High-sensitive sensory neurons exacerbate rosacea-like dermatitis in mice by activating γδ T cells directly

• Published in: Nature communications Vol. 15; no. 1; pp. 7265 - 15
• Main Authors: Zhang, Yiya, Li, Tao, Zhao, Han, Xiao, Xin, Hu, Ximin, Wang, Ben, Huang, Yingxue, Yin, Zhinan, Zhong, Yun, Li, Yangfan, Li, Ji
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14/19; 14/69; 38/77; 631/250/1619/554/2509; 631/250/347; 631/250/371; 692/699/4033; 82/58; Ablation; Animals; Calcitonin gene-related peptide; Calcitonin Gene-Related Peptide - metabolism; Capsaicin; Capsaicin - pharmacology; Dermatitis; Dermatitis - immunology; Dermatitis - metabolism; Dermatitis - pathology; Disease Models, Animal; Effectiveness; Humanities and Social Sciences; Humans; Hypersensitivity; Interleukin-17 - immunology; Interleukin-17 - metabolism; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Neuropeptides; Nociceptors; Nociceptors - metabolism; Pain perception; Receptor activity modifying proteins; Receptors; Receptors, Antigen, T-Cell, gamma-delta - genetics; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Receptors, Calcitonin Gene-Related Peptide - metabolism; Rosacea; Rosacea - immunology; Science; Science (multidisciplinary); Sensory neurons; Sensory Receptor Cells - metabolism; Skin - immunology; Skin - metabolism; Skin - pathology; Skin diseases; Skin lesions; Stimulation; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50970-1

Rosacea patients show facial hypersensitivity to stimulus factors (such as heat and capsaicin); however, the underlying mechanism of this hyperresponsiveness remains poorly defined. Here, we show capsaicin stimulation in mice induces exacerbated rosacea-like dermatitis but has no apparent effect on normal skin. Nociceptor ablation substantially reduces the hyperresponsiveness of rosacea-like dermatitis. Subsequently, we find that γδ T cells express Ramp1, the receptor of the neuropeptide CGRP, and are in close contact with these nociceptors in the skin. γδ T cells are significantly increased in rosacea skin lesions and can be further recruited and activated by neuron-secreted CGRP. Rosacea-like dermatitis is reduced in T cell receptor δ-deficient (Tcrd −/− ) mice, and the nociceptor-mediated aggravation of rosacea-like dermatitis is also reduced in these mice. In vitro experiments show that CGRP induces IL17A secretion from γδ T cells by regulating inflammation-related and metabolism-related pathways. Finally, rimegepant, a CGRP receptor antagonist, shows efficacy in the treatment of rosacea-like dermatitis. In conclusion, our findings demonstrate a neuron-CGRP-γδT cell axis that contributes to the hyperresponsiveness of rosacea, thereby showing that targeting CGRP is a potentially effective therapeutic strategy for rosacea. Rosacea is a common chronic inflammatory cutaneous disease that is exacerbated by heat and capsaicin pepper stimulation. Here the authors use a mouse model of rosacea and demonstrate functions of nociceptors, response to the neuropeptide CGRP and involvement of γδ T cells in the aggravation of rosacea like-disease.