PTK6 regulates secretory cell production and innate immunity in a sex-dependent manner in the intestine

PTK6 regulates regeneration and repair of the intestinal epithelium. Analysis of publicly available datasets showed Ptk6 is upregulated in tuft cells upon activation of type 2 immunity. We found that disruption of Ptk6 influences gene expression involved in intestinal immune responses. Administration of succinate, which mimics infection and activates tuft cells, revealed PTK6-dependent activation of innate immune responses in male but not female mice. In contrast to wild type and Ptk6-/- female mice, Ptk6-/- male mice do not upregulate innate immunity or differentiation of secretory cell lineages following succinate treatment. Mechanistically, we found PTK6 regulates IL-25 expression and its effector functions, which are required for activation of type 2 innate immunity only in male mice. In patients with Crohn’s disease, PTK6 is upregulated in tuft cells in noninflamed regions of intestine. These data highlight roles for PTK6 in regulating sex differences in intestinal innate immunity and provide insight into the regulation of IL-25.