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J Mol Med (Berl). 2019 Nov 30. doi: 10.1007/s00109-019-01853-2. [Epub ahead of print]

Keratinocyte-specific ablation of Mcpip1 impairs skin integrity and promotes local and systemic inflammation.

Author information

1
Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.
2
Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.
3
Molecular Signaling and Cell Death Unit, VIB Center for Inflammation Research Center, Ghent, Belgium.
4
Department of Biomedical Molecular Biology, Ghent University, Technologiepark 71, 9052, Ghent, Belgium.
5
Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Marymoncka 99/103, 01-813, Warsaw, Poland.
6
Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
7
Department of Biomedical Science and Shock/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, 5100 Rockhill Rd, Kansas City, MO, 64110, USA.
8
Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.
9
Current address: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Rue Gabrielle Perret-Gentil 4, 1211, Geneva, Switzerland.
10
Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University de Barcelona, Gran Via de les Corts Catalanes 585, 08007, Barcelona, Spain.
11
Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland. jolanta.jura@uj.edu.pl.

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: Loss of murine epidermal Mcpip1 upregulates transcripts related to inflammation and keratinocyte differentiation. Keratinocyte Mcpip1 function is essential to maintain the integrity of skin in adult mice. Ablation of Mcpip1 in mouse epidermis leads to the development of local and systemic inflammation.

KEYWORDS:

MCPIP1; Regnase-1; Skin inflammation; ZC3H12A

PMID:
31786670
DOI:
10.1007/s00109-019-01853-2

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