Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation.
Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation.
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DOI：
10.1084/jem.20112258
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发表时间：
2012-06-04
期刊：
影响因子：
--
通讯作者：
Blobel CP
中科院分区：
文献类型：
--
作者：
Franzke CW;Cobzaru C;Triantafyllopoulou A;Löffek S;Horiuchi K;Threadgill DW;Kurz T;van Rooijen N;Bruckner-Tuderman L;Blobel CP
EGFR需要ADAM17活性来维持皮肤屏障的动态平衡。ADAM17是一种去整合素和金属蛋白酶17，广泛表达并能裂解细胞表面的膜蛋白，如表皮生长因子受体配体、L-选择素和肿瘤坏死因子，从而调节对组织损伤和炎症的反应。然而，目前对其在皮肤动态平衡中的作用知之甚少。我们发现在角质形成细胞中缺乏ADAM17的小鼠(A17ΔKC)在出生时具有正常的表皮屏障和皮肤结构，但出生后不久就出现明显的表皮屏障完整性缺陷，成年后发展为慢性皮炎。表皮分化蛋白的异常表达在出生后2d开始明显，随后是转谷氨酰胺酶活性降低，经皮水分丢失，促炎细胞因子IL-36α上调，炎性免疫细胞浸润。在A17ΔKC小鼠的皮肤中，表皮生长因子受体的活性显著降低，用重组转化生长因子-α局部治疗A17 TGM KC小鼠可显著提高TGM活性并减少皮肤炎症。最后，我们发现在角质形成细胞中缺乏表皮生长因子受体的小鼠(EGFRΔKC)与A17ΔKC小鼠非常相似。总之，这些结果确认了ADAM17-EGFR信号轴在维持出生后表皮屏障的动态平衡中的关键作用，并表明该途径可能是治疗表皮屏障缺陷的良好靶点。
EGFR requires ADAM17 activity to preserve skin barrier homeostasis. ADAM17 (a disintegrin and metalloproteinase 17) is ubiquitously expressed and cleaves membrane proteins, such as epidermal growth factor receptor (EGFR) ligands, l-selectin, and TNF, from the cell surface, thus regulating responses to tissue injury and inflammation. However, little is currently known about its role in skin homeostasis. We show that mice lacking ADAM17 in keratinocytes (A17ΔKC) have a normal epidermal barrier and skin architecture at birth but develop pronounced defects in epidermal barrier integrity soon after birth and develop chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 d after birth, followed by reduced transglutaminase (TGM) activity, transepidermal water loss, up-regulation of the proinflammatory cytokine IL-36α, and inflammatory immune cell infiltration. Activation of the EGFR was strongly reduced in A17ΔKC skin, and topical treatment of A17ΔKC mice with recombinant TGF-α significantly improved TGM activity and decreased skin inflammation. Finally, we show that mice lacking the EGFR in keratinocytes (EgfrΔKC) closely resembled A17ΔKC mice. Collectively, these results identify a previously unappreciated critical role of the ADAM17–EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier and suggest that this pathway could represent a good target for treatment of epidermal barrier defects.
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影响因子：
4.4
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