Infection regulates pro-resolving mediators that lower antibiotic requirements
Open accessAbstract
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 (10(5) 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 (10(7) 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 (R(i)). Host-directed RvD1 actions enhanced ciprofloxacin's therapeutic actions. In 10(7) 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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SPMs suppress inflammation but, unlike anti-inflammatory drugs, promote both repair and continued pathogen clearance.
“From a translational perspective, SPMs suppress inflammation but, unlike anti-inflammatory drugs, these pro-resolving mediators promote both repair and continued pathogen clearance33,213–215.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [214]
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- Authors
- Chiang, N., Fredman, G., Bäckhed, F., Oh, S. F., Vickery, T., Schmidt, B. A., & Serhan, C. N.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Gothenburg (SE)
- Corresponding author
- Serhan, Charles N.
- ORCID
- Venue
- Nature
- Published
- 2012-04
- Volume
- 484
- Issue
- 7395
- Pages
- 524-528
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3340015
- OpenAlex
- W2148536296
- Cited by
- 664
- References
- 29
- Citations by year
- 2026: 28 · 2025: 39 · 2024: 37 · 2023: 39 · 2022: 55 · 2021: 53 · 2020: 69 · 2019: 49 · 2018: 42 · 2017: 48 · 2016: 48 · 2015: 44 · 2014: 38 · 2013: 52 · 2012: 19
- FWCI
- 45.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of General Medical Sciences (P01GM095467, R01GM038765, R01-GM38765)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- specialized pro-resolving mediators, resolvin D5, protectin D1, Escherichia coli peritonitis, Staphylococcus aureus skin infection, antibiotic dose reduction, infection resolution, phagocytosis, NF-κB, TNF-α, leukotriene B4, leukotriene C4, leukotriene E4, leukotriene A4
- MeSH terms
- Animals, Anti-Bacterial Agents, Docosahexaenoic Acids, Escherichia coli, Escherichia coli Infections, Humans, Hypothermia, Macrophages, Male, Mice, Inbred C57BL, Neutrophils, Peritonitis, Phagocytosis, Skin Diseases, Staphylococcal Infections, Staphylococcus aureus, Vancomycin, Microbial Viability, Mice
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