HMGB1-mediated chromatin remodeling attenuates Il24 gene expression for the protection from allergic contact dermatitis
HMGB1-mediated chromatin remodeling attenuates Il24 gene expression for the protection from allergic contact dermatitis
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DOI：
10.1073/pnas.2022343118
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发表时间：
2020-12
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通讯作者：
Naoyuki Senda;H. Yanai;Sana Hibino;Lei Li;Y. Mizushima;T. Miyagaki;Mai Saeki;Y. Kishi;S. Hangai
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作者：
Naoyuki Senda;H. Yanai;Sana Hibino;Lei Li;Y. Mizushima;T. Miyagaki;Mai Saeki;Y. Kishi;S. Hangai
高迁移率族蛋白1（HMGB 1）蛋白因其在许多病理条件（如皮肤炎症）中的促炎功能而受到关注。在这项研究中，Cre/loxP工程改造的小鼠品系允许在角质形成细胞中有条件地消融HMGB 1。当在HMGB 1突变小鼠中诱导过敏性接触性皮炎时，突变小鼠的皮肤炎症加剧。白细胞介素-24（IL-24），一种与皮肤炎症性疾病相关的促炎细胞因子，在这些小鼠的皮肤病变中表达升高。我们还举出的证据表明，HMGB 1抑制组蛋白H3（lys 4）（H3 K4 me 3）的结合，在角质形成细胞中的IL 24基因启动子。因此，我们的研究揭示了核HMGB 1的一个方面，抑制IL 24基因抑制过敏性炎症性皮肤病。角质形成细胞中炎性细胞因子的失调促进皮肤炎症的发病，例如变应性接触性皮炎（ACD）。高迁移率族蛋白1（HMGB 1）作为损伤相关的分子模式分子，在其细胞外释放后参与促进皮肤炎症。然而，角质形成细胞中的HMGB 1是否以及如何导致ACD和其他皮肤疾病仍然难以捉摸。在这项研究中，我们产生了条件性敲除小鼠，其中Hmgb 1基因在角质形成细胞中特异性缺失，并研究了其在ACD模型中的作用。有趣的是，突变小鼠表现出皮肤炎症加剧，伴随着2，4-二硝基氟苯诱导的ACD中耳朵增厚增加。白细胞介素-24（IL-24）的mRNA表达在突变小鼠的皮肤病变中升高，白细胞介素-24（IL-24）是一种已知对ACD发病机制有重要作用的细胞因子。与组成型表达一样，IL-4诱导的IL-24 mRNA在Hmgb 1缺陷型角质形成细胞中的表达也增加，这可能是突变小鼠ACD恶化的原因。从机制上讲，我们观察到三甲基组蛋白H3（lys 4）（H3 K4 me 3），转录活性基因的标志，在hmgb 1缺陷细胞的IL 24基因的启动子区域的结合增加。因此，核HMGB 1是一个关键的“守门人”，因为真皮内稳态取决于其在染色质重塑中的功能。我们的研究揭示了核HMGB 1的一个方面，即其在角质形成细胞中对皮肤稳态的调节功能。
Significance High-mobility group box 1 protein (HMGB1) protein gained attention for its proinflammatory function in a number of pathological conditions, such as skin inflammation. In this study, a Cre/loxP-engineered mouse strain allowed for HMGB1 conditionally ablated in keratinocytes. When allergic contact dermatitis was induced in the HMGB1 mutant mice, skin inflammation was exacerbated in the mutant mice. Expression of interleukin-24 (IL-24), a proinflammatory cytokine associated to skin inflammatory disorders, was elevated in skin lesions of these mice. We also adduced evidence that that HMGB1 represses the binding of histone H3 (lys4) (H3K4me3) to the Il24 gene promoter in keratinocytes. Therefore, our study revealed a facet of nuclear HMGB1 that represses the Il24 gene for the suppression of allergic inflammatory skin disorders. Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the Hmgb1 gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4–induced Il24 mRNA, expression was also augmented in the Hmgb1-deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the Il24 gene in the hmgb1-deficient cells. Thus, the nuclear HMGB1 is a critical “gate keeper” in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.