The development of wound therapy targeting integrins is hampered by inadequate understanding of integrin function in cutaneous wound healing and the wound microenvironment. Following cutaneous injury, keratinocytes migrate to restore the skin barrier, and macrophages aid in debris clearance. Thus, both keratinocytes and macrophages are critical to the coordination of tissue repair. Keratinocyte integrins have been shown to participate in this coordinated effort by regulating secreted factors, some of which crosstalk to distinct cells in the wound microenvironment. Epidermal integrin α3β1 is a receptor for laminin-332 in the cutaneous basement membrane. Here we show that wounds deficient in epidermal α3β1 express less epidermal-derived macrophage colony-stimulating factor 1 (CSF-1), the primary macrophage-stimulating growth factor. α3β1-deficient wounds also have fewer wound-proximal macrophages, suggesting that keratinocyte α3β1 may stimulate wound macrophages through the regulation of CSF-1. Indeed, using a of immortalized keratinocytes, we demonstrate that keratinocyte-derived CSF-1 supports macrophage growth, and that α3β1 regulates expression through stimulation of Yes-associated protein (YAP)-Transcriptional enhanced associate domain (TEAD)-mediated transcription. Consistently, α3β1-deficient wounds display a substantially reduced number of keratinocytes with YAP-positive nuclei. Overall, our current findings identify a novel role for epidermal integrin α3β1 in regulating the cutaneous wound microenvironment by mediating paracrine crosstalk from keratinocytes to wound macrophages, implicating α3β1 as a potential target of wound therapy.

中文翻译：

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角质形成细胞整合素 α3β1 通过 YAP/TEAD 依赖性机制诱导巨噬细胞刺激因子 CSF-1 的表达。

由于对皮肤伤口愈合和伤口微环境中整合素功能的了解不足，阻碍了针对整合素的伤口治疗的发展。皮肤损伤后，角质细胞迁移以恢复皮肤屏障，巨噬细胞帮助清除碎片。因此，角质形成细胞和巨噬细胞对于协调组织修复至关重要。角质形成细胞整合素已被证明通过调节分泌因子参与这种协调工作，其中一些因子与伤口微环境中的不同细胞相互作用。表皮整合素 α3β1 是皮肤基底膜中层粘连蛋白 332 的受体。在这里，我们发现表皮α3β1缺陷的伤口表达较少的表皮源性巨噬细胞集落刺激因子1（CSF-1），即主要的巨噬细胞刺激生长因子。α3β1 缺陷的伤口也具有较少的伤口近端巨噬细胞，这表明角质形成细胞 α3β1 可能通过 CSF-1 的调节刺激伤口巨噬细胞。事实上，使用永生化角质形成细胞，我们证明角质形成细胞衍生的 CSF-1 支持巨噬细胞生长，并且 α3β1 通过刺激 Yes 相关蛋白 (YAP) 转录增强关联域 (TEAD) 介导的转录来调节表达。一致地，α3β1 缺陷的伤口显示具有 YAP 阳性细胞核的角质形成细胞数量大幅减少。总的来说，我们目前的研究结果确定了表皮整合素α3β1通过介导从角质形成细胞到伤口巨噬细胞的旁分泌串扰来调节皮肤伤口微环境的新作用，这表明α3β1是伤口治疗的潜在靶点。