Inhibition of the alternative pathway of complement activation reduces inflammation in experimental autoimmune uveoretinitis

We have shown previously that complement factor H (CFH) and complement factor B (CFB) are constitutively expressed by retinal pigment epithelial cells and their production is regulated by inflammatory cytokines, suggesting that the alternative pathway (AP) of complement activation might play a role in retinal inflammation. In this study, we further investigated the role of the AP in retinal inflammation using experimental autoimmune uveoretinitis (EAU) as a model. Mice with EAU show increased levels of C3d deposition and CFB expression in the retina. Retinal inflammation was suppressed clinically and histologically by blocking AP‐mediated complement activation with a complement receptor of the Ig superfamily fusion protein (CRIg‐Fc). In line with reduced inflammation, C3d deposition and CFB expression were markedly decreased by CRIg‐Fc treatment. Treatment with CRIg‐Fc also led to reduced T‐cell proliferation and IFN‐γ, TNF‐α, IL‐17, and IL‐6 cytokine production by T cells, and reduced nitric oxide production in BM‐derived macrophages. Our results suggest that AP‐mediated complement activation contributes significantly to retinal inflammation in EAU. CRIg‐Fc suppressed retinal inflammation in EAU by blocking AP‐mediated complement activation with probable direct effects on C3/C5 activation of macrophages, thus leading to reduced nitric oxide production by infiltrating CRIg^? macrophages.