Infection regulates pro-resolving mediators that lower antibiotic requirements
Open Access
- 25 April 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 484 (7395), 524-528
- https://doi.org/10.1038/nature11042
Abstract
Resolvins and protectins are anti-inflammatory and pro-resolving lipid mediators that are shown to resolve infections, and their administration lowers required doses of antibiotics and shortens infections. Bacterial infections can result in the generation of infection-resolving anti-inflammatory lipid derivatives. This paper reports the use of a murine Escherichia coli peritonitis model relevant to human infections to identify specialized host-produced pro-resolving mediators (SPMs) termed resolvin D5 and protectin D1, which may be directly involved in resolving infections. The administration of these two mediators improves infection-related signs, increases clearance of infection-causing bacteria and increases survival. When administered with antibiotics, resolvin D5 and protectin D1 acted together to further reduce the duration and severity of infection. The SPMs also enhanced antibiotic clearance of Staphylococcus aureus murine skin infections. The spread of antibiotic resistance is a major concern, so the prospect that therapeutic use of host-derived molecules might help to limit antibiotic dose rates is of potential clinical importance. Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown1,2,3,4. Here, we performed exudate leukocyte trafficking and mediator-metabololipidomics of murine peritoneal Escherichia coli infections with temporal identification of pro-inflammatory (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPMs). In self-resolving E. coli exudates (105 colony forming units, c.f.u.), the dominant SPMs identified were resolvin (Rv) D5 and protectin D1 (PD1), which at 12 h were at significantly greater levels than in exudates from higher titre E. coli (107 c.f.u.)-challenged mice. Germ-free mice had endogenous RvD1 and PD1 levels higher than in conventional mice. RvD1 and RvD5 (nanograms per mouse) each reduced bacterial titres in blood and exudates, E. coli-induced hypothermia and increased survival, demonstrating the first actions of RvD5. With human polymorphonuclear neutrophils and macrophages, RvD1, RvD5 and PD1 each directly enhanced phagocytosis of E. coli, and RvD5 counter-regulated a panel of pro-inflammatory genes, including NF-κB and TNF-α. RvD5 activated the RvD1 receptor, GPR32, to enhance phagocytosis. With self-limited E. coli infections, RvD1 and the antibiotic ciprofloxacin accelerated resolution, each shortening resolution intervals (Ri). Host-directed RvD1 actions enhanced ciprofloxacin’s therapeutic actions. In 107 c.f.u. E. coli infections, SPMs (RvD1, RvD5, PD1) together with ciprofloxacin also heightened host antimicrobial responses. In skin infections, SPMs enhanced vancomycin clearance of Staphylococcus aureus. These results demonstrate that specific SPMs are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance.This publication has 27 references indexed in Scilit:
- Metabolomics‐Lipidomics of Eicosanoids and Docosanoids Generated by PhagocytesCurrent Protocols in Immunology, 2011
- n–3 Fatty Acids in Cardiovascular DiseaseThe New England Journal of Medicine, 2011
- Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammationJCI Insight, 2011
- Saturated‐efferocytosis generates pro‐resolving CD11blow macrophages: Modulation by resolvins and glucocorticoidsEuropean Journal of Immunology, 2010
- Resolvin D1 binds human phagocytes with evidence for proresolving receptorsProceedings of the National Academy of Sciences of the United States of America, 2010
- Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsisNature, 2009
- 15-Epi-lipoxin A4Inhibits Myeloperoxidase Signaling and Enhances Resolution of Acute Lung InjuryAmerican Journal of Respiratory and Critical Care Medicine, 2009
- Phosphodiesterase 4 inhibition but not beta-adrenergic stimulation suppresses tumor necrosis factor-alpha release in peripheral blood mononuclear cells in septic shockCritical Care, 2008
- Mechanisms underlying the resistance to diet-induced obesity in germ-free miceProceedings of the National Academy of Sciences of the United States of America, 2007
- Food-Related Illness and Death in the United StatesEmerging Infectious Diseases, 1999