B7-H3 blockade decreases macrophage inflammatory response and alleviates clinical symptoms of arthritis

Abstract

Background: The costimulatory molecule B7-H3 is an immunoregulatory protein that plays an important role in the course of autoimmune diseases. It is also involved in the regulation of in ammatory responses in the body. Studies have shown that B7-H3 is highly expressed in peripheral blood monocytes of rheumatoid arthritis (RA) patients and its expression is closely related to the clinical parameters of the disease. In this study we aimed to determine what the implication of high B7-H3 expression for the disease severity in human RA and mouse model of arthritis is, and whether targeting this molecule could constitute a new therapeutic approach.Methods: We combined histopathological scoring of the joint cavity of collagen-induced arthritis (CIA) mice with immuno uorescent studies of B7-H3 expression on macrophages. We assessed the function of B7-H3 in relation with the pro-in ammatory role of macrophage through small RNA interference. Then we studied the molecular pathways liking B7-H3 with the pro-in ammatory activity of macrophages by multiplex ow cytometry, western blot and quantitative real-time PCR. The therapeutic bene t of anti-B7-H3 blocking was probed in mouse with CIA.Results: Histopathological and histological examination showed a positive correlation between expression of B7-H3 on macrophages and disease activity score, degree of destruction of the joint cavity, and pannus formation. It was also correlated with increased expression of the pro-in ammatory cytokine TNF-α in the joint cavity tissue and TNF-α level in peripheral serum. Knocking down B7-H3 expression through stable expression of small interfering RNA in human and mouse mononuclear phagocytic cell lines weakened the in ammatory response of the cells. Further molecular analyses indicated that the regulation of the in ammatory response through B7-H3 involved NF-κB signaling. Treatment of CIA mice with anti-B7-H3 reduced the clinical manifestation of arthritis and downregulated the expression of proin ammatory cytokines.Conclusions: We con rmed increased expression of B7-H3 in arthritis and established a positive correlation between disease severity and expression of B7-H3 on macrophages. Through functional approaches in vitro and in vivo, we also demonstrated the therapeutic bene ts of targeting B7-H3 for dampening macrophages' in ammatory responses in RA.