Słoniecka Marta, Le Roux Sandrine, Zhou Qingjun, Danielson Patrik
Department of Integrative Medical Biology (M.S., S.LR., Q.Z., P.D.) and Department of Clinical Sciences, Ophthalmology, Umeå University, Umeå, Sweden (M.S.); and Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Qingdao, China (Q.Z.).
Department of Integrative Medical Biology (M.S., S.LR., Q.Z., P.D.) and Department of Clinical Sciences, Ophthalmology, Umeå University, Umeå, Sweden (M.S.); and Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Qingdao, China (Q.Z.)
Mol Pharmacol. 2016 Feb;89(2):215-25. doi: 10.1124/mol.115.101014. Epub 2015 Dec 8.
Keratocytes, the resident cells of the corneal stroma, are responsible for maintaining turnover of this tissue by synthesizing extracellular matrix components. When the cornea is injured, the keratocytes migrate to the wounded site and participate in the stromal wound healing. The neuropeptide substance P (SP), which is also known to be produced by non-neuronal cells, has previously been implicated in epithelial wound healing after corneal injury. Corneal scarring, which occurs in the stroma when the process of wound healing has malfunctioned, is one of the major causes of preventable blindness. This study aimed to elucidate the potential role of SP in keratocyte migration and therefore in stromal wound healing. We report that the expression and secretion of SP in human keratocytes are increased in response to injury in vitro. Moreover, SP enhances the migration of keratocytes by inducing the actin cytoskeleton reorganization and focal adhesion formation through the activation of the phosphatidylinositide 3-kinase and Ras-related C3 botulinum toxin substrate 1/Ras homolog gene family, member A pathway. Furthermore, SP stimulation leads to upregulated expression of the proinflammatory and chemotactic cytokine interleukin-8 (IL-8), which also contributes significantly to SP-enhanced keratocyte migration and is able to attract neutrophils. In addition, the preferred SP receptor, the neurokinin-1 receptor, is necessary to induce keratocyte migration and IL-8 secretion. In conclusion, we describe new mechanisms by which SP enhances migration of keratocytes and recruits neutrophils, two necessary steps in the corneal wound-healing process, which are also likely to occur in other tissue injuries.
角膜细胞是角膜基质的驻留细胞，负责通过合成细胞外基质成分来维持该组织的更新。当角膜受伤时，角膜细胞迁移至伤口部位并参与基质伤口愈合。神经肽P物质（SP）也由非神经元细胞产生，此前已被认为与角膜损伤后的上皮伤口愈合有关。角膜瘢痕形成发生在伤口愈合过程出现故障时的基质中，是可预防失明的主要原因之一。本研究旨在阐明SP在角膜细胞迁移以及因此在基质伤口愈合中的潜在作用。我们报告，体外损伤会导致人角膜细胞中SP的表达和分泌增加。此外，SP通过激活磷脂酰肌醇3激酶和Ras相关C3肉毒杆菌毒素底物1/Ras同源基因家族成员A途径，诱导肌动蛋白细胞骨架重组和粘着斑形成，从而增强角膜细胞的迁移。此外，SP刺激导致促炎和趋化细胞因子白细胞介素-8（IL-8）表达上调，这也对SP增强的角膜细胞迁移有显著贡献，并且能够吸引中性粒细胞。此外，首选的SP受体神经激肽-1受体对于诱导角膜细胞迁移和IL-8分泌是必需的。总之，我们描述了SP增强角膜细胞迁移和募集中性粒细胞的新机制，这是角膜伤口愈合过程中的两个必要步骤，也可能发生在其他组织损伤中。
