High-sensitive sensory neurons exacerbate rosacea-like dermatitis in mice by activating γδ T cells directly
Yiya Zhang, Tao Li, Han Zhao, X. Y. Xiao, Ximin Hu, Ben Wang, Yingxue Huang, Zhinan Yin, Yun Zhong, Yangfan Li, Ji Li
Abstract
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.