Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Infection regulates pro-resolving mediators that lower antibiotic requirements

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Houck, J. C., ed. Chemical Messengers of the Inflammatory Process (Elsevier/North-Holland Biomedical Press, 1979)

    Google Scholar 

  2. 2

    Mantovani, A., Cassatella, M. A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nature Rev. Immunol. 11, 519–531 (2011)

    CAS  Article  Google Scholar 

  3. 3

    Medzhitov, R. Inflammation 2010: new adventures of an old flame. Cell 140, 771–776 (2010)

    CAS  Article  Google Scholar 

  4. 4

    Serhan, C. N. Resolution phases of inflammation: novel endogenous anti-inflammatory and pro-resolving lipid mediators and pathways. Annu. Rev. Immunol. 25, 101–137 (2007)

    CAS  Article  Google Scholar 

  5. 5

    Stables, M. J. & Gilroy, D. W. Old and new generation lipid mediators in acute inflammation and resolution. Prog. Lipid Res. 50, 35–51 (2011)

    CAS  Article  Google Scholar 

  6. 6

    Henneke, P. & Golenbock, D. T. Phagocytosis, innate immunity, and host-pathogen specificity. J. Exp. Med. 199, 1–4 (2004)

    CAS  Article  Google Scholar 

  7. 7

    Rossi, A. G. et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nature Med. 12, 1056–1064 (2006)

    CAS  Article  Google Scholar 

  8. 8

    Dinarello, C. A. Anti-inflammatory agents: present and future. Cell 140, 935–950 (2010)

    CAS  Article  Google Scholar 

  9. 9

    Navarro-Xavier, R. A. et al. A new strategy for the identification of novel molecules with targeted proresolution of inflammation properties. J. Immunol. 184, 1516–1525 (2010)

    CAS  Article  Google Scholar 

  10. 10

    Schif-Zuck, S. et al. Satiated-efferocytosis generates pro-resolving CD11blow macrophages: modulation by resolvins and glucocorticoids. Eur. J. Immunol. 41, 366–379 (2011)

    CAS  Article  Google Scholar 

  11. 11

    De Caterina, R. n−3 fatty acids in cardiovascular disease. N. Engl. J. Med. 364, 2439–2450 (2011)

    CAS  Article  Google Scholar 

  12. 12

    Morris, T. et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J. Immunol. 183, 2089–2096 (2009)

    CAS  Article  Google Scholar 

  13. 13

    Oh, S. F., Pillai, P. S., Recchiuti, A., Yang, R. & Serhan, C. N. Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation. J. Clin. Invest. 121, 569–581 (2011)

    CAS  Article  Google Scholar 

  14. 14

    Spite, M. et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461, 1287–1291 (2009)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Mead, P. S. et al. Food-related illness and death in the United States. Emerg. Infect. Dis. 5, 607–625 (1999)

    CAS  Article  Google Scholar 

  16. 16

    Klingensmith, M. E. & Soybel, D. I. in The Physiological Basis of Modern Surgical Care ( Miller, T. A. & Rowlands, B. J. eds) 478–490 (Mosby Year Book, 1998)

    Google Scholar 

  17. 17

    Xu, Y. N., Zhang, Z., Ma, P. & Zhang, S. H. Adenovirus-delivered angiopoietin 1 accelerates the resolution of inflammation of acute endotoxic lung injury in mice. Anesth. Analg. 112, 1403–1410 (2011)

    Article  Google Scholar 

  18. 18

    Serhan, C. N. et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter pro-inflammation signals. J. Exp. Med. 196, 1025–1037 (2002)

    CAS  Article  Google Scholar 

  19. 19

    Bäckhed, F., Manchester, J. K., Semenkovich, C. F. & Gordon, J. I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl Acad. Sci. USA 104, 979–984 (2007)

    ADS  Article  Google Scholar 

  20. 20

    Krishnamoorthy, S. et al. Resolvin D1 binds human phagocytes with evidence for pro-resolving receptors. Proc. Natl Acad. Sci. USA 107, 1660–1665 (2010)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Grkovich, A., Johnson, C. A., Buczynski, M. W. & Dennis, E. A. Lipopolysaccharide-induced cyclooxygenase-2 expression in human U937 macrophages is phosphatidic acid phosphohydrolase-1-dependent. J. Biol. Chem. 281, 32978–32987 (2006)

    CAS  Article  Google Scholar 

  22. 22

    Jin, S. L., Lan, L., Zoudilova, M. & Conti, M. Specific role of phosphodiesterase 4B in lipopolysaccharide-induced signaling in mouse macrophages. J. Immunol. 175, 1523–1531 (2005)

    CAS  Article  Google Scholar 

  23. 23

    Link, A., Selejan, S., Maack, C., Lenz, M. & Böhm, M. Phosphodiesterase 4 inhibition but not beta-adrenergic stimulation suppresses tumor necrosis factor-alpha release in peripheral blood mononuclear cells in septic shock. Crit. Care 12, R159 (2008)

    Article  Google Scholar 

  24. 24

    Stables, M. J. et al. Priming innate immune responses to infection by cyclooxygenase inhibition kills antibiotic-susceptible and -resistant bacteria. Blood 116, 2950–2959 (2010)

    CAS  Article  Google Scholar 

  25. 25

    World Health Organization. Antibiotics Resistance, Factsheet No. 194 http://www.who.int/mediacentre/factsheets/fs194/en/ (February 2011)

  26. 26

    Seki, H. et al. The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury. J. Immunol. 184, 836–843 (2010)

    CAS  Article  Google Scholar 

  27. 27

    El Kebir, D. et al. 15-epi-lipoxin A4 inhibits myeloperoxidase signaling and enhances resolution of acute lung injury. Am. J. Respir. Crit. Care Med. 180, 311–319 (2009)

    CAS  Article  Google Scholar 

  28. 28

    Prescott, D. & McKay, D. M. Aspirin-triggered lipoxin enhances macrophage phagocytosis of bacteria while inhibiting inflammatory cytokine production. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G487–G497 (2011)

    CAS  Article  Google Scholar 

  29. 29

    Yang, R., Chiang, N., Oh, S. F. & Serhan, C. N. Metabolomics-lipidomics of eicosanoids and docosanoids generated by phagocytes. Curr. Protoc. Immunol. 95, 14.26.11–14.26.26 (2011)

    Article  Google Scholar 

  30. 30

    Winyard, P. G., Willoughby, D. A., eds. Inflammation Protocols (Humana, 2003)

    Book  Google Scholar 

Download references

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.).

Author information

Affiliations

Authors

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.

Corresponding author

Correspondence to Charles N. Serhan.

Ethics declarations

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.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-3, Supplementary Figures 1-11 and an additional reference. (PDF 24452 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing