RT Journal Article
SR Electronic
T1 Substance P Enhances Keratocyte Migration and Neutrophil Recruitment Through Interleukin-8
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.101014
DO 10.1124/mol.115.101014
A1 Marta Słoniecka
A1 Sandrine Le Roux
A1 Qingjun Zhou
A1 Patrik Danielson
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/12/08/mol.115.101014.abstract
AB Keratocytes are the resident cells of the corneal stroma responsible for maintaining the 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. As 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 were 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 Rac1/RhoA 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.