Epidermal EGFR Controls Cutaneous Host Defense and Prevents Inflammation
Epidermal EGFR Controls Cutaneous Host Defense and Prevents Inflammation
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DOI：
10.1126/scitranslmed.3005886
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发表时间：
2013-08-21
影响因子：
17.1
通讯作者：
Sibilia, Maria
中科院分区：
文献类型：
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作者：
Lichtenberger, Beate M.;Gerber, Peter A.;Sibilia, Maria
表皮生长因子受体（EGFR）在组织稳态和肿瘤进展中起重要作用。然而，接受EGFR抑制剂（EGFRIs）治疗的癌症患者经常出现痤疮样皮肤毒性，这是患者治疗反应的一个强有力的预测指标。我们发现EGFRI诱导的早期皮疹炎症浸润以树突状细胞、巨噬细胞、粒细胞、肥大细胞和T细胞为主。EGFRIs诱导表皮角质形成细胞中趋化因子（CCL2、CCL5、CCL27和CXCL14）的表达，并损害抗菌肽和皮肤屏障蛋白的产生。相应地，egfr处理的角质形成细胞促进淋巴细胞募集，但对金黄色葡萄球菌的细胞毒性活性大大降低。缺乏表皮EGFR（EGFR(Delta ep)）的小鼠表现出类似的表型，伴随着趋化因子驱动的皮肤炎症，毛囊变性，宿主防御功能下降，皮肤屏障功能不足，以及早期死亡。在Rag2-、MyD88-和ccl2缺乏的背景下或缺乏表皮朗格汉斯细胞的小鼠中，皮肤毒性没有改善。在无毛（hr/hr）的背景下，皮肤表型也没有恢复，这表明皮肤炎症不是由毛囊变性引起的。使用肥大细胞抑制剂治疗可减少T细胞的迁移，这表明肥大细胞在egfr介导的皮肤病理中发挥作用。我们的研究结果表明，角化细胞中的EGFR信号调节涉及皮肤炎症、屏障功能和先天宿主防御的关键因素，为了解EGFR诱导的皮肤病理的潜在机制提供了见解。
The epidermal growth factor receptor (EGFR) plays an important role in tissue homeostasis and tumor progression. However, cancer patients treated with EGFR inhibitors (EGFRIs) frequently develop acneiform skin toxicities, which are a strong predictor of a patient's treatment response. We show that the early inflammatory infiltrate of the skin rash induced by EGFRI is dominated by dendritic cells, macrophages, granulocytes, mast cells, and T cells. EGFRIs induce the expression of chemokines (CCL2, CCL5, CCL27, and CXCL14) in epidermal keratinocytes and impair the production of antimicrobial peptides and skin barrier proteins. Correspondingly, EGFRI-treated keratinocytes facilitate lymphocyte recruitment but show a considerably reduced cytotoxic activity against Staphylococcus aureus. Mice lacking epidermal EGFR (EGFR(Delta ep)) show a similar phenotype, which is accompanied by chemokine-driven skin inflammation, hair follicle degeneration, decreased host defense, and deficient skin barrier function, as well as early lethality. Skin toxicities were not ameliorated in a Rag2-, MyD88-, and CCL2-deficient background or in mice lacking epidermal Langerhans cells. The skin phenotype was also not rescued in a hairless (hr/hr) background, demonstrating that skin inflammation is not induced by hair follicle degeneration. Treatment with mast cell inhibitors reduced the immigration of T cells, suggesting that mast cells play a role in the EGFRI-mediated skin pathology. Our findings demonstrate that EGFR signaling in keratinocytes regulates key factors involved in skin inflammation, barrier function, and innate host defense, providing insights into the mechanisms underlying EGFRI-induced skin pathologies.