HMGB1-mediated chromatin remodeling attenuates Il24 gene expression for the protection from allergic contact dermatitis
| Autor: | Yu Mizushima, Lei Li, Tadatsugu Taniguchi, Sana Hibino, Yusuke Kishi, Hideyuki Yanai, Shinichi Sato, Mai Saeki, Tomomitsu Miyagaki, Makoto Sugaya, Junko Nishio, Naoyuki Senda, Sho Hangai |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Multidisciplinary medicine.medical_treatment HMGB1 Gene chemical and pharmacologic phenomena Inflammation Biology HMGB1 Chromatin remodeling Cell biology Proinflammatory cytokine 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Cytokine Gene expression Conditional gene knockout medicine biology.protein medicine.symptom 030215 immunology |
| Zdroj: | Proceedings of the National Academy of Sciences. 118 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2022343118 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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