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

Sci Immunol. 2022 Jun 24;7(72):eabe0584. doi: 10.1126/sciimmunol.abe0584. Epub 2022 Jun 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Homeostasis
  • Immunity, Innate*
  • Inflammation
  • Lymphocytes
  • Mice
  • Neurons
  • TRPM Cation Channels* / genetics


  • TRPM Cation Channels
  • TRPM8 protein, mouse