Indiana Center for Regenerative Medicine and Engineering, Department of Surgery, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
J Invest Dermatol. 2023 Oct;143(10):2052-2064.e5. doi: 10.1016/j.jid.2023.03.1671. Epub 2023 Apr 10.
Repair of epithelial defect is complicated by infection and related metabolites. Pyocyanin (PYO) is one such metabolite that is secreted during Pseudomonas aeruginosa infection. Keratinocyte (KC) migration is required for the closure of skin epithelial defects. This work sought to understand PYO-KC interaction and its significance in tissue repair. Stable Isotope Labeling by Amino acids in Cell culture proteomics identified mitochondrial dysfunction as the top pathway responsive to PYO exposure in human KCs. Consistently, functional studies showed mitochondrial stress, depletion of reducing equivalents, and adenosine triphosphate. Strikingly, despite all stated earlier, PYO markedly accelerated KC migration. Investigation of underlying mechanisms revealed, to our knowledge, a previously unreported function of keratin 6A in KCs. Keratin 6A was PYO inducible and accelerated closure of epithelial defect. Acceleration of closure was associated with poor quality healing, including compromised expression of apical junction proteins. This work recognizes keratin 6A for its role in enhancing KC migration under conditions of threat posed by PYO. Qualitatively deficient junctional proteins under conditions of defensive acceleration of KC migration explain why an infected wound close with deficient skin barrier function as previously reported.
上皮缺损的修复受到感染和相关代谢物的影响。绿脓菌素（PYO）是铜绿假单胞菌感染时分泌的一种代谢物。角质形成细胞（KC）的迁移对于皮肤上皮缺损的闭合是必需的。这项工作旨在了解 PYO-KC 的相互作用及其在组织修复中的意义。稳定同位素标记的氨基酸在细胞培养蛋白质组学中鉴定出线粒体功能障碍是对人 KC 中 PYO 暴露反应的首要途径。一致地，功能研究表明存在线粒体应激、还原当量耗竭和三磷酸腺苷。值得注意的是，尽管前面提到了所有这些，PYO 还是明显加速了 KC 的迁移。对潜在机制的研究揭示了，据我们所知，角蛋白 6A 在 KC 中的一个以前未被报道的功能。角蛋白 6A 可被 PYO 诱导，并加速上皮缺陷的闭合。闭合的加速与愈合质量差有关，包括顶端连接蛋白表达受损。这项工作认识到角蛋白 6A 在受到 PYO 威胁的情况下增强 KC 迁移的作用。在 KC 迁移防御性加速的情况下，连接蛋白质量不足，这解释了为什么之前有报道称感染性伤口会因皮肤屏障功能不足而闭合。
