The interaction of ceramide 1-phosphate with group IVA cytosolic phospholipase A2 coordinates acute wound healing and repair

The sphingolipid ceramide 1-phosphate (C1P) directly binds to and activates group IVA cytosolic phospholipase
A2 (cPLA2α) to stimulate the production of eicosanoids. Because eicosanoids are important in wound healing, we
examined the repair of skin wounds in knockout (KO) mice lacking cPLA2α and in knock-in (KI) mice in which
endogenous cPLA2 was replaced with a mutant form having an ablated C1P interaction site. Wound closure rate
was not affected in the KO or KI mice, but wound maturation was enhanced in the KI mice compared to that
in wild-type controls. Wounds in KI mice displayed increased infiltration of dermal fibroblasts into the wound
environment, increased wound tensile strength, and a higher ratio of type I:type III collagen. In vitro, primary
dermal fibroblasts (pDFs) from KI mice showed substantially increased collagen deposition and migration velocity
compared to pDFs from wild-type and KO mice. KI mice also showed an altered eicosanoid profile of reduced
proinflammatory prostaglandins (PGE2 and TXB2) and an increased abundance of certain hydroxyeicosatetraenoic
acid (HETE) species. Specifically, an increase in 5-HETE enhanced dermal fibroblast migration and collagen deposition. This gain-of-function role for the mutant cPLA2α was also linked to the relocalization of cPLA2α and 5-HETE biosynthetic enzymes to the cytoplasm and cytoplasmic vesicles. These findings demonstrate the regulation of key wound-healing mechanisms in vivo by a defined protein-lipid interaction and provide insights into the roles
that cPLA2α and eicosanoids play in orchestrating wound repair.