TRPV1 alleviates osteoarthritis by inhibiting M1 macrophage polarization via CA2+/CAMKII/NRF2 signaling pathway

Abstract

Purpose: To investigate the role and regulatory mechanism of transient receptor potential vanilloid 1 (TRPV1) in the M1 macrophage polarization and pathogenesis of osteoarthritis (OA). Methods: The levels of TRPV1 and macrophage markers (F4/80 and iNOS) were analyzed in the synovium of OA patients and in a rat OA model (radial transection of the medial meniscus) by immunofluorescence and immunohistochemical staining. The role of TRPV1 was examined using the rat OA model by intra-articular injection of capsaicin (CPS), a specific TRPV1 agonist. The levels of hyperplasia and cell infiltration of synovium, osteophyte formation and cartilage damage were assessed by a synovitis score, micro-CT and the Osteoarthritis Research Society International score, respectively. RAW264.7 cells were used to explore the mechanisms of M1 macrophage polarization by TRPV1. Results: TRPV1 expression and M1 macrophage infiltration were simultaneously increased in both human and rat OA synovium. More than 90% of the infiltrated M1 macrophages expressed TRPV1. The intra-articular injection of CPS significantly attenuated OA phenotypes, including joint swelling, synovitis, cartilage damage, and osteophyte formation. CPS treatment markedly reduced M1 macrophage infiltration in the synovium. TRPV1-evoked Ca2+ influx promoted the phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) and facilitated the nuclear localization of nuclear factor-erythroid 2-related factor 2 (Nrf2), which ultimately resulted in the inhibition of M1 macrophage polarization. Conclusions: TRPV1 attenuates the progression of OA by inhibiting M1 macrophage polarization in synovium via the Ca2+/CaMKII/Nrf2 signaling pathway. TRPV1 can be a therapeutic target for synovitis in OA