Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis

Abstract

A growing body of evidence indicates that resolution of acute inflammation is an active process1,2. Resolvins are a new family of lipid mediators enzymatically generated within resolution networks that possess unique and specific functions to orchestrate catabasis2,3. Resolvin D2 (RvD2) was originally identified in resolving exudates, yet its individual contribution in resolution remained to be elucidated. Here, we established RvD2’s potent stereoselective actions in reducing excessive neutrophil trafficking to inflammatory loci. RvD2 decreased leukocyte:endothelial interactions in vivo by endothelial-dependent nitric oxide production, and direct modulation of leukocyte adhesion receptor expression. In microbial sepsis initiated by cecal ligation and puncture (CLP), RvD2 sharply decreased both local and systemic bacterial burden, excessive cytokine production and neutrophil recruitment, while increasing peritoneal mononuclear cells and macrophage phagocytosis. These multi-level pro-resolving actions of RvD2 translate to increased survival from CLP-induced sepsis and surgery. Together, these results identify RvD2 as a potent endogenous regulator of excessive inflammatory responses that acts via multiple cellular targets to stimulate resolution and preserve immune vigilance.