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

doi:10.1007/s11684-019-0722-8

Front. Med.

2020, Vol. 14

Issue (3) : 305-317 https://doi.org/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

Jun Yang¹, Lianqing Wang^1,², Yingzhi Huang¹, Keqiang Liu¹, Chaoxia Lu¹, Nuo Si¹, Rongrong Wang¹, Yaping Liu¹(

), Xue Zhang¹(

)

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

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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 Ncstn^flox/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 Ncstn^flox/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

Corresponding Author(s): Yaping Liu,Xue Zhang

Just Accepted Date: 21 November 2019 Online First Date: 25 December 2019 Issue Date: 08 June 2020

Cite this article:

Jun Yang,Lianqing Wang,Yingzhi Huang, 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[J]. Front. Med., 2020, 14(3): 305-317.

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https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0722-8
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I3/305

Fig.1 Mouse mutant construction and verification. (A) Conditional Ncstn knockout strategy. (B) Primers used for genotyping the mice. (C) Agarose gel results showing the genotypes of the mice. K5-Cre mice were named WT. The cKO/cKO group was Ncstn^flox/flox;K5-Cre. The cKO/+ group corresponded to Ncstn^flox/+;K5-Cre. M, DNA marker (DL2000). (D) The knockout efficiency of Ncstn in the skin of WT and Ncstn^flox/flox;K5-Cre mice was determined at the mRNA level on P0 and P30. Data shown were mean±standard deviation (SD) of three independent experiments, and each experiment was performed in duplicate. Two asterisks denoted P<0.01. The ratio of Ncstn to b-actin in WT mice was set to 1. The (E) presence/absence and (F) quantification level of Ncstn protein in WT and Ncstn^flox/flox;K5-Cre mice skin were determined on P30. (G) Immunofluorescence staining results for Ncstn (green) and keratin 5 (red) in the skin of WT (a–c) and Ncstn^flox/flox;K5-Cre (d–f) mice on P30. Scale bar= 50? mm.

Fig.2 Phenotypic and pathophysiologic characterization of the mouse model. (A) The skin appearance of Ncstn^flox/flox;K5-Cre and WT mice at the indicated postnatal ages. (B) Hematoxylin- and eosin-stained skin sections on P15, P30, and P45. Scale bar= 50 mm. (C) mRNA expression of Notch1 in the skin of WT and Ncstn^flox/flox;K5-Cre mice on P0 and P30, ascertained by qRT-PCR. Data shown were mean±SD of three experiments, and each experiment was performed in duplicate. The ratio of Notch1 to b-actin in WT mice on P0 was set to 1. Two asterisks denoted P<0.01. Western blot was used to determine the (D) presence/absence and (E) quantification level of the cleaved Notch1 (NICD) in the mouse skin. Results of quantitative reverse-transcription polymerase chain reaction for (F) Il23a, (G) Tnf-a, (H) Il1b, and (I) Tlr4. Data shown were mean±SD of three experiments, and each experiment was performed in duplicate. The ratio of the gene of interest to b-actin in WT mice on P0 was set to 1.

Fig.3 Result of microarray analysis of Ncstn^flox/flox;K5-Cre mice. (A) The scatter plot on P0, P10, P15, P30, and P45 and (B) the hierarchical clustering map. (C) Three genes were screened from the intersection of four sets of data (P0, P10, P15, and P30) and intersected with the fifth set of data (P45), leaving only two differentially expressed genes.

Fig.4 Upregulation of IL-36a and LCN2 in the skin of the mouse model. Results of the quantitative reverse-transcription polymerase chain reaction and Western blot analysis of (A, B) IL-36a and (C, D) LCN2 expression in the skin of WT and Ncstn^flox/flox;K5-Cre mice on P0, P15, P30, and P45. Data shown were mean±SD of three independent experiments, and each experiment was performed in duplicate. The ratio of the gene of interest to b-actin in WT mice on P0 was set to 1. Immunohistochemistry results for (E) CD68 (a marker of macrophages) and CD11c (a marker of dendritic cells), (F) IL-36a and keratin 5 (markers of keratinocytes), (G) RORgt (a marker of Th17 cells and ILC3) and IL-17A, and (H) TNF-a on P30 in the skin of WT and Ncstn^flox/flox;K5-Cre mice. Arrows specify the positively stained areas. Scale bar= 50 mm. The cKO/cKO group corresponded to Ncstn^flox/flox;K5-Cre mice.

Fig.5 RNA-seq analysis of Ncstn^flox/flox;K5-Cre mice versus K5-cre mice on P0 and P30. (A) Heat clustering map; (B,C) enriched pathways; (D,E) enriched gene ontology terms; and (F,G) volcano plot.

Fig.6 Increased Sprr2dexpression in the skin of the AI mouse model. The mRNA expression level of the Sprr2 gene cluster in the skin of Ncstn^flox/flox;K5-Cre mice compared with that of WT mice at four stages (A–D). The ratio of the gene of interest to b-actin in WT mice on P0 was set to 1. Data shown were mean±SD of three experiments, and each experiment was performed in duplicate. The cKO/cKO group corresponded to Ncstn^flox/flox;K5-Cre mice.

Fig.7 Upregulation of SPRR2 in both NCSTN- and NOTCH1-downregulated HaCaT cells. siRNA-induced downregulation of (A, D) mRNA and (B, E) protein expression levels of NCSTN and NOTCH1 was depicted in HaCaT cells. Two asterisks denoted P<0.01. The ratio of the gene of interest to b-actin in the blank control was set to 1. The mRNA expression levels of IL-36a, LCN2, and SPRR2 were measured through quantitative reverse-transcription polymerase chain reaction in HaCaT cells in which (C) NCSTN or (F) NOTCH1 was knocked down. The ratio of the gene of interest to b-actin in the negative control was set to 1. Data shown were mean±SD of three experiments, and each experiment was performed in duplicate. NC, negative control. Blank, blank control.

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