Ceramide kinase regulates acute wound healing by suppressing 5-oxo-ETE biosynthesis and signaling via its receptor OXER1

De(C1P)hering the role of ceramide-1-phosphate levels in skin wound healing

“…This provision was important in terms of the possibility of translating the results to humans, since human skin wounds heal primarily by re-epithelialization rather than by contraction, as does rodent skin (2). The mechanism by which CERK inhibition with SYR382141 accelerated wound healing seemed to be due at least in part to the observed increases in the expression of fibroblast activation protein, the number of infiltrating cells, and type 1 collagen deposition (5). These results supported the idea that inhibition of CERK-derived C1P formation may lead to a transition from the inflammatory stage to the proliferation phase required for proper wound healing.…”

“…The findings from Maus et al (5) are an important contribution to the current body of research on molecular mediators, specifically bioactive lipids, in the important and all-encompassing biological process of inflammation. A study by Pettus et al (6) confirmed that CERK-derived C1P is required for the release of arachidonic acid and production of eicosanoids-both of which are essential for the inflammatory stage of wound healing.…”

“…Compared with sham controls, wild-type primary dermal fibroblasts treated with a CERK inhibitor or lacking Cerk were found to exhibit an increase in migration velocity. In addition, the lipidomic analysis of C1P-reduced primary dermal fibroblasts showed an increase in the lipoxygenase-derived hydroxyeicosatetraenoic acid (HETE) 5-HETE, as well as the biologically active metabolite of 5-HETE, 5-oxo-HETE, compared with the control; this increase was also observed in acute skin wounds with CERK inhibition (5). Dermal fibroblasts from mice genetically engineered to possess a gene encoding a mutant cPLA 2 α (mutant cPLA 2 α knock-in mice) that did not interact with C1P showed similarly enhanced 5-oxo-HETE levels and accelerated migration.…”

“…There has been an interest in understanding the biological markers and signaling molecules that mediate wound healing in order to better develop pharmacological therapies that promote targeted healing. In this issue of the Journal of Lipid Research, Maus et al (5) demonstrated that a decrease in the levels of ceramide-1-phosphate (C1P), accomplished either through inhibiting or genetically ablating the anabolic enzyme ceramide kinase (CERK), resulted in a significant acceleration of skin wound healing. In particular, this study used a newly formulated CERK inhibitor, SYR382141, that could be used in mice in vivo and was found to block the production of CERK-derived C1P in a similar manner to a previously established CERK inhibitor.…”

“…In this study, Maus et al (5) not only examined closure rates of acute wounds in mice but also performed lipidomic and migration analyses after mechanical trauma on isolated mouse dermal fibroblasts that were treated with exogenous CERK inhibitors or were derived from Cerk-null mice. Compared with sham controls, wild-type primary dermal fibroblasts treated with a CERK inhibitor or lacking Cerk were found to exhibit an increase in migration velocity.…”