Activation of TRPV1 receptor facilitates myelin repair following demyelination via the regulation of microglial function

Jing-xian Sun1, Ke-ying Zhu2, Yu-meng Wang1, Dan-jie Wang1, Mi-zhen Zhang1, Heela Sarlus2, Irene Benito-Cuesta2, Xiao-qiang Zhao1, Zao-feng Zou1,3, Qing-yang Zhong1, Yi Feng1, Shuai Wu4, Yan-qing Wang1, Robert A. Harris2, Jun Wang1
1 Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, China
2 Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital at Solna, Stockholm, Sweden
3 Department of General Surgery, Jiading Hospital of Traditional Chinese Medicine, Shanghai 201800, China
4 Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Correspondence to: Robert A. Harris:, Jun Wang:,
DOI: 10.1038/s41401-022-01000-7
Received: 27 March 2022
Accepted: 12 September 2022
Advance online: 13 October 2022


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.
Keywords: TRPV1; capsaicin; microglia; remyelination; phagocytosis

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