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TRPV1+ sensory nerves modulate corneal inflammation after epithelial abrasion via RAMP1 and SSTR5 signaling

Abstract

Timely initiation and termination of inflammatory response after corneal epithelial abrasion is critical for the recovery of vision. The cornea is innervated with rich sensory nerves with highly dense TRPV1 nociceptors. However, the roles of TRPV1+ sensory neurons in corneal inflammation after epithelial abrasion are not completely understood. Here, we found that depletion of TRPV1+ sensory nerves using resiniferatoxin (RTX) and blockade of TRPV1 using AMG-517 delayed corneal wound closure and enhanced the infiltration of neutrophils and γδ T cells to the wounded cornea after epithelial abrasion. Furthermore, depletion of TRPV1+ sensory nerves increased the number and TNF-α production of corneal CCR2+ macrophages and decreased the number of corneal CCR2 macrophages and IL-10 production. In addition, the TRPV1+ sensory nerves inhibited the recruitment of neutrophils and γδ T cells to the cornea via RAMP1 and SSTR5 signaling, decreased the responses of CCR2+ macrophages via RAMP1 signaling, and increased the responses of CCR2 macrophages via SSTR5 signaling. Collectively, our results suggest that the TRPV1+ sensory nerves suppress inflammation to support corneal wound healing via RAMP1 and SSTR5 signaling, revealing potential approaches for improving defective corneal wound healing in patients with sensory neuropathy.

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Fig. 1: Effects of resiniferatoxin (RTX) treatment on corneal wound healing.
Fig. 2: Effects of resiniferatoxin (RTX) treatment on transcriptomic profiles of wounded corneas.
Fig. 3: Effects of ablation of TRPV1+ sensory nerves on corneal inflammation after epithelial abrasion.
Fig. 4: Influence of TRPV1 blockade on corneal wound healing and inflammation after epithelial abrasion.
Fig. 5: Analysis of the signaling of TRPV1+ sensory nerves suppressing the responses of neutrophils and γδ T cells in the cornea.
Fig. 6: Effect of TRPV1+ sensory nerves on the responses of corneal macrophages.
Fig. 7: Effect of calcitonin gene-related peptide (CGRP) or L-817,818 on corneal wound healing in resiniferatoxin (RTX)-treated mice.
Fig. 8: Model showing how TRPV1+ sensory nerves modulate corneal inflammation after corneal injury.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China through Grants 82171014 (to Z.L.), 32100715 (to J.L.), and 81770962 (to Z.L.), the Science and Technology Program of Guangzhou of China through Grant 202102020002 (to J.L.), and the PhD Start-up Fund of the Natural Science Foundation of Guangdong Province of China through Grant 2018A030310605 (to J.L.).

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Z.L. and J.L. conceived and designed the study. S.H. analyzed immunostaining and performed qPCR. R.Y., X.C., F.L., X.S., and P.X. helped with treatment of the animals, including the establishment of corneal injured model and drug treatment. J.L. performed flow cytometry analysis. Y.H., Y.X., and T.F. conducted the statistical analysis. J.L. drafted the first version of the paper. Z.L. critically reviewed and revised the paper for intellectual content. All authors critiqued the manuscript and approved its submission.

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Correspondence to Zhijie Li.

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Liu, J., Huang, S., Yu, R. et al. TRPV1+ sensory nerves modulate corneal inflammation after epithelial abrasion via RAMP1 and SSTR5 signaling. Mucosal Immunol 15, 867–881 (2022). https://doi.org/10.1038/s41385-022-00533-8

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