Sphingosine 1-Phosphate Receptor 2 Is Central to Maintaining Epidermal Barrier Homeostasis

The outer layer of the epidermis composes the skin barrier, a sophisticated filter constituted by layers of corneocytes in a lipid matrix. The matrix lipids, especially the ceramide-generated sphingosine 1-phosphate, are the messengers that the skin barrier uses to communicate with the basal layer of the epidermis where replicating keratinocytes are located. Sphingosine 1-phosphate is a bioactive sphingolipid mediator involved in various cellular functions through S1PR1‒5, expressed by keratinocytes. We discovered that the S1pr2 absence is linked to an impairment in the skin barrier function. Although S1pr2^-/- mouse skin has no difference in its phenotype and barrier function compared with that of wild-type mouse, after tape stripping, S1pr2^-/- mouse showed significantly higher transepidermal water loss and required another 24 hours to normalize their transepidermal water loss levels. Moreover, after epicutaneous Staphylococcus aureus application, impaired S1pr2^-/- mouse epidermal barrier function allowed deeper bacterial penetration and denser neutrophil infiltration in the dermis. Microarray and RNA sequence of S1pr2^-/- mouse epidermis linked the barrier dysfunction with a decrease in FLG2 and tight junction components. In conclusion, S1pr2^-/- mice have compromised skin barrier function and increased bacteria permeability, making them a suitable model for diseases that present similar characteristics, such as atopic dermatitis.