{"title":"IL-38 通过促进朗格汉斯细胞迁移加重特应性皮炎","authors":"Chengcheng Yue, Yawen Hu, Jiadong Yu, Hong Zhou, Pei Zhou, Jing Hu, Xiaoyan Wang, Linna Gu, Ya Li, Yuting Feng, Fanlian Zeng, Fulei Zhao, Guolin Li, Qixiang Zhao, Chen Zhang, Huaping Zheng, Wenling Wu, Xinai Cui, Nongyu Huang, Zhen Wang, Kaijun Cui, Jiong Li","doi":"10.7150/ijbs.93843","DOIUrl":null,"url":null,"abstract":"<p><p>Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a poorly characterized IL-1 family cytokine, its role and mechanism in the pathogenesis of AD is elusive. Here, we show that IL-38 is mainly secreted by epidermal keratinocytes and highly expressed in the skin and downregulated in AD lesions. We generated IL-38 keratinocyte-specific knockout mice (<i>K14<sup>Cre/+</sup>-IL-38<sup>f/f</sup></i> ) and induced AD models by 2,4-dinitrofluorobenzene (DNFB). Unexpectedly, after treatment with DNFB, <i>K14<sup>Cre/+</sup>-IL-38<sup>f/f</sup></i> mice were less susceptible to cutaneous inflammation of AD. Moreover, keratinocyte-specific deletion of IL-38 suppressed the migration of Langerhans cells (LCs) into lymph nodes which results in disturbed differentiation of CD4<sup>+</sup>T cells and decreased the infiltration of immune cells into AD lesions. LCs are a type of dendritic cell that reside specifically in the epidermis and regulate immune responses. We developed LC-like cells <i>in vitro</i> from mouse bone marrow (BM) and treated with recombined IL-38. The results show that IL-38 depended on IL-36R, activated the phosphorylated expression of IRAK4 and NF-κB P65 and upregulated the expression of CCR7 to promoting the migration of LCs, nevertheless, the upregulation disappeared with the addition of IL-36 receptor antagonist (IL-36RA), IRAK4 or NF-κB P65 inhibitor. Furthermore, after treatment with IRAK4 inhibitors, the experimental AD phenotypes were alleviated and so IRAK4 is considered a promising target for the treatment of inflammatory diseases. Overall, our findings indicated a potential pathway that IL-38 depends on IL-36R, leading to LCs migration to promote AD by upregulating CCR7 via IRAK4/NF-κB and implied the prevention and treatment of AD, supporting potential clinical utilization of IRAK4 inhibitors in AD treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2000,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186352/pdf/","citationCount":"0","resultStr":"{\"title\":\"IL-38 Aggravates Atopic Dermatitis via Facilitating Migration of Langerhans cells.\",\"authors\":\"Chengcheng Yue, Yawen Hu, Jiadong Yu, Hong Zhou, Pei Zhou, Jing Hu, Xiaoyan Wang, Linna Gu, Ya Li, Yuting Feng, Fanlian Zeng, Fulei Zhao, Guolin Li, Qixiang Zhao, Chen Zhang, Huaping Zheng, Wenling Wu, Xinai Cui, Nongyu Huang, Zhen Wang, Kaijun Cui, Jiong Li\",\"doi\":\"10.7150/ijbs.93843\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a poorly characterized IL-1 family cytokine, its role and mechanism in the pathogenesis of AD is elusive. Here, we show that IL-38 is mainly secreted by epidermal keratinocytes and highly expressed in the skin and downregulated in AD lesions. We generated IL-38 keratinocyte-specific knockout mice (<i>K14<sup>Cre/+</sup>-IL-38<sup>f/f</sup></i> ) and induced AD models by 2,4-dinitrofluorobenzene (DNFB). Unexpectedly, after treatment with DNFB, <i>K14<sup>Cre/+</sup>-IL-38<sup>f/f</sup></i> mice were less susceptible to cutaneous inflammation of AD. Moreover, keratinocyte-specific deletion of IL-38 suppressed the migration of Langerhans cells (LCs) into lymph nodes which results in disturbed differentiation of CD4<sup>+</sup>T cells and decreased the infiltration of immune cells into AD lesions. LCs are a type of dendritic cell that reside specifically in the epidermis and regulate immune responses. We developed LC-like cells <i>in vitro</i> from mouse bone marrow (BM) and treated with recombined IL-38. The results show that IL-38 depended on