The transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel that is activated by capsaicin (CAP), the main component of chili pepper. Despite studies in several neurological diseases, the role of TRPV1 in demyelinating diseases remains unknown. Herein, we reported that TRPV1 expression was increased within the corpus callosum during demyelination in a cuprizone (CPZ)-induced demyelination mouse model. TRPV1 deficiency exacerbated motor coordinative dysfunction and demyelination in CPZ-treated mice, whereas the TRPV1 agonist CAP improved the behavioral performance and facilitated remyelination. TRPV1 was predominantly expressed in Iba1+ microglia/macrophages in human brain sections of multiple sclerosis patients and mouse corpus callosum under demyelinating conditions. TRPV1 deficiency decreased microglial recruitment to the corpus callosum, with an associated increase in the accumulation of myelin debris. Conversely, the activation of TRPV1 by CAP enhanced the recruitment of microglia to the corpus callosum and potentiated myelin debris clearance. Using real-time live imaging we confirmed an increased phagocytic function of microglia following CAP treatment. In addition, the expression of the scavenger receptor CD36 was increased, and that of the glycolysis regulators Hif1a and Hk2 was decreased. We conclude that TRPV1 is an important regulator of microglial function in the context of demyelination and may serve as a promising therapeutic target for demyelinating diseases such as multiple sclerosis.
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This study was supported by the National Natural Science Foundation of China (82074538, 81671597), the Innovative Research Team of High-Level Local Universities in Shanghai (2019-2023), the Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01) and the Development Project of Shanghai Peak Disciplines-Integrated Chinese and Western Medicine. KZ was sponsored by China Scholarship Council (201700260280). We thank Meng Sun from Karolinska Institutet for the help with setting up IncuCyte. We thank Jingdian Zhang and Shengduo Pei from Karolinska Institutet for sharing experimental reagents and materials for pilot tests.
The authors declare no competing interests.
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Sun, Jx., Zhu, Ky., Wang, Ym. et al. Activation of TRPV1 receptor facilitates myelin repair following demyelination via the regulation of microglial function. Acta Pharmacol Sin 44, 766–779 (2023). https://doi.org/10.1038/s41401-022-01000-7