TRPV1 alleviates osteoarthritis by inhibiting M1 macrophage polarization via Ca2+/CaMKII/Nrf2 signaling pathway

Ziying Sun,Rui Wu,Yannick Xiaofan Yang,Shiro Ikegawa,Jia Xu,Zhongyang Lv,Hu Guo,Xingquan Xu,Jiawei Li,Qing Jiang,Dongquan Shi,Kuoyang Sun

doi:10.1038/s41419-021-03792-8

Abstract

Osteoarthritis (OA) is the major course of joint deterioration, in which M1 macrophage-driven synovitis exacerbates the pathological process. However, precise therapies for M1 macrophage to decrease synovitis and attenuate OA progression have been scarcely proposed. Transient receptor potential vanilloid 1 (TRPV1) is a cation channel that has been implicated in pain perception and inflammation. In this study, we investigated the role of TRPV1 in the M1 macrophage polarization and pathogenesis of OA. We demonstrated that 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. In the rat OA model, intra-articular injection of capsaicin (CPS), a specific TRPV1 agonist, significantly attenuated OA phenotypes, including joint swelling, synovitis, cartilage damage, and osteophyte formation. CPS treatment markedly reduced M1 macrophage infiltration in the synovium. Further mechanistic analyses showed that 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. Taken together, our findings establish that TRPV1 attenuates the progression of OA by inhibiting M1 macrophage polarization in synovium via the Ca2+/CaMKII/Nrf2 signaling pathway. These results highlight the effect of targeting TRPV1 for the development of a promising therapeutic strategy for OA.

Highlights

Osteoarthritis (OA) is the most common form of joint deterioration, manifesting several symptoms that weaken the quality of life, such as pain, joint stiffness, and dysfunction[1]
The proportion of cells positive for CD163 and CD206 (M2 macrophage markers) showed no significant difference among each group (Supplementary Fig. 1A–D). These results suggest that M1 but not M2 macrophages accumulate in OA synovium, accompanied by significantly increased Transient receptor potential vanilloid 1 (TRPV1) expression
Despite the TRPV1 activation, the expression of M1 macrophage markers at both the messenger RNA (mRNA) and protein levels was significantly increased after ethylenediaminetetraacetic acid (EDTA) treatment (Supplementary Fig. 5A, B). These findings suggest that Ca2+ influx resulting from TRPV1 activation plays an indispensable role in the activation of Nrf[2], which promotes the inhibition of M1 macrophage polarization

Summary

Introduction

Osteoarthritis (OA) is the most common form of joint deterioration, manifesting several symptoms that weaken the quality of life, such as pain, joint stiffness, and dysfunction[1]. OA increases socioeconomic burden due to growing prevalence and incidence[2]. There is no Synovial inflammation (synovitis) is highly correlated with the progression and severity of OA3,4. OA is well established as a low-grade inflammatory disease primarily mediated by the activity of innate immune cells, especially macrophages[5]. Macrophages can be generally classified as inflammatory M1 macrophages and antiinflammatory M2 macrophages[6]. Emerging evidence reveals that the M1 macrophage polarization in the synovium plays a critical role in the development of OA7,8. Conditional depletion of macrophages failed to mitigate OA and instead resulted in increased inflammatory cytokines in joint synovial fluid[9], highlighting the difficulty of targeting the highly complex

Methods

Results

Conclusion