S1P, Generated by Sphingosine Kinase 1, Negatively Affects Corneal Wound Healing Process by Activating TGF-β/Smad...

Abnormal healing of corneal injury can lead to corneal opacity, a leading cause of blindness. This process is extremely complex and involves precise interactions of multiple signaling pathways. A lack of understanding of these complex interactions provides a major challenge in developing therapeutic strategies. Both sphingosine-1-phosphate (S1P) and transforming growth factor beta (TGFβ) signaling have been associated with tissue fibrosis. The purpose of this study was to understand the interplay between S1P and TGFβ signaling in the process of corneal wound healing and fibrosis. Mice lacking the Sphingosine kinase 1 gene (Sphk1^-/-) and their wildtype littermates were subjected to corneal injury by alkali burn. The progress of wound healing and the expression and activation of TGFβ signaling intermediates and profibrotic proteins were measured at different days postinjury (DPI). We observed that reduction of S1P signaling in Sphk1^-/- mice induced the closure of corneal epithelial layer at a faster rate than its wildtype littermates following alkali burn. Reduced activation of profibrotic proteins Smad2 and 3, along with reduced expression of Smad4 and higher expression of antifibrotic protein Smad7, was also observed in the Sphk1^-/- mice as compared to the wildtype littermates following corneal injury. Inhibition of S1P signaling by exogenous delivery of a small-molecule inhibitor of sphingosine kinase 1 (SphK1) could accelerate corneal wound healing in similarly injured wildtype (Sphk1^+/+) mice. These results suggest that S1P signaling positively influences TGFβ signaling pathways that negatively affect corneal wound healing by delaying the process and inducing fibrotic development. Thus, inhibition of S1P signaling could be an effective therapeutic option to accelerate corneal wound healing and thereby prevent corneal fibrosis/scar formation.