Activation of skin-resident group 2 innate lymphoid cells by cold-sensing TRPM8+ neuron-derived signals in thermo-homeostatic regulation and tissue inflammation

Abstract

Abstract Innate lymphoid cells (ILCs) in the skin are a heterogeneous population of innate lymphocytes that function in local homeostatic regulation but could also cause inflammation. How homeostatic versus inflammatory functions of skin ILCs are regulated is poorly understood. To explore this question, we analyzed gene expression profiles of skin ILCs of wild-type and Rag1−/− mice and discovered that the chemokine receptor CCR10+ skin ILCs dominant in the health skin were of homeostatic properties while CCR10− skin ILCs are activated effector cells with elevated expression of various stimulatory cytokine receptors and signaling molecules. In stearoyl-CoA desaturase 1-knockout (KO) mice whose skin was defective in thermohomeostatic maintenance due to impaired fatty acid synthesis and lipid barrier formation, there was predominant activation of CCR10−CD81+ST2+ group 2 ILCs (ILC2s) while raising these mice at a thermo-neutral room temperature or feeding them with high-fat diet reduced the ILC2 activation, suggesting that skin ILC2s are activated by cold-induced signals to help thermo-homeostatic maintenance. Consistent with this, topical application of menthol, an agonist ligand for the cold-sensing receptor TRPM8, led to activation of CCR10−CD81+ST2+ skin ILC2s and increased dermal adipocyte maturation and uncoupling protein 1 production. Furthermore, compared to wild-type controls, menthol-treated TRPM8-KO and IL-18-KO mice had reduced CCR10−CD81+ activated skin ILC2s, suggesting that IL-18 mediated the TRPM8 activation of skin ILC2s. Our study reveals a neuron-derived cold-sensing pathway in activation of skin ILC2s that helps thermo-regulation but could also cause tissue inflammation if chronically activated.