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. 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. They are heavily influenced by cellular antioxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2 (Nrf-2), and the HDL/ApoA1/PON1 complex. The performance and survival of individual immune cells is under redox control and depends on intracellular and extracellular levels of ROS/RNS. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor-κB (NF-κB), HIF1α, the mechanistic target of rapamycin (mTOR), the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway, mitogen-activated protein (MAP) kinases, 5' AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR). 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 (NK) 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 immune-inflammatory response is associated with increased nitro-oxidative stress. Similarly, patient D4, who showed CD69 up-regulation in association with TCR V chains 1 and 8 (Table I), shows CVB4-specific T cell clonal bands in association with the same TCR V chains. Heteroduplex analysis shows the appearance of CVB4-specific clonal bands associated with the V8 and 5 families. Subject D7 shows CD69 up-regulation among CD4 T cells with TCR V5 and 8 chains (Table I). Similarly, V families not induced to express CD69 (V chains 7 and 8) are associated with proliferation of fewer novel CVB4-specific clones. As shown, a higher frequency of clones is seen among T cells bearing TCR V1, 5.1, 5.2, and 6, mirroring those V families up-regulating CD69 in this individual. Healthy donor C7 shows CVB4- induced CD69 up-regulation by CD4 T cells bearing V chains 1, 2, 5, and 6 (Table I), but not V7 or 8 cells. Bands generated from CVB4-specific T cell clones have no corresponding band generated by the control preparation and are labeled (). For each TCR V shown, analyses represent cells stimulated with CVB4 lysates (B4) or control uninfected lysates (U). Heteroduplex analysis of TCR V expression by T cell clones activated by CVB4 Ags. These findings provide further support for an important role of LXRs in the coordinated regulation of lipid metabolic and inflammatory gene programs in macrophages. We show that the ARL7 promoter contains a functional LXRE and can be transactivated by LXRs in a sequence-specific manner, indicating that ARL7 is a direct target of LXR. ARL7 has previously been shown to transport cholesterol to the membrane for ABCA1-associated removal and thus may be integral to the LXR-dependent efflux pathway. We further utilized VP16-LXRα-expressing macrophages to identify and validate new targets for LXRs, including the gene encoding ADP-ribosylation factor-like 7 (ARL7). Moreover, VP16-LXRα expression also suppressed the induction of inflammatory genes by lipopolysaccharide to a comparable degree as synthetic agonist. Analysis of gene expression in primary macrophages derived from two independent VP16-LXRα transgenic lines confirmed the ability of LXR to drive expression of genes involved in cholesterol efflux and fatty acid synthesis. These mice exhibit increased LXR signaling selectively in adipose and macrophages. We generated transgenic mice expressing a constitutively active VP16-LXRα protein from the aP2 promoter. Here, we describe an LXR gain-of-function system that does not depend on the addition of exogenous ligand. One complicating factor in studies utilizing synthetic LXR agonists is the potential for pharmacologic and receptor-independent effects. Ligand activation of liver X receptors (LXRs) has been shown to impact both lipid metabolism and inflammation.
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