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

Abstract

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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Fig. 1: TRPV1 deficiency exacerbates motor coordinative dysfunction and demyelination.
Fig. 2: Activation of TRPV1 enhances remyelination.
Fig. 3: TRPV1 is predominantly expressed in microglia in the homeostatic and demyelinating CNS.
Fig. 4: TRPV1 modulates the migration of microglia.
Fig. 5: TRPV1 function determines the clearance of myelin debris following demyelination.
Fig. 6: TRPV1 regulates microglial phagocytosis.
Fig. 7: The scavenger receptor CD36 is involved during TRPV1 activation.
Fig. 8: A summary of the findings of the current study.

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Acknowledgements

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.

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We follow the International Committee of Medical Journal Editors (ICMJE) recommendations for assigning the authorship. JW designed and coordinated the experiments. JXS and KYZ performed most experiments and wrote the manuscript with assistance from YMW, HS, IBC, MZZ and DJW. MZZ, ZFZ, XQZ and QYZ were involved in behavioral tests. RAH and JW supervised the study with scientific input (with contributions from YMW, SW and YF). All the authors reviewed and revised the manuscript.

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Correspondence to Robert A. Harris or Jun Wang.

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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 (2022). https://doi.org/10.1038/s41401-022-01000-7

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  • DOI: https://doi.org/10.1038/s41401-022-01000-7

Keywords

  • TRPV1
  • capsaicin
  • microglia
  • remyelination
  • phagocytosis

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