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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 γ-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-1β, 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 involved in the malfunction of the skin barrier in the pathogenesis of AI.

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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; No. 81230015), and the Beijing Municipal Science and Technology Commission (No. Z151100003915078) for Xue Zhang and by the National NSFC (No. 31271345) for Yaping Liu.

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  1. The authors contributed equally to this work.

Authors and Affiliations

  1. McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China

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

  2. Center of Translational Medicine, Central Hospital of Zibo, Shandong University, Zibo, 255036, China

    Lianqing Wang

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  1. Jun Yang
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Correspondence to Yaping Liu or Xue Zhang.

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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).

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Yang, J., Wang, L., Huang, Y. et al. 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. 14, 305–317 (2020). https://doi.org/10.1007/s11684-019-0722-8

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