Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release.
Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release.
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DOI：
10.1016/j.jaci.2018.08.042
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Miller LS
中科院分区：
文献类型：
--
作者：
Archer NK;Jo JH;Lee SK;Kim D;Smith B;Ortines RV;Wang Y;Marchitto MC;Ravipati A;Cai SS;Dillen CA;Liu H;Miller RJ;Ashbaugh AG;Uppal AS;Oyoshi MK;Malhotra N;Hoff S;Garza LA;Kong HH;Segre JA;Geha RS;Miller LS
特应性皮炎（AD）与表皮屏障缺陷、生态失调和抓挠引起的皮肤损伤有关。特别是，具有功能丧失聚丝蛋白突变的AD患者的屏障缺陷性表皮具有增加的IL-1α和IL-1β水平，但是诱导IL-1α和/或IL-1β的机制以及它们是否有助于AD中的异常皮肤炎症尚不清楚。我们试图确定皮肤损伤、生态失调和表皮IL-1α和IL-1β增加导致丝蛋白缺陷小鼠损伤诱导皮肤炎症小鼠模型中皮肤炎症发展的机制。进行野生型、丝聚蛋白缺陷型（ft/ft）和MyD 88缺陷型ft/ft小鼠的皮肤损伤，并通过数码摄影、组织学分析和流式细胞术评估随后的皮肤炎症。ELISA法检测IL-1α和IL-1β蛋白表达，免疫荧光和免疫电镜观察。通过16 S rDNA测序确定皮肤微生物组的组成。ft/ft小鼠的皮肤损伤诱导慢性皮肤炎症，涉及角质形成细胞的生态失调驱动的细胞内IL-1α释放。IL-1α在体内是皮肤炎症所必需和充分的，在体外由角质形成细胞在各种刺激下分泌。局部抗生素或ft/ft小鼠与未受影响的野生型小鼠共饲养以分别改变或混合皮肤微生物群，解决了皮肤炎症并恢复了角质形成细胞细胞内IL-1α定位。综上所述，皮肤损伤、生态失调和聚丝蛋白缺乏引发角质形成细胞胞内IL-1α释放，足以驱动慢性皮肤炎症，这对AD发病机制和潜在的治疗靶点有影响。我们的数据表明，损伤和生态失调驱动角质形成细胞释放细胞内IL-1α，介导丝聚蛋白缺陷小鼠的慢性炎症。IL-1α和生态失调可能是减少特应性皮炎皮肤炎症的治疗靶点。
Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis and skin injury from scratching. In particular, the barrier defective epidermis of AD patients with loss-of-function filaggrin mutations has increased IL-1α and IL-1β levels but the mechanisms by which IL-1α and/or IL-1β are induced and whether they contribute to the aberrant skin inflammation in AD is unknown. We sought to determine the mechanisms by which skin injury, dysbiosis and increased epidermal IL-1α and IL-1β contribute to the development of skin inflammation in a mouse model of injury-induced skin inflammation in filaggrin-deficient mice. Skin injury of wild-type, filaggrin-deficient (ft/ft), and MyD88-deficient ft/ft mice was performed and ensuing skin inflammation was evaluated by digital photography, histologic analysis and flow cytometry. IL-1α and IL-1β protein expression was measured by ELISA and visualized by immunofluorescence and immuno-electron microscopy. The composition of skin microbiome was determined by 16S rDNA sequencing. Skin injury of ft/ft mice induced chronic skin inflammation involving dysbiosis-driven intracellular IL-1α release from keratinocytes. IL-1α was necessary and sufficient for skin inflammation in vivo and secreted from keratinocytes by various stimuli in vitro. Topical antibiotics or co-housing of ft/ft mice with unaffected wild-type mice to alter or intermix skin microbiota, respectively, resolved the skin inflammation and restored keratinocyte intracellular IL-1α localization. Taken together, skin injury, dysbiosis and filaggrin deficiency triggered keratinocyte intracellular IL-1α release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and for potential therapeutic targets. Our data demonstrate that injury and dysbiosis drive intracellular IL-1α release from keratinocytes to mediate chronic inflammation in filaggrin-deficient mice. IL-1α and dysbiosis could represent therapeutic targets to reduce skin inflammation in atopic dermatitis.
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影响因子：
6.7
作者：
Guerra ES;Lee CK;Specht CA;Yadav B;Huang H;Akalin A;Huh JR;Mueller C;Levitz SM
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Levitz SM
影响因子：
64.8
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Miller, Lloyd S.
影响因子：
11.4
作者：
Dupont, Nicolas;Jiang, Shanya;Deretic, Vojo
通讯作者：
Deretic, Vojo
影响因子：
6.5
作者：
Brown, Sara J.;McLean, W. H. Irwin
通讯作者：
McLean, W. H. Irwin