Abstract
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 the epidermis (Mcpip1EKO). Mcpip1 loss in keratinocytes resulted in the upregulated expression of transcripts encoding factors related to inflammation and keratinocyte differentiation, such as IL-36α/γ cytokines, S100a8/a9 antibacterial peptides, and Sprr2d/2h proteins. Upon aging, the Mcpip1EKO mice showed impaired skin integrity that led to the progressive development of spontaneous skin pathology and systemic inflammation. Furthermore, we found that the lack of epidermal Mcpip1 expression impaired the balance of keratinocyte proliferation and differentiation. Overall, we provide evidence that keratinocyte-specific Mcpip1 activity is crucial for the maintenance of skin integrity as well as for the prevention of excessive local and systemic inflammation.
Key messages
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Loss of murine epidermal Mcpip1 upregulates transcripts related to inflammation and keratinocyte differentiation.
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Keratinocyte Mcpip1 function is essential to maintain the integrity of skin in adult mice.
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Ablation of Mcpip1 in mouse epidermis leads to the development of local and systemic inflammation.
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Acknowledgments
For the Krt14Cre mice, we are very thankful to Prof. Carien Niessen (Germany). We are grateful to the staff of the animal facility of the Faculty of Biochemistry, Biophysics and Biotechnology for help with animal breeding.
Funding
This research was supported by grants from the National Science Centre: PRELUDIUM 2014/13/N/NZ3/00729 (to P.K.) and OPUS 2016/23/B/NZ3/00792 (to J.J.). The Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University is a partner of the Leading National Research Centre (KNOW) supported by the Ministry of Science and Higher Education. W.D. was supported by the Flanders Institute for Biotechnology (VIB), a UGent grant (GOA-01G01914) and by Methusalem grant (BO16/MET_V/007, Ghent University).
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P.K. and A.L.-C. designed and performed the experiments, and analyzed the data. P.K. performed all the animal work and histological analyses. A.P., I.R., M.K., and M.M. performed RNA sequencing. P.Kw. and J.C performed and analyzed flow cytometry data. R.P., W.S., and J.B. helped with the experiments. W.D., M.D., and L.S.-B. contributed to data interpretation. M.F. contributed mice. A.L.-C. drafted the main manuscript text; P.K. and J.J. edited it. J.J. coordinated and supervised the project. All authors reviewed the final version of the manuscript.
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Konieczny, P., Lichawska-Cieslar, A., Kwiecinska, P. et al. Keratinocyte-specific ablation of Mcpip1 impairs skin integrity and promotes local and systemic inflammation. J Mol Med 97, 1669–1684 (2019). https://doi.org/10.1007/s00109-019-01853-2
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DOI: https://doi.org/10.1007/s00109-019-01853-2