Department of Biological Sciences, Sang-Huh College of Lifescience, Konkuk University, Seoul 05029, Republic of Korea.
Division of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 05029, Republic of Korea.
Proc Natl Acad Sci U S A. 2022 Sep 13;119(37):e2123451119. doi: 10.1073/pnas.2123451119. Epub 2022 Sep 6.
Filaggrin (FLG), an essential structural protein for skin barrier function, is down-regulated under chronic inflammatory conditions, leading to disruption of the skin barrier. However, the detailed molecular mechanisms of how FLG changes in the context of chronic inflammation are poorly understood. Here, we identified the molecular mechanisms by which inflammatory cytokines inhibit FLG expression in the skin. We found that the AP1 response element within the -343/+25 of the promoter was necessary for TNFα + IFNγ-induced down-regulation of promoter activity. Using DNA affinity precipitation assay, we observed that AP1 subunit composition binding to the promoter was altered from c-FOS:c-JUN (at the early time) to FRA1:c-JUN (at the late time) in response to TNFα + IFNγ stimulation. Knockdown of FRA1 or c-JUN abrogated TNFα + IFNγ-induced FLG suppression. Histone deacetylase (HDAC) 1 interacted with FRA1:c-JUN under TNFα + IFNγ stimulation. Knockdown of HDAC1 abrogated the inhibitory effect of TNFα + IFNγ on FLG expression. The altered expression of FLG, FRA1, c-JUN, and HDAC1 was confirmed in mouse models of 2,4-dinitrochlorobenzene-induced atopic dermatitis and imiquimod-induced psoriasis. Thus, the current study demonstrates that TNFα + IFNγ stimulation suppresses FLG expression by promoting the FRA1:c-JUN:HDAC1 complex. This study provides insight into future therapeutic strategies targeting the FRA1:c-JUN:HDAC1 complex to restore impaired FLG expression in chronic skin inflammation.
丝聚合蛋白（FLG）是皮肤屏障功能的重要结构蛋白，在慢性炎症条件下其表达下调，导致皮肤屏障破坏。然而，FLG 在慢性炎症背景下如何变化的详细分子机制尚不清楚。在这里，我们确定了炎性细胞因子抑制皮肤中 FLG 表达的分子机制。我们发现，启动子-343/+25 内的 AP1 反应元件对于 TNFα+IFNγ诱导的启动子活性下调是必要的。通过 DNA 亲和沉淀试验，我们观察到，AP1 亚基组成结合到启动子上的变化，从 c-FOS:c-JUN（在早期）到 FRA1:c-JUN（在晚期），以响应 TNFα+IFNγ刺激。FRA1 或 c-JUN 的敲低消除了 TNFα+IFNγ诱导的 FLG 抑制。组蛋白去乙酰化酶（HDAC）1 在 TNFα+IFNγ 刺激下与 FRA1:c-JUN 相互作用。HDAC1 的敲低消除了 TNFα+IFNγ 对 FLG 表达的抑制作用。在 2,4-二硝基氯苯诱导的特应性皮炎和咪喹莫特诱导的银屑病小鼠模型中，证实了 FLG、FRA1、c-JUN 和 HDAC1 的表达改变。因此，本研究表明，TNFα+IFNγ 刺激通过促进 FRA1:c-JUN:HDAC1 复合物抑制 FLG 表达。这项研究为未来针对 FRA1:c-JUN:HDAC1 复合物的治疗策略提供了深入的了解，以恢复慢性皮肤炎症中受损的 FLG 表达。
