20-HETE mediated TRPV1 activation drives allokinesis via MrgprA3+ neurons in chronic dermatitis
Guang Yu1,2*, Pei Liu1*, Xiaobao Huang3*, Mingxin Qi2, Xue Li2, Weimeng Feng1, Erxin Shang1, Yuan Zhou2, Changming Wang2, Yan Yang2, Chan Zhu2, Fang Wang3, Zongxiang Tang2, Jinao Duan1
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China.
- Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
- Department of Dermatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
* Guang Yu, Pei Liu and Xiaobao Huang are co-first authors.
Corresponding author: Guang Yu, E-mail: yuguang@njucm.edu.cn; Zongxiang Tang, E-mail: tangzxlab@njucm.edu.cn; Jinao Duan, E-mail: dja@njucm.edu.cn (J.D.).
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Received: 2023.04.12; Accepted: 2024.01.26; Published: 2024.02.04
Abstract
Rationale: Noxious stimuli are often perceived as itchy in patients with chronic dermatitis (CD); however, itch and pain mechanisms of CD are not known.
Methods: TRPV1 involvement in CD was analyzed using a SADBE induced CD-like mouse model, and several loss- and gain-of-function mouse models. T rigeminal TRPV1 channel and Mrgpr A3+ neuron functions were analyzed by calcium imaging and whole-cell patch-clamp recordings. Lesional CD-like skin from mice were analyzed by unbiased metabolomic analysis. 20-HETE availability in human and mouse skin were determined by LC/MS and ELISA. And finally, HET0016, a selective 20-HETE synthase inhibitor, was used to evaluate if blocking skin TRPV1 activation alleviates CD-associated chronic itch or pain.
Results: While normally a pain inducing chemical, capsaicin induced both itch and pain in mice with CD condition. DREADD silencing of MrgprA3+ primary sensory neurons in these mice selectively decreased capsaicin induced scratching, but not pain-related wiping behavior. In the mice with CD condition, MrgprA3+ neurons showed elevated ERK phosphorylation. Further experiments showed that MrgprA3+ neurons from MrgprA3;Braf mice, which have constitutively active BRAF in MrgprA3+ neurons, were significantly more excitable and responded more strongly to capsaicin. Importantly, capsaicin induced both itch and pain in MrgprA3;Braf mice in an MrgprA3+ neuron dependent manner. Finally, the arachidonic acid metabolite 20-HETE, which can activate TRPV1, was significantly elevated in the lesional skin of mice and patients with CD. Treatment with the selective 20-HETE synthase inhibitor HET0016 alleviated itch in mice with CD condition.
Conclusion: Our results demonstrate that 20-HETE activates TRPV1 channels on sensitized MrgprA3+ neurons, and induces allokinesis in lesional CD skin. Blockade of 20-HETE synthesis or silencing of TRPV1-MrgprA3+ neuron signaling offers promising therapeutic strategies for alleviating CD-associated chronic itch.
Keywords: 20-HETE, TRPV1, allokinesis, MrgprA3+ neurons, chronic dermatitis