Activation of CD81 <sup>+</sup> skin ILC2s by cold-sensing TRPM8 <sup>+</sup> neuron-derived signals maintains cutaneous thermal homeostasis
Ming Xu, Chao Li, Jie Yang, Amy Ye, Liping Yan, Beng San Yeoh, Lai Shi, Yu Shin Kim, Joonsoo Kang, Matam Vijay–Kumar, Na Xiong
Abstract
As the outermost barrier tissue of the body, the skin harbors a large number of innate lymphoid cells (ILCs) that help maintain local homeostasis in the face of changing environments. How skin-resident ILCs are regulated and function in local homeostatic maintenance is poorly understood. We here report the discovery of a cold-sensing neuron-initiated pathway that activates skin group 2 ILCs (ILC2s) to help maintain thermal homeostasis. In stearoyl-CoA desaturase 1 (SCD1) knockout mice whose skin is defective in heat maintenance, chronic cold stress induced excessive activation of CCR10 − CD81 + ST2 + skin ILC2s and associated inflammation. Mechanistically, stimulation of the cold-sensing receptor TRPM8 expressed in sensory neurons of the skin led to increased production of IL-18, which, in turn, activated skin ILC2s to promote thermogenesis. Our findings reveal a neuroimmune link that regulates activation of skin ILC2s to support thermal homeostasis and promotes skin inflammation after hyperactivation.