Keratinocyte expression of Mcpip1 is essential for the maintenance of skin integrity and for the control of local and systemic inflammation

MCPIP1 (Regnase-1, encoded by the ZC3H12A gene) regulates the mRNA stability of several inflammatory cytokines. Due to the critical role of this RNA endonuclease in the suppression of inflammation, Mcpip1 deficiency in mice leads to the development of postnatal multiorgan inflammation and premature death. Here, we generated mice with conditional deletion of Mcpip1 in keratinocytes (K14CreMcpip1fl/fl, herein Mcpip1EKO). These mice progressively developed spontaneous skin pathology with neutrophil-dominated systemic inflammation. We attributed this phenotype to the elevated levels of keratinocyte-specific Il36a/Il36? and S100a8/a9 transcripts, and transient activation of Il6, Tnfa and Il33 cytokine genes specifically in the skin of the Mcpip1EKO mice. Furthermore, we showed that epidermal expression of Mcpip1 ensures proper keratinocyte proliferation and differentiation balance. Overall, we provide evidence that keratinocyte-specific Mcpip1 function is crucial for the maintenance of skin integrity as well as for prevention of local and systemic inflammatory overactivity.