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Activation of CD81+ skin ILC2s by cold-sensing TRPM8+ neuron-derived signals maintains cutaneous thermal homeostasis

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. Description Skin-resident ILC2s are activated by signals from cold-sensing neurons to aid in regulation of thermal homeostasis in skin. Skin ILC2s turn up the heat Skin is a critical barrier tissue that supports organismal homeostasis through multiple pathways including maintenance of skin temperature in cold environments. Xu et al. analyzed how defects in the skin lipid barrier of stearoyl-CoA desaturase-1 (SCD-1) knockout mice that impaired maintenance of thermal homeostasis led to increased skin inflammation. Cold ambient temperatures activated TRPM8+ sensory neurons, triggering increased release of IL-18 and activation of dermal group 2 innate lymphoid cells (ILC2s). The activated ILC2s, in turn, released IL-5 enhancing expression of uncoupling protein-1 (UCP1) by dermal cells, resulting in increased thermogenesis. The neuroimmune circuit identified in this study that connects cold sensing to activation of skin ILC2s provides fresh mechanistic insights into how changes in environmental temperatures can regulate the inflammatory tone of the skin.