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

ABSTRACT

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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    • "The discrepancy between our data and past findings likely relates to relatively modest changes in NO production (4-fold increase) that occurred with OGR1-deficiency. In support of this notion, it is reported that concentrations of chemical NO donors required to inhibit T cell proliferation (10–100 μM), are lower than the levels that induce T cell apoptosis or inhibit Th17 differentiation (>100 μM) [42, 44]. Overall, our findings suggest that OGR1 modulates NO production by macrophages within a modest range to selectively impact T cell proliferation. "
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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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    • "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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