Zhang Yuanyuan, Jia Weixue, Wang Xue, Mao Qiuxia, Luo Lingling, Kong Lingzhuo, Guo Youming, Mo Ran, Bu Wenbo, Li Chengrang
Hospital for Skin Diseases (Institute of Dermatology), Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, 210042, China.
Department of Dermatology and Venereology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210008, China.
Heliyon. 2024 May 23;10(11):e31509. doi: 10.1016/j.heliyon.2024.e31509. eCollection 2024 Jun 15.
Acne inversa (AI) is an inflammatory skin disease associated with nicastrin (NCSTN) mutations. Despite the dysregulated bacterial-host immune interactions being an essential event in AI, the interaction between bacteria and keratinocytes in AI pathophysiology remains unclear. In this study, the NCSTN gene was suppressed using short hairpin RNA in HaCaT cells. Using RNA sequencing, real-time polymerase chain reaction, and western blotting, the expression of IL-36 cytokines was analyzed. The impact of on AI keratinocyte inflammation and underlying regulatory molecules was investigated by exposing the HaCaT cells to . By stimulating NCSTN knockdown HaCaT cells with IFN-γ, the expression and regulatory mechanism of Cathepsin S (Cat S), an IL-36γ cleavage and activating protease, were investigated. After NCSTN knockdown, the IL-36α expression increased, and the IL-36Ra expression was downregulated. NCSTN/MEK/ERK impairment-induced Krüppel-like factor 4 (KLF4) up-regulation in concert with -induced nuclear factor kappa B elevation acts synergistically to promote IL-36γ production with the subsequent IL-8 activation in HaCaT cells. NCSTN/MEK/ERK impairment was also observed in familial AI lesions. IFN-γ-induced Cat S in keratinocytes was enhanced after NCSTN knockdown. The expression of IFN-II pathway molecules was significantly upregulated in both NCSTN knockdown HaCaT cells and familial AI lesions. The Cat S expression was significantly elevated in the patient's AI lesions. Our findings suggested a synergistic relationship between and NCSTN/MAPK/KLF4 axis in IL-36γ-induced familial AI keratinocytes.
反向性痤疮（AI）是一种与尼卡斯特林（NCSTN）突变相关的炎症性皮肤病。尽管细菌与宿主免疫相互作用失调是AI中的一个关键事件，但AI病理生理学中细菌与角质形成细胞之间的相互作用仍不清楚。在本研究中，使用短发夹RNA在HaCaT细胞中抑制NCSTN基因。通过RNA测序、实时聚合酶链反应和蛋白质印迹分析白细胞介素-36（IL-36）细胞因子的表达。通过将HaCaT细胞暴露于……来研究……对AI角质形成细胞炎症和潜在调节分子的影响。通过用γ干扰素刺激NCSTN基因敲低的HaCaT细胞，研究组织蛋白酶S（Cat S，一种IL-36γ裂解和激活蛋白酶）的表达及调节机制。NCSTN基因敲低后，IL-36α表达增加，IL-36Ra表达下调。NCSTN/丝裂原活化蛋白激酶/细胞外信号调节激酶（MEK/ERK）损伤诱导的Krüppel样因子4（KLF4）上调与……诱导的核因子κB升高协同作用，促进HaCaT细胞中IL-36γ的产生及随后的IL-8激活。在家族性AI病变中也观察到NCSTN/MEK/ERK损伤。NCSTN基因敲低后，角质形成细胞中γ干扰素诱导的Cat S增强。在NCSTN基因敲低的HaCaT细胞和家族性AI病变中，IFN-II途径分子的表达均显著上调。患者AI病变中Cat S表达显著升高。我们的研究结果表明，在IL-36γ诱导的家族性AI角质形成细胞中，……与NCSTN/丝裂原活化蛋白激酶/蛋白激酶B（MAPK）/KLF4轴之间存在协同关系。
