Abstract
Soluble CD83 (sCD83) is the extracellular domain of the membrane-bound CD83 molecule, and known for its immunoregulatory functions. Whether and how sCD83 participates in the pathogenesis of uveitis, a serious inflammatory disease of the eye that can cause visual disability and blindness, is unknown. By flow cytometry and imaging studies, we show that sCD83 alleviates experimental autoimmune uveitis (EAU) through a novel mechanism. During onset and recovery of EAU, the level of sCD83 rises in the serum and aqueous humor, and CD83+ leukocytes infiltrate the inflamed eye. Systemic or topical application of sCD83 exerts a protective effect by decreasing inflammatory cytokine expression, reducing ocular and splenic leukocyte including CD4+ T cells and dendritic cells (DCs). Mechanistically, sCD83 induces tolerogenic DCs by decreasing the synaptic expression of co-stimulatory molecules and hampering the calcium response in DCs. These changes are caused by a disruption of the cytoskeletal rearrangements at the DC–T cell contact zone, leading to altered localization of calcium microdomains and suppressed T-cell activation. Thus, the ability of sCD83 to modulate DC-mediated inflammation in the eye could be harnessed to develop new immunosuppressive therapeutics for autoimmune uveitis.
Highlights
Uveitis is an inflammatory eye disease that causes visual impairment and blindness [1]
CD83+ leukocytes were absent in the eyes of control mice, while 18.6 ± 3.2% of CD45+ infiltrating leukocytes were CD83 positive in experimental autoimmune uveitis (EAU) conditions, including CD4+ T cells, B cells, dendritic cells (DCs), and NK cells (Figures 1D,E)
We describe the beneficial effect of Soluble CD83 (sCD83) on autoimmune uveitis in mice, and identify an immunomodulatory role of sCD83 on DCs to further inhibit T-cell activation
Summary
Uveitis is an inflammatory eye disease that causes visual impairment and blindness [1]. Longterm corticosteroid treatment can cause serious systemic and ocular side effects such as hypertension, diabetes, cataracts, and glaucoma. To prevent these complications, corticosteroid-sparing therapies with immunomodulatory activity have been developed, and clinical results are promising [4, 5]. Experimental autoimmune uveitis (EAU) can be induced by adoptively transferring mature DCs pulsed with uveitogenic antigens [16], and was ameliorated by injection of immature DCs through inhibiting uveitogenic CD4+ T-cell activation and differentiation [17, 18]. Modulating DC biology could be a means to alleviate or prevent disease
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