IL-31 targets the hair follicle bulge across species and delays plucking-induced anagen in mice.

IL-31 is a type 2 cytokine best known for actions on sensory neurons, whereas its targets within skin epithelium remain incompletely defined. Here, reanalysis of public single-cell RNA-sequencing datasets, together with in situ hybridization, revealed that Il31ra is predominantly expressed in the bulge and secondary hair germ (sHG) of mouse hair follicles. In isolated mouse keratinocytes, recombinant IL-31 (rIL-31) induced region-specific JAK-STAT signaling-associated transcriptional responses in bulge cells. In vivo rIL-31 injection activated STAT3, STAT5, and ERK1/2 in the bulge and sHG of mouse hair follicles, and these responses were abolished in keratinocyte-specific Il31ra-deficient mice. Exogenous IL-31 delayed plucking-induced anagen in control mice but not in keratinocyte-specific Il31ra-deficient mice. Consistent with these findings, analysis of human scalp skin demonstrated that IL31RA is also predominantly localized to the bulge compartment. In normal human skin explants, rIL-31 activated STAT5 in the bulge compartment ex vivo. Together, these data identify the hair follicle bulge as a conserved epithelial target of IL-31 signaling and support a role for this pathway in modulating hair regeneration in mice.