Adrenomedullin-RAMP2 System Modulates Inflammation and Tissue Repair in Experimental Autoimmune Uveitis Via T-Cell and M2 Macrophage Regulation

PURPOSE: Adrenomedullin (AM), a peptide produced by various cells, exerts diverse physiological effects and is regulated by receptor activity-modifying proteins (RAMP2 and 3). Experimental autoimmune uveitis (EAU) is a well-established model for studying human autoimmune uveitis. Hence, we investigated the pathophysiological roles of the AM-RAMP system in uveitis using an optimized EAU mouse model. METHODS: Female wild-type (WT), AM knockout, RAMP2KO, and RAMP3KO mice were immunized with the human interphotoreceptor retinoid-binding protein. The expression of macrophage-related genes and inflammatory cytokines in the retina and spleen was analyzed using real-time polymerase chain reaction. EAU-induced WT mice received human recombinant AM; therapeutic effects were evaluated via clinical and histologic scores, quantification of T-cell and macrophage infiltration in the retina, and the number of splenic regulatory T cells (Tregs) and M2 macrophages using flow cytometry. RESULTS: Compared with WT mice, EAU-induced AMKO and RAMP2KO mice had significantly increased retinal inflammatory cell infiltration and worsened clinical scores, whereas RAMP3KO mice did not. Proinflammatory cytokine expression was suppressed in the retina of EAU-induced WT mice that received AM. However, anti-inflammatory cytokine expression was upregulated compared with that in the vehicle group. Additionally, there was reduced retinal infiltration of T cells and macrophages, leading to improved clinical and histologic scores. AM administration also suppressed EAU-induced splenomegaly and increased the number of Tregs and M2 macrophages, possibly contributing to resolving inflammation. CONCLUSIONS: AM exerts an anti-inflammatory effect in uveitis by activating Tregs and M2 macrophages through RAMP2. Its administration is a potential adjunctive therapy for uveitis.