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Theranostics 2024; 14(4):1615-1630. doi:10.7150/thno.85214 This issue Cite

Research Paper

20-HETE mediated TRPV1 activation drives allokinesis via MrgprA3⁺ neurons in chronic dermatitis

Guang Yu^1,2*✉, Pei Liu^1*, Xiaobao Huang^3*, Mingxin Qi², Xue Li², Weimeng Feng¹, Erxin Shang¹, Yuan Zhou², Changming Wang², Yan Yang², Chan Zhu², Fang Wang³, Zongxiang Tang^2✉, Jinao Duan^1✉

1. 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.
2. Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
3. 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: yuguangedu.cn; Zongxiang Tang, E-mail: tangzxlabedu.cn; Jinao Duan, E-mail: djaedu.cn (J.D.).

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. Trigeminal TRPV1 channel and MrgprA3⁺ 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

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