Anti-inflammatory effect of retinoic acid on experimental autoimmune uveoretinitis.
ABSTRACT To determine whether an active metabolite of vitamin A, all-trans retinoic acid (ATRA), reduces inflammation in experimental autoimmune uveoretinitis (EAU).
Naive CD4(+) T cells were activated with anti-CD3, anti-CD28 and transforming growth factor (TGF)-beta, in the presence or absence of ATRA. Intracellular expression of transcription factor forkhead box P3 (Foxp3) and interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. C57BL/6 mice were immunised with human interphotoreceptor retinoid binding protein peptide 1-20 (IRBP(1-20)). ATRA was administered intraperitoneally every other day (0.2 mg/mouse per day) from day 0 to day 21. In vivo-primed draining lymph node cells from vehicle-treated or ATRA-treated mice were stimulated with IRBP(1-20) and the culture supernatant fraction was harvested for assay of interferon (IFN)-gamma and IL-17 by ELISA.
ATRA synergised with TGF-beta to induce Foxp3(+) T regulatory cells (Treg) and reciprocally inhibited development of IL-17-producing T helper cells (Th17) induced by TGF-beta and IL-6. ATRA treatment reduced the severity of EAU clinically, and IFN-gamma and IL-17 production were significantly reduced in ATRA-treated mice.
These findings demonstrate that ATRA treatment ameliorates severity of EAU and reduces the Th1/Th17 responses. ATRA may represent a new therapeutic modality for human refractory uveitis.
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ABSTRACT: Although vitamin A was recognized as an "anti-infective vitamin" over 90 years ago, the mechanism of how vitamin A regulates immunity is only beginning to be understood. Early studies which focused on the immune responses in vitamin A-deficient (VAD) animals clearly demonstrated compromised immunity and consequently increased susceptibility to infectious disease. The active form of vitamin A, retinoic acid (RA), has been shown to have a profound impact on the homing and differentiation of leukocytes. Both pharmacological and genetic approaches have been applied to the understanding of how RA regulates the development and differentiation of various immune cell subsets, and how RA influences the development of immunity versus tolerance. These studies clearly show that RA profoundly impacts on cell- and humoral-mediated immunity. In this review, the early findings on the complex relationship between VAD and immunity are discussed as well as vitamin A metabolism and signaling within hematopoietic cells. Particular attention is focused on how RA impacts on T-cell lineage commitment and plasticity in various diseases. Copyright © 2015 the American Physiological Society.Physiological Reviews 01/2015; 95(1):125-148. · 29.04 Impact Factor
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ABSTRACT: Abstract Uveitis, recurrent oral and genital ulcerations associated with skin lesions are the major symptoms of a chronic multisystemic inflammatory disorder known as Behçet's disease (BD). High prevalence of this dreaded disease has been observed in the Mediterranean basin, including Algeria and along the Silk Road. Although the etiologic agent of this disease remains uncertain, many hypotheses have been advanced in its pathogenesis. Our team has previously reported high levels of nitric oxide (NO) in sera of BD patients, suggesting its deleterious effect during chronic inflammation. In our current study, the aim is to investigate the ex vivo immunomodulatory effect of all-trans-retinoic acid (ATRA) on NO pathway in Algerian BD patients. First, peripheral blood mononuclear cells isolated from active and inactive BD patients and healthy controls were cultured with different concentrations of ATRA. NO production was estimated with the Griess method. To elucidate the underlying mechanisms of ATRA effect on NO production, we analyze inducible nitric oxide synthase expression and nuclear factor-κB (NF-κB) activity by immunofluorescence test. Our results revealed a higher production of NO in active BD compared with the inactive stage and healthy controls. We observed that ATRA inhibits NO production in BD both in active and inactive stages and inhibits NF-κB translocation. In conclusion, we report a relationship between NO production and the disease activity. ATRA down-regulates NO production in BD patients. This immunomodulatory effect seems to be mediated through NF-κB pathway. All these findings suggest that ATRA could be considered as a promising therapy for BD.Immunopharmacology and Immunotoxicology 12/2013; · 1.36 Impact Factor
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ABSTRACT: BACKGROUND: We previously reported that the peripheral regulatory T cells (pTregs) generated 'on-demand' in the retina were crucial to retinal immune privilege, and in vitro analysis of retinal dendritic cells (DC) showed they possessed antigen presenting cell (APC) activity that promoted development of the Tregs and effector T cells (Teffs). Here, we expanded these findings by examining whether locally generated, locally acting pTregs were protective against spontaneous autoimmunity and autoimmunity mediated by interphotoreceptor retinoid-binding protein (IRBP). We also examined the APC capacity of retinal DC in vivo. METHODS: Transgenic (Tg) mice expressing diphtheria toxin receptor (DTR) and/or green fluorescent protein (GFP) under control of the endogenous FoxP3 promoter (GFP only in FG mice, GFP and DTR in FDG mice) or the CD11c promoter (GFP and DTR in CDG mice) were used in conjunction with Tg mice expressing beta-galactosidase (betagal) as retinal neo-self antigen and betagal-specific TCR Tg mice (BG2). Retinal T cell responses were assayed by flow cytometry and retinal autoimmune disease assessed by histological examination. RESULTS: Local depletion of the Tregs enhanced actively induced experimental autoimmune uveoretinitis to the highly expressed retinal self-antigen IRBP in FDG mice and spontaneous autoimmunity in betagal-FDG-BG2 mice, but not in mice lacking autoreactive T cells or their target antigen in the retina. The presence of retinal betagal downregulated the generation of antigen-specific Teffs and pTregs within the retina in response to local betagal challenge. Retinal DC depletion prevented generation of Tregs and Teffs within retina after betagal injection. Microglia remaining after DC depletion did not make up for loss of DC-dependent antigen presentation. CONCLUSIONS: Our results suggest that local retinal Tregs protect against spontaneous organ-specific autoimmunity and that T cell responses within the retina require the presence of local DC.Journal of Neuroinflammation 12/2014; 11(1):205. · 4.90 Impact Factor