Sensory ASIC3 channel exacerbates psoriatic inflammation via a neurogenic pathway in female mice

Chen Huang, Pei-Yi Sun, Yiming Jiang, Yuandong Liu, Zhichao Liu, Shao-Ling Han, Bao-Shan Wang, Yong-Xin Huang, An-Ran Ren, Jian-Fei Lu, Qin Jiang, Ying Li, Michael X. Zhu, Zhirong Yao, Yang Tian, Xin Qi (), Wei-Guang Li () and Tian-Le Xu ()
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Chen Huang: Shanghai Jiao Tong University School of Medicine
Pei-Yi Sun: Shanghai Jiao Tong University School of Medicine
Yiming Jiang: Shanghai Jiao Tong University School of Medicine
Yuandong Liu: East China Normal University
Zhichao Liu: East China Normal University
Shao-Ling Han: Shanghai Jiao Tong University School of Medicine
Bao-Shan Wang: Shanghai Jiao Tong University School of Medicine
Yong-Xin Huang: Shanghai Jiao Tong University School of Medicine
An-Ran Ren: Shanghai Jiao Tong University School of Medicine
Jian-Fei Lu: Shanghai Jiao Tong University School of Medicine
Qin Jiang: Shanghai Jiao Tong University School of Medicine
Ying Li: Shanghai Jiao Tong University School of Medicine
Michael X. Zhu: The University of Texas Health Science Center at Houston
Zhirong Yao: Shanghai Jiao Tong University School of Medicine
Yang Tian: East China Normal University
Xin Qi: Shanghai Jiao Tong University School of Medicine
Wei-Guang Li: Shanghai Jiao Tong University School of Medicine
Tian-Le Xu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.

Date: 2024
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DOI: 10.1038/s41467-024-49577-3

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