononucleotide adenylyl transferase, which catalyzes the formation of NAD+ synthesis from nicotinamide mononucleotide as part of the salvage pathway [482], is dependent on ample supplies of ATP [483,484,485].

An important adverse consequence of depleted NAD+ levels is the compromised mitochondrial NADPH production by malic enzyme 2, IDH, methylenetetrahydrofolate dehydrogenase 2, and aldehyde dehydrogenase, which are all NAD+ dependent [486, 487]. Lowered levels of malic enzyme 2 and IDH may affect the TCA cycle [488, 489]. NAD+ deficiency can impair the PPP's ability to produce NADPH via decreased hexokinase activity [490,491,492].

Chronic nitro-oxidative stress and the inhibition of antioxidant systems and TCA activity

Chronic nitro-oxidative stress may cause nitrosylation and hyperoxidation of the key cysteine residues within TRX and thioredoxin reductase thereby compromising or abrogating TRX activity [493,494,495,496]. Chronically elevated ROS/RNS decrease GSH system activity [497, 498]. Mechanistically, this is achieved via the oxidation and nitrosylation or tyrosine nitration or via inhibiting the activity of GSH, glutathione peroxidase, and glutathione reductase [13, 321, 499]. Increased production of radical species also raises the activity of multidrug resistance-associated proteins, resulting in extrusion of GSH and GSSH into the intercellular environment. The decreased importation of cysteine, which follows, leads to reduced synthesis of replacement GSH [500,501,502,503]. A state of persistent nitro-oxidative stress may also cause Nrf-2 inhibition via several mechanisms, including activation of MAPK kinase, decreased DJ-1 [459, 504], and reduced TRX system activity [505, 506].

Oxidation and/or nitrosylation of functional cysteine groups in several TCA enzymes may cause adverse effects on the metabolism of immune cells. Such inactivated enzymes are α-ketoglutarate dehydrogenase [507,508,509] and conitase, which catalyze the conversion of citrate to isocitrate [510, 511], IDH [512,513,514], ME2 [515, 516], and pyruvate dehydrogenase kinase [517]. The negative consequences of lowered α-ketoglutarate dehydrogenase and aconitase are of particular importance, and may lead to reduced TCA cycle activity and NADPH synthesis [518, 519] and accumulation of citrate [519]. The inactivation of pyruvate dehydrogenase kinase also results in adverse metabolic consequences by attenuating the conversion of pyruvate to acetyl-CoA [517].

Detrimental effects of chronic nitro-oxidative stress on the HDL complex

Chronically elevated ROS/RNS levels are a cause of depleted circulating HDL [520,521,522], ApoA1 [522,523,524], and PON1 [525, 526] levels. Chronic oxidative stress induces HDL [527,528,529] and ApoA1 [521, 530, 531] dysfunctions. PON1 is rendered dysfunctional in such an environment, which appears to be mediated by the high activity of MPO [525, 526, 532]. The mechanisms underpinning the development of a dysfunctional HDL particle and reduced activity of ApoA1 are complex and readers are referred to the work of Morris et al. [41].

Chronic nitro-oxidative stress and the advent of immunosuppression

Chronic nitro-oxidative stress can induce the development of endotoxin tolerance by provoking IDO activation [533, 534]. Increased IDO activity upregulates the tryptophan catabolite (TRYCAT) pathway, as well as TGF-β1 and IL-10 [535, 536], which exert multiple inhibitory effects on TLR signaling [537, 538]. Neutrophils with endotoxin tolerance are characterized by decreased oxidative burst, downregulated TLR-4 receptors, and impaired cell adhesion, rolling, and migration [539,540,541]. Macrophages with endotoxin tolerance display significant dysregulation of their function as APCs [542]. Impaired antigen presentation is also seen in DCs following IDO activation [542]. In this state, DC activation of naive T cells leads to Th-2 polarization [543, 544]. DCs may inhibit T memory and T effector cells and induce CD4 and CD8 T-cell anergy and activation of Tregs [545, 546]. This explains that prolonged endotoxin tolerance is typified by impaired proliferation and anergy of CD4 T and CD8 T cells and increased Treg cell numbers [547,548,549]. Finally, endotoxin tolerance is characterized by a reduced number and cytolytic function of NK cells [550,551,552].

Summary and conclusion

The functions, performance, and survival of immune cells are strongly regulated by redox mechanisms, including intracellular and extracellular ROS/RNS and oxidized phospholipids, cellular antioxidants such as glutathione, thioredoxin, the HDL complex, and Nrf-2. Hypernitrosylation and chronic nitro-oxidative stress may inhibit these antioxidant systems, thereby decreasing the activity levels of the TCA cycle, mitochondrial functions, and immune cell metabolism. As such, redox mechanisms regulate and modulate many different immune functions, including but not limited to macrophage and Th cell polarization, phagocytosis, production of pro- and anti-inflammatory cytokines, metabolic reprogramming of immune cells, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, TLR activity, and endotoxin tolerance. ROS/RNS, oxidized phospholipids, and the key antioxidant systems could be regarded as new drug targets in the treatment and prevention of immune disorders.

요약 및 결론

면역 세포의 기능, 성능 및 생존은 

세포 내 및 세포 외 ROS/RNS 및 산화 인지질, 

글루타치온, 

티오레독신, 

HDL 복합체 및 Nrf-2와 같은 

세포 항산화제 등의 산화 환원 메커니즘에 의해 강력하게 조절됩니다. 

과니트로실화 및 만성 니트로 산화 스트레스는 

이러한 항산화 시스템을 억제하여 

TCA 주기, 

미토콘드리아 기능 및 

면역 세포 대사의 활성 수준을 감소시킬 수 있습니다. 

이처럼 

산화 환원 메커니즘은 

대식세포 및 Th 세포 분극화, 

식균 작용, 

염증 및 항염증 사이토카인 생성, 

면역 세포의 대사 재프로그램, 

면역 훈련 및 내성, 

화학 작용, 

병원체 감지, 

항바이러스 및 항균 효과, 

TLR 활성 및 내독소 내성 등 다양한 면역 기능을 조절하고 조절합니다. 

ROS/RNS, 

산화 인지질 및 주요 항산화 시스템은 

면역 질환의 치료 및 예방에 있어 

새로운 약물 표적으로 간주될 수 있습니다.

References

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