IL-36R, activated the phosphorylated expression of IRAK4 and NF-κB P65 and upregulated the expression of CCR7 to promoting the migration of LCs, nevertheless, the upregulation disappeared with the addition of IL-36 receptor antagonist (IL-36RA), IRAK4 or NF-κB P65 inhibitor. Furthermore, after treatment with IRAK4 inhibitors, the experimental AD phenotypes were alleviated and so IRAK4 is considered a promising target for the treatment of inflammatory diseases. Overall, our findings indicated a potential pathway that IL-38 depends on IL-36R, leading to LCs migration to promote AD by upregulating CCR7 via IRAK4/NF-κB and implied the prevention and treatment of AD, supporting potential clinical utilization of IRAK4 inhibitors in AD treatment.</p>\",\"PeriodicalId\":13762,\"journal\":{\"name\":\"International Journal of Biological Sciences\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2024-05-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186352/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Biological Sciences\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.7150/ijbs.93843\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Biological Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.7150/ijbs.93843","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
特应性皮炎(AD)是一种常见的炎症性皮肤病,涉及免疫细胞和角质形成细胞之间的相互作用失调。白细胞介素-38(IL-38)是一种表征不清的 IL-1 家族细胞因子,其在特应性皮炎发病机制中的作用和机制尚不明确。在这里,我们发现 IL-38 主要由表皮角质细胞分泌,在皮肤中高表达,在 AD 病变中下调。我们产生了IL-38角质细胞特异性基因敲除小鼠(K14Cre/+-IL-38f/f),并用2,4-二硝基氟苯(DNFB)诱导了AD模型。出乎意料的是,经 DNFB 处理后,K14Cre/+-IL-38f/f 小鼠对 AD 皮肤炎症的敏感性降低。此外,IL-38的角质细胞特异性缺失抑制了朗格汉斯细胞(LCs)向淋巴结的迁移,从而导致CD4+T细胞的分化紊乱,并减少了免疫细胞对AD病变的浸润。LCs是一种树突状细胞,专门驻留在表皮并调节免疫反应。我们从小鼠骨髓(BM)中体外培养出LC样细胞,并用重组的IL-38处理。结果表明,IL-38依赖于IL-36R,能激活IRAK4和NF-κB P65的磷酸化表达,并上调CCR7的表达,从而促进LCs的迁移,但加入IL-36受体拮抗剂(IL-36RA)、IRAK4或NF-κB P65抑制剂后,上调作用消失。此外,用IRAK4抑制剂治疗后,实验性AD表型得到缓解,因此IRAK4被认为是治疗炎症性疾病的一个有希望的靶点。总之,我们的研究结果表明了一种潜在的途径,即IL-38依赖于IL-36R,通过IRAK4/NF-κB上调CCR7,导致LCs迁移以促进AD,并暗示了IRAK4抑制剂在AD预防和治疗中的潜在临床应用。
IL-38 Aggravates Atopic Dermatitis via Facilitating Migration of Langerhans cells.
Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a poorly characterized IL-1 family cytokine, its role and mechanism in the pathogenesis of AD is elusive. Here, we show that IL-38 is mainly secreted by epidermal keratinocytes and highly expressed in the skin and downregulated in AD lesions. We generated IL-38 keratinocyte-specific knockout mice (K14Cre/+-IL-38f/f ) and induced AD models by 2,4-dinitrofluorobenzene (DNFB). Unexpectedly, after treatment with DNFB, K14Cre/+-IL-38f/f mice were less susceptible to cutaneous inflammation of AD. Moreover, keratinocyte-specific deletion of IL-38 suppressed the migration of Langerhans cells (LCs) into lymph nodes which results in disturbed differentiation of CD4+T cells and decreased the infiltration of immune cells into AD lesions. LCs are a type of dendritic cell that reside specifically in the epidermis and regulate immune responses. We developed LC-like cells in vitro from mouse bone marrow (BM) and treated with recombined IL-38. The results show that IL-38 depended on IL-36R, activated the phosphorylated expression of IRAK4 and NF-κB P65 and upregulated the expression of CCR7 to promoting the migration of LCs, nevertheless, the upregulation disappeared with the addition of IL-36 receptor antagonist (IL-36RA), IRAK4 or NF-κB P65 inhibitor. Furthermore, after treatment with IRAK4 inhibitors, the experimental AD phenotypes were alleviated and so IRAK4 is considered a promising target for the treatment of inflammatory diseases. Overall, our findings indicated a potential pathway that IL-38 depends on IL-36R, leading to LCs migration to promote AD by upregulating CCR7 via IRAK4/NF-κB and implied the prevention and treatment of AD, supporting potential clinical utilization of IRAK4 inhibitors in AD treatment.
期刊介绍:
The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.