Calcitriol Suppresses Antiretinal Autoimmunity through Inhibitory Effects on the Th17 Effector Response

Abstract

Experimental autoimmune uveitis (EAU) serves as a model for human autoimmune uveitis and for cell-mediated autoimmunity in general. EAU induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein in CFA is driven by the Th17 response. Oral calcitriol (1,25-dihydroxyvitamin D3) prevented as well as partly reversed disease and suppressed immunological responses. In vitro, calcitriol directly suppressed IL-17 induction in purified naive CD4+ T cells without inhibiting Th17 lineage commitment, as reflected by unaltered RORγt, STAT3, and FoxP3 expression. In contrast, in vivo treatment with calcitriol of mice challenged for EAU impaired commitment to the Th17 lineage, as judged by reduction of both RORγt and IL-17 in CD4+ T cells. Innate immune response parameters in draining lymph nodes of treated mice were suppressed, as was production of IL-1, IL-6, TNF-α, and IL-12/IL-23p40, but not IL-10, by explanted splenic dendritic cells (DC). Finally, supernatants of calcitriol-conditioned bone marrow-derived DC had reduced ability to support Th17 polarization of naive CD4+ T cells in vitro and in vivo. Thus, calcitriol appears to suppress autoimmunity by inhibiting the Th17 response at several levels, including the ability of DC to support priming of Th17 cells, the ability of CD4+ T cells to commit to the Th17 lineage, and the ability of committed Th17 T cells to produce IL-17.

Serum vitamin D status is associated with the presence but not the severity of primary open angle glaucoma

“…It also accelerates neuronal growth in a dose-dependent way in rat hippocampal cell cultures [28]. Parallel, the anti-inflammatory properties of vitamin D may be involved as there is evidence for a pivotal role of vitamin D in the immune system [29,30] by modulating effect on the immune cells that produce vitamin D and express the VDR. Finally, the antioxidant properties of vitamin D against oxidative stress of reactive oxygen and nitrogen species in the central nervous system [31] should also be mentioned.…”

Role of vitamin D in immune responses and autoimmune diseases, with emphasis on its role in multiple sclerosis

“…in vitro, although CD8 + T cells express substantial amounts of VDR [35] . An alternative way by which 1,25(OH) 2 D 3 suppresses immune responses is through inhibiting the Th17 response at several levels, including suppressing the ability of CD4 + T cells to commit to the Th17 lineage, and inhibiting Th17-related IL-17 production [36] . Besides increasing Th2 cytokines IL-4 and IL-5, 1,25(OH) 2 D 3 can also suppress immunoglobulin production and B cell proliferation and differentiation [37,38] .…”

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

“…(1,25(OH)2D3) exerts immunomodulatory effects on T cells from patients with SR asthma patients, enhancing the impaired steroid-induced IL-10 response in these individuals (31), while others have highlighted the capacity of this molecule to inhibit Th17 responses (32)(33)(34)(35).…”