TAGAP activates Th17 cell differentiation by promoting RhoA and NLRP3 to accelerate rheumatoid arthritis development

Abstract

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disorder that can give rise to joint swelling and inflammation, potentially affecting the entire body, closely linked to the state of T cells. The T-cell activation Rho GTPase activating protein (TAGAP) is associated with many autoimmune diseases including RA and is directly linked to the differentiation of Th17 cells. The present study intends to investigate the influence of TAGAP on the RA progression and its mechanism to empower new treatments for RA. A collagen-induced-arthritis (CIA) rat model was constructed, as well as the extraction of CD4+ T cells. RT-qPCR, H&E staining and safranin O/fast green staining revealed that TAGAP interference reduced TAGAP production in the ankle joint of CIA rats, and joint inflammation and swelling were alleviated, which reveals that TAGAP interference reduces synovial inflammation and cartilage erosion in the rat ankle joint. Expression of inflammatory factors (TNF-α, IL-1β, and IL-17) revealed that TAGAP interference suppressed the inflammatory response. Expression of pro-inflammatory cytokines, matrix-degrading enzymes, and anti-inflammatory cytokines at the mRNA level was detected by RT-qPCR and revealed that TAGAP interference contributed to the remission of RA. Mechanistically, TAGAP interference caused a significant decrease in the levels of RhoA and NLRP3. Assessment of Th17/Treg levels by flow cytometry revealed that TAGAP promotes Th17 cells differentiation and inhibits Treg cells differentiation in vitro and in vivo. In conclusion, TAGAP interference may decrease the differentiation of Th17 cells by suppressing the expression of RhoA and NLRP3 to slow down the RA progression.