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

Abstract

Resolvins, locally acting factors derived from omega-3 fatty acids, have been recognized as inflammation-resolving mediators. Experiments in a mouse abdominal sepsis model now show that resolvin D2 (RvD2) inhibits neutrophil trafficking to inflammatory sites and decreases leukocyte interactions with endothelial cells in a nitric oxide-dependent manner. RvD2's cellular and molecular actions translated to a dramatic increased survival. This work points to RvD2 as a potent anti-inflammatory agent and suggests new therapeutic approaches that do not compromise host defences. Evidence indicates that resolution of acute inflammation is an active process, and resolvins — a family of lipid mediators enzymatically generated within resolution networks — possess unique and specific functions to orchestrate catabasis, the phase in which disease declines. Resolvin D2 is now shown to reduce excessive neutrophil trafficking to inflammatory sites and to decrease leukocyte interactions with endothelial cells in a nitric-oxide-dependent manner. 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 catabasis, the phase in which disease declines2,3. Resolvin D2 (RvD2) was originally identified in resolving exudates, yet its individual contribution in resolution remained to be elucidated. Here, we establish 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 by direct modulation of leukocyte adhesion receptor expression. In mice with microbial sepsis initiated by caecal ligation and puncture, 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 sepsis induced by caecal ligation and puncture 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.