Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis.
A growing body of evidence indicates that resolution of acute inflammation is an active process. 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 declines. 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.
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Matthew
M
Spite
Lucy V
LV
Norling
Lisa
L
Summers
Rong
R
Yang
Dianne
D
Cooper
Nicos A
NA
Petasis
Roderick J
RJ
Flower
Mauro
M
Perretti
Charles N
CN
Serhan
D000818:Animals; D004281:Docosahexaenoic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004926:Escherichia coli / Q000254:growth & development / Q000302:isolation & purification; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D010529:Peritoneal Cavity / Q000166:cytology / Q000382:microbiology; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D010587:Phagocytosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*
D017382:Reactive Oxygen Species; C545423:resolvin D2; D004281:Docosahexaenoic Acids; D009569:Nitric Oxide