Infection Regulates Pro-Resolving Mediators that Lower Antibiotic Requirements

By Chia Nan, G. Fredman, F. Bäckhed, Sungwhan F. Oh, Thad W. Vickery, Birgitta A. Schmidt, C. Serhan. Nature, 2012

652 citations recorded by the source corpus.

Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown. 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.

Subfields: Epidemiology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9318b48393f4756ea1a70d591c05a3ebc5822004

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. B. Levy
2. M. Perretti
3. C. Serhan

In Immunology

1. C. Serhan
2. B. Levy
3. M. Perretti
4. Oliver Soehnlein
5. A. Ortega-Gómez
6. D. Gilroy
7. P. Calder
8. Nikolaos G. Frangogiannis

In Molecular Biology

1. C. Serhan
2. B. Levy
3. Oliver Soehnlein
4. M. Perretti
5. A. Ortega-Gómez

Citations in the corpus

• Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. (2018, background): “SPMs also decrease production of IL-2, IFN-γ , and TNF-α by CD8 + T cells.”
• Pro-Resolving lipid mediators and Mechanisms in the resolution of acute inflammation (2014, background): “…et al. (2012) √ Candida yeast + Haas-Stapleton et al. (2007) √ Acid-induced lung injury + Levy and Serhan (2014) RvD1, RvD5, PD1 √ E. coli peritonitis infection + Chiang et al. (2012) RvD1 √ Acute lung injury + Wang et al. (2011) RvD2 √ Cecal ligation and puncture sepsis + Spite et al. (2009) √…”
• Resolution of inflammation: an integrated view (2013, positive): “Therapies that actively promote resolution may also have the advantage of enhancing innate immune responses to bacterial infections (Chiang et al, 2012), whereas established anti-inflammatory therapies such as anti-TNF strategies may be immunosuppressive (Bruns et al, 2009).”