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Marta Urszula Sloniecka, Sandrine Le Roux, Ludvig Backman, Patrik Danielson; Substance P induces keratocyte migration through chemotactic interleukin-8. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4684.
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The process of corneal wound healing plays a critical role in the preservation of corneal transparency after injury. The process includes epithelial cell migration and proliferation, extracellular matrix remodeling, and keratocyte apoptosis and differentiation into myofibroblasts. These events are regulated by various cytokines and growth factors. Substance P (SP), a neuropeptide normally stored in neurons, has also been found in non-neuronal cells of collagenous tissues like tendons, in which SP’s proliferative effect has been studied. In the cornea, SP and its preferred receptor, the neurokinin 1 receptor (NK-1 R), have been found in both epithelium and keratocytes. However, SP’s role in the corneal stroma has not yet been thoroughly investigated. Interleukin-8 (IL-8), a pro-inflammatory cytokine, plays an important role in inflammation and wound healing. It is able to recruit both T-cells and nonspecific inflammatory cells into inflamed sites by activating neutrophils. Furthermore, IL-8 is chemotactic for fibroblasts, accelerates their migration, and can stimulate deposition of substances involved in wound healing. Both human keratocytes and epithelial cells have been shown to synthesize and secrete IL-8 following cytokine stimulation and/or infection. We hypothesize that SP, upon injury, is able to induce keratocyte migration via IL-8, thus facilitating wound healing.
Primary human keratocytes were derived from healthy corneas obtained from donated transplantation graft leftovers. Gene expression was assessed by qPCR. Secretion of IL-8 was measured by ELISA. A wound healing assay was used for observing SP-induced migration of keratocytes and wound closure.
Stimulation of limbal and central keratocytes with SP led to increased levels of IL-8 mRNA. SP directly stimulated the release of IL-8 from these cells. Furthermore, SP stimulation increased migration of keratocytes and led to wound closure. Interestingly, this effect of SP on limbal keratocytes was more pronounced than on central keratocytes, and it was abolished when cells were treated with neutralizing IL-8 antibody.
SP stimulates production and secretion of IL-8 by human keratocytes, and it also increases migration of limbal and, to a lesser extent, central keratocytes via IL-8 signaling. This suggests that SP may play a role in corneal wound closure, inflammation, and perhaps extracellular matrix remodeling.
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