Abstract
Objective. The costimulatory molecule B7-H3 is an immunoregulatory protein, which 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, and whether targeting this molecule could constitute a new therapeutic approach. Methods. In this study we analyzed B7-H3 expression on macrophage in human RA and mouse model of arthritis and assessed the function of B7-H3 in relation with the pro-inflammatory role of macrophage through small RNA interference. Then we studied the molecular pathways liking B7-H3 with TNF-α. The therapeutic benefit of anti-B7-H3 blocking was probed in mouse with CIA. Results. We found a positive correlation between expression of B7-H3 on macrophages and disease activities, pathological evaluation and pro-inflammatory cytokine TNF-α. Knocking down B7-H3 expression weakened the inflammatory response of the mouse mononuclear phagocytic cell. Further molecular analyses indicated that the regulation of the inflammatory 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 pro-inflammatory cytokines. Conclusion. We confirmed 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 benefits of targeting B7-H3 for dampening macrophages’ inflammatory responses in RA.
Highlights
The costimulatory molecule B7-H3 is an immunoregulatory protein that plays an important role in the course of autoimmune diseases
We studied the effects of reduced B7-H3 expression on the cellular inflammatory response and related signaling pathways through in vitro experiments, and we treated collagen-induced arthritis (CIA) mice with anti-B7-H3 in vivo to explore the possible role of this molecule in rheumatoid arthritis (RA) treatment
3.1 B7-H3 was highly expressed on macrophages in synovial tissue of RA patients and CIA mice
Summary
The costimulatory molecule B7-H3 is an immunoregulatory protein that plays an important role in the course of autoimmune diseases It is involved in the regulation of inflammatory responses in the body. Rheumatoid arthritis (RA) is an autoimmune disease with symmetric polyarthritis as its main clinical manifestation. It is the most common autoimmune disease, and it is characterized by massive inflammatory cell infiltration, abnormal hyperplasia of synovial tissue, and progressive destruction of articular cartilage and bone [1]. The long-lasting and repeated attacks of inflammation lead to the destruction of cartilage and bone in the joints, dysfunction of joints, and even physical disability. Its pathogenesis has not been fully elucidated, and it still lacks specific treatment [3]
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