Myeloid sphingolipid regulation of tissue resolution and regeneration responses

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SUMMARY Myeloid cells of the innate immune system (neutrophils and macrophages) interact closely with the vascular endothelium to modulate inflammatory and resolution responses. During early stages of the inflammatory response, inappropriate neutrophils activation causes vascular and parenchymal injury. However, in late stages of inflammation, precisely-controlled neutrophil resolution mechanisms are now considered to be critical to limit tissue damage and initiate regeneration of new vascular channels and parenchymal tissues. Even though neutrophil function in early stages of inflammatory processes is well understood, their involvement in resolution responses is poorly understood. We have found that the sphingosine 1-phosphate (S1P) receptor-1 (S1PR1), a G protein-coupled receptor (GPCR) with well-established functions in vascular and adaptive immune (T and B) cells, regulates neutrophil resolution responses. Specifically, S1PR1 signaling induces a non-inflammatory, long-lived neutrophil phenotype that undergoes efficient phagocytosis. We also found that this novel and unappreciated function of neutrophil S1PR1 signaling axis is critical for efficient recovery from virus-induced lung injury and chemical-induced acute liver failure. To activate this beneficial process, we developed a novel biologic based on our knowledge of S1P chaperones. We hypothesize that local S1PR1 signaling in neutrophils is a general mechanism that resolves inflammatory tissue injury and thus enable vascular and parenchymal regeneration in multiple organ systems. Furthermore, we posit that therapeutic activation of this signaling axis may provide a novel strategy to control chronic smoldering inflammation that lead to fibrotic diseases and organ dysfunction. To test this hypothesis, we will examine GPCR proximal mechanisms and nuclear transcriptional events that are regulated by S1PR1 in tissue neutrophils during resolution responses. Second, we will examine the importance of this signaling axis in resolution responses that are induced after virus-induced lung injury and chemical-induced liver injury in mouse models. Third, we will obtain proof-of-concept data to activate this signaling axis that utilize engineered designer HDL particles that contain ApoA1 and ApoM to stimulate neutrophil resolution responses and enhance vascular endothelial survival and regeneration. These data are anticipated to reveal novel mechanisms of resolution processes and enable innovative therapeutic strategies to control chronic inflammatory diseases.