Regulation of type 17 helper T-cell function by nitric oxide during inflammation

Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow G12 8TA, Scotland.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2011; 108(22):9220-5. DOI: 10.1073/pnas.1100667108
Source: PubMed


Type 17 helper T (Th17) cells are implicated in the pathogenesis many of human autoimmune diseases. Development of Th17 can be enhanced by the activation of aryl hydrocarbon receptor (AHR) whose ligands include the environmental pollutant dioxin, potentially linking environmental factors to the increased prevalence of autoimmune disease. We report here that nitric oxide (NO) can suppress the proliferation and function of polarized murine and human Th17 cells. NO also inhibits AHR expression in Th17 cells and the downstream events of AHR activation, including IL-22, IL-23 receptor, and Cyp1a1. Conversely, NO did not affect the polarization of Th17 cells from mice deficient in AHR. Furthermore, mice lacking inducible nitric oxide synthase (Nos2(-/-)) developed more severe experimental autoimmune encephalomyelitis than WT mice, with elevated AHR expression, increased IL-17A, and IL-22 synthesis. NO may therefore represent an important endogenous regulator to prevent overexpansion of Th17 cells and control of autoimmune diseases caused by environmental pollutants.

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    • "Consistently, retroviral transductions of Ahr alone or combined with RORc2 under different skewing conditions, except for Th17 cells, are insufficient to induce the production of IL-17 and IL-22 [38, 44]. Interesting data indicate that nitric oxide (NO) suppresses the differentiation and functions of polarized human and murine Th17 cells, and deletion of inducible NO synthase (iNOS) in mice (Nos2−/−) results in more severe EAE manifested by an increased production of IL-17A [50]. The authors suggest that NO also inhibits the expression of Ahr in Th17 cells concomitant with the inhibition of IL-22, IL-23r, and CYP1A1. "
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    ABSTRACT: The immune system is regulated by distinct signaling pathways that control the development and function of the immune cells. Accumulating evidence suggest that ligation of aryl hydrocarbon receptor (Ahr), an environmentally responsive transcription factor, results in multiple cross talks that are capable of modulating these pathways and their downstream responsive genes. Most of the immune cells respond to such modulation, and many inflammatory response-related genes contain multiple xenobiotic-responsive elements (XREs) boxes upstream. Active research efforts have investigated the physiological role of Ahr in inflammation and autoimmunity using different animal models. Recently formed paradigm has shown that activation of Ahr by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3'-diindolylmethane (DIM) prompts the differentiation of CD4(+)Foxp3(+) regulatory T cells (Tregs) and inhibits T helper (Th)-17 suggesting that Ahr is an innovative therapeutic strategy for autoimmune inflammation. These promising findings generate a basis for future clinical practices in humans. This review addresses the current knowledge on the role of Ahr in different immune cell compartments, with a particular focus on inflammation and autoimmunity.
    01/2014; 2014(2-3):520763. DOI:10.1155/2014/520763
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    • "In a previous study, Bacellar et al. [8] verified that in lesions of cutaneous and mucosal leishmaniasis patients, the intensity of the inflammatory infiltration is directly correlated to the number of cells expressing this cytokine. In addition, a decreased quantity of IL-17 exhibited by SH patients under antigenic stimulus may be, at least in part, due to a suppressive effect exerted by NO levels, which impair the polarization and the stabilization of IL-17-producing cells [37]. The inverse situation seems to occur with the treated patients, which exhibited a considerable quantity of IL-17 and low levels of NO. "
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    • "NO has a variety of effects, depending on its relative concentration and the environment in which it is produced. In particular, NO has many roles in immune responses18, including the control of infection and the regulation of signaling cascades, transcription factors, vascular responses, leukocyte rolling, migration, cytokine production and T-cell differentiation19,20,21,22,23. However, the role of NO in promoting or inhibiting septic shock remains controversial. "
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