Phospholipase Cδ1 regulates p38 MAPK activity and skin barrier integrity

Keratinocytes undergo a unique type of programmed cell death known as cornification, which leads to the formation of the stratum corneum (SC), the main physical barrier of the epidermis. A defective epidermal barrier is a hallmark of the two most common inflammatory skin disorders, psoriasis, and atopic dermatitis. However, the detailed molecular mechanisms of skin barrier formation are not yet fully understood. Here, we showed that downregulation of phospholipase C (PLC) delta 1, a Ca2+-mobilizing and phosphoinositide-metabolizing enzyme abundantly expressed in the epidermis, impairs the barrier functions of the SC. PLC delta 1 downregulation also impairs localization of tight junction proteins. Loss of PLC delta 1 leads to a decrease in intracellular Ca2+ concentrations and nuclear factor of activated T cells activity, along with hyperactivation of p38 mitogen-activated protein kinase (MAPK) and inactivation of RhoA. Treatment with a p38 MAPK inhibitor reverses the barrier defects caused by PLC delta 1 downregulation. Interestingly, this treatment also attenuates psoriasis-like skin inflammation in imiquimod-treated mice. These findings demonstrate that PLC delta 1 is essential for epidermal barrier integrity. This study also suggests a possible link between PLC delta 1 downregulation, p38 MAPK hyperactivation, and barrier defects in psoriasis-like skin inflammation.