Sphingosine 1 phosphate production is an important mediator of skin inflammation and host defense in hyperglycemic mice.

Abstract Staphylococcus aureus (MRSA) skin infections are characterized by the initial recruitment of neutrophils followed by the establishment of a localized abscess. An abscess comprises a fibrous capsule, viable and apoptotic neutrophils, and bacteria in the abscess core. Along with eliminating bacteria, the clearance of dead neutrophils (efferocytosis) is crucial to restoring tissue homeostasis. Efferocytosis is a tightly regulated process initiated when dying cells secrete “find-me” signals such as Sphingosine 1 phosphate (S1P) that trigger phagocyte migration resulting in apoptotic neutrophil clearance. S1P binds to five different G protein-coupled receptors (S1PR1–5). Our data show that obese and hyperglycemic mice are more susceptible to MRSA skin infection, characterized by increased lesion size, bacterial loads, and poor abscess formation. In hyperglycemic mice, we also observed increased dead cells on days 1 and 9 post-infection with MRSA. When we assessed in vivo efferocytosis, we observed a lower ratio of ingestion of dead cells in the skin of hyperglycemic mice compared to euglycemic mice. Imaging mass spectrometry and lipidomic analysis revealed that while S1P levels are decreased, phosphoethanolamine (a product of the S1P degradation) is increased before and on day 1 post-infection in obese mice. We found that S1pr3 is significantly increased, whereas S1pr4 and S1pr5 are decreased in the infected skin obese. Topical S1P treatment reduced lesion size and bacterial load in the skin of hyperglycemic mice. Our data suggest that S1P deficiency during skin infections culminates in less efferocytosis, accumulation of dead cells, uncontrolled infection, and delay in the resolution of the infection.