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Infection regulates pro-resolving mediators that lower antibiotic requirements

Nature volume 484, pages 524–528 (2012)Cite this article

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Abstract

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.

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Figure 1: Profiling of SPMs in E. coli infections.
Figure 2: RvD1 and RvD5 protect mice during infection by enhancing bacterial killing and preventing hypothermia.
Figure 3: SPMs enhance human macrophage phagocytosis of E. coli.
Figure 4: SPMs and antibiotics accelerate resolution and enhance bacterial killing.

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Acknowledgements

The authors thank M. Small for assistance with manuscript preparation, J. Lederer for cytokine measurements, J. Dalli for discussions, and N. Petasis for preparation of deuterium-labelled RvD1. This work was supported in part by NIH grants P01GM095467 and R01GM38765 (C.N.S.).

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Authors and Affiliations

  1. Department of Anesthesiology, Center for Experimental Therapeutics and Reperfusion Injury, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Nan Chiang, Gabrielle Fredman, Sungwhan F. Oh, Thad Vickery, Birgitta A. Schmidt & Charles N. Serhan

  2. Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, University of Gothenburg, SE-413 45 Gothenburg, Sweden ,

    Fredrik Bäckhed

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Contributions

N.C., G.F. and S.F.O. contributed to experimental design, carried out experiments and data analyses. T.V. and S.F.O. performed metabololipidomics and lipid mediator analyses. F.B. carried out experiments with germ-free mice and contributed to manuscript composition. B.A.S. carried out dermatopathology. All authors contributed to manuscript presentation and figure preparation. N.C. and C.N.S. carried out overall experimental design and C.N.S. conceived of the overall research plan.

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Correspondence to Charles N. Serhan.

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Competing interests

C.N.S. is an inventor on patents (resolvins) assigned to BWH and licensed to Resolvyx Pharmaceuticals. C.N.S. is a scientific founder of Resolvyx Pharmaceuticals and owns equity in the company. C.N.S.’ interests were reviewed and are managed by the Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies.

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Chiang, N., Fredman, G., Bäckhed, F. et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524–528 (2012). https://doi.org/10.1038/nature11042

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