Redox regulation of the immune response

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.

Keywords: Antioxidants; Immune response; Inflammation; Oxidative and nitrosative stress; Physiological stress.

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

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

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

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

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

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