TRPV1 channel mediates NLRP3 inflammasome-dependent neuroinflammation in microglia

Yahui Zhang,Peiyu Liang,Biwen Peng,Yuanteng Fan,Baohua Hou,Xiaohua He,Xinyi Zhang,Yifan Wu,Taoxiang Chen,Song Han,Wanhong Liu,Xin Lu,Jun Yin,Yumin Liu

doi:10.1038/s41419-021-04450-9

Abstract

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease in the central nervous system (CNS). The NLRP3 inflammasome is considered an important regulator of immunity and inflammation, both of which play a critical role in MS. However, the underlying mechanism of NLRP3 inflammasome activation is not fully understood. Here we identified that the TRPV1 (transient receptor potential vanilloid type 1) channel in microglia, as a Ca2+ influx-regulating channel, played an important role in NLRP3 inflammasome activation. Deletion or pharmacological blockade of TRPV1 inhibited NLRP3 inflammasome activation in microglia in vitro. Further research revealed that TRPV1 channel regulated ATP-induced NLRP3 inflammasome activation through mediating Ca2+ influx and phosphorylation of phosphatase PP2A in microglia. In addition, TRPV1 deletion could alleviate mice experimental autoimmune encephalomyelitis (EAE) and reduce neuroinflammation by inhibiting NLRP3 inflammasome activation. These data suggested that the TRPV1 channel in microglia can regulate NLRP3 inflammasome activation and consequently mediate neuroinflammation. Meanwhile, our study indicated that TRPV1–Ca2+–PP2A pathway may be a novel regulator of NLRP3 inflammasome activation, pointing to TRPV1 as a potential target for CNS inflammatory diseases.

Highlights

Multiple sclerosis is a chronic neurodegenerative autoimmune disease of the central nervous system (CNS) that affects millions of people worldwide [1, 2].Experimental autoimmune encephalomyelitis (EAE) is one of the most widely used animal models to study MS
To investigate the role of TRPV1 in neuroinflammation in vivo, we checked the expression of TRPV1 in the spinal cord tissues of EAE mice, and found that TRPV1 protein level was much higher in EAE mice than that in control mice (Fig. 1D, E) and TRPV1 was mainly located in Iba-1-positive microglia in EAE mice (Fig. 1F)
These data showed that TRPV1 expressed on the plasma membrane of microglia was upregulated during neuroinflammation in vitro and in vivo, suggesting that TRPV1 might play a functional role in regulating neuroinflammation

Summary

INTRODUCTION

Multiple sclerosis is a chronic neurodegenerative autoimmune disease of the CNS that affects millions of people worldwide [1, 2]. Recent studies have indicated that calcium influx or mobilization is critical for NLRP3 inflammasome activation, and TRPM2, TRPA1, and TRPV2 was the involved ion channel mediating calcium influx in the different stressed conditions [23, 24, 26,27,28]. It is unclear whether there is any other TRP channel responsible for NLRP3 inflammasome activation in microglia.

MATERIALS AND METHODS

RESULTS

DISCUSSION