Keratin 5-Cre-driven deletion of Ncstn in an acne inversa-like mouse model leads to a markedly increased IL-36a and Sprr2 expression

Jun Yang, Lianqing Wang, Yingzhi Huang, Keqiang Liu, Chaoxia Lu, Nuo Si, Rongrong Wang, Yaping Liu, Xue Zhang

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Front. Med. ›› 2020, Vol. 14 ›› Issue (3) : 305-317. DOI: 10.1007/s11684-019-0722-8
RESEARCH ARTICLE

Keratin 5-Cre-driven deletion of Ncstn in an acne inversa-like mouse model leads to a markedly increased IL-36a and Sprr2 expression

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Abstract

Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in g-secretase component genes. We and other researchers showed that nicastrin (NCSTN) is the most frequently mutated gene in familial AI. In this study, we generated a keratin 5-Cre-driven epidermis-specific Ncstn conditional knockout mutant in mice. We determined that this mutant recapitulated the major phenotypes of AI, including hyperkeratosis of hair follicles and inflammation. In Ncstnflox/flox;K5-Cre mice, the IL-36a expression level markedly increased starting from postnatal day 0 (P0), and this increase occurred much earlier than those of TNF-α, IL-23A, IL-1b, and TLR4. RNA-Seq analysis indicated that Sprr2d, a member of the small proline-rich protein 2 family, in the skin tissues of the Ncstnflox/flox;K5-Cre mice was also upregulated on P0. Quantitative reverse-transcription polymerase chain reaction showed that other Sprr2 genes had a similar expression pattern. Our findings suggested that IL-36a might be a key inflammatory cytokine in the pathophysiology of AI and implicate malfunction of the skin barrier in the pathogenesis of AI.

Keywords

acne inversa mouse model / interleukin 1 family, member 6 / small proline rich protein 2D / key inflammatory cytokine

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Jun Yang, Lianqing Wang, Yingzhi Huang, Keqiang Liu, Chaoxia Lu, Nuo Si, Rongrong Wang, Yaping Liu, Xue Zhang. Keratin 5-Cre-driven deletion of Ncstn in an acne inversa-like mouse model leads to a markedly increased IL-36a and Sprr2 expression. Front. Med., 2020, 14(3): 305‒317 https://doi.org/10.1007/s11684-019-0722-8

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Acknowledgements

This work was financially supported by the National Key Research and Development Program of China (No. 2016YFC0905100), the CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-1-002), the National Natural Science Foundation of China (NSFC; Nos. 81788101 and 81230015), and the Beijing Municipal Science and Technology Commission (No. Z151100003915078) for Xue Zhang and by the National NSFC (No. 31271345) for Yaping Liu.

Compliance with ethics guidelines

Jun Yang, Lianqing Wang, Yingzhi Huang, Keqiang Liu, Chaoxia Lu, Nuo Si, Rongrong Wang, Yaping Liu, and Xue Zhang state no conflict of interest. All animal studies and procedures were approved by the Institutional Animal Care and Use Committee of Peking Union Medical College (Beijing, China).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-019-0722-8 and is accessible for authorized users.

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2019 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature
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