Infection regulates pro-resolving mediators that lower antibiotic requirements
Nan Chiang, Gabrielle Fredman, Fredrik Bäckhed, Sungwhan F Oh, Thad Vickery, Birgitta A Schmidt, Charles N Serhan, Nan Chiang, Gabrielle Fredman, Fredrik Bäckhed, Sungwhan F Oh, Thad Vickery, Birgitta A Schmidt, Charles N Serhan
Abstract
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.
Figures
References
- Houck JC, editor. Chemical Messengers of the Inflammatory Process. Elsevier/North-Holland Biomedical Press; 1979.
- Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 2011;11:519–531.
- Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell. 2010;140:771–776.
- Serhan CN. Resolution phases of inflammation: novel endogenous anti-inflammatory and pro-resolving lipid mediators and pathways. Annu. Rev. Immunol. 2007;25:101–137.
- Stables MJ, Gilroy DW. Old and new generation lipid mediators in acute inflammation and resolution. Prog. Lipid Res. 2011;50:35–51.
- Henneke P, Golenbock DT. Phagocytosis, innate immunity, and host-pathogen specificity. J. Exp. Med. 2004;199:1–4.
- Rossi AG, et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat. Med. 2006;12:1056–1064.
- Dinarello CA. Anti-inflammatory agents: present and future. Cell. 2010;140:935–950.
- Navarro-Xavier RA, et al. A new strategy for the identification of novel molecules with targeted proresolution of inflammation properties. J. Immunol. 2010;184:1516–1525.
- Schif-Zuck S, et al. Satiated-efferocytosis generates pro-resolving CD11blow macrophages: Modulation by resolvins and glucocorticoids. Eur. J. Immunol. 2011;41:366–379.
- De Caterina R. n-3 fatty acids in cardiovascular disease. N. Engl. J. Med. 2011;364:2439–2450.
- Morris T, et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J. Immunol. 2009;183:2089–2096.
- Oh SF, Pillai PS, Recchiuti A, Yang R, Serhan CN. Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation. J. Clin. Invest. 2011;121:569–581.
- Spite M, et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature. 2009;461:1287–1291.
- Mead PS, et al. Food-related illness and death in the United States. Emerg. Infect. Dis. 1999;5:607–625.
- Klingensmith ME, Soybel DI. In: The Physiological Basis of Modern Surgical Care. Miller TA, Rowlands BJ, editors. Mosby Year Book; 1998. pp. 478–490.
- Xu YN, Zhang Z, Ma P, Zhang SH. Adenovirus-delivered angiopoietin 1 accelerates the resolution of inflammation of acute endotoxic lung injury in mice. Anesth. Analg. 2011;112:1403–1410.
- Serhan CN, 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. 2002;196:1025–1037.
- Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl. Acad. Sci. U.S.A. 2007;104:979–984.
- Krishnamoorthy S, et al. Resolvin D1 binds human phagocytes with evidence for pro-resolving receptors. Proc. Natl. Acad. Sci. U.S.A. 2010;107:1660–1665. doi:doi: 10.1073/pnas.0907342107.
- Grkovich A, Johnson CA, Buczynski MW, Dennis EA. Lipopolysaccharide-induced cyclooxygenase-2 expression in human U937 macrophages is phosphatidic acid phosphohydrolase-1-dependent. J. Biol. Chem. 2006;281:32978–32987.
- Jin SL, Lan L, Zoudilova M, Conti M. Specific role of phosphodiesterase 4B in lipopolysaccharide-induced signaling in mouse macrophages. J. Immunol. 2005;175:1523–1531.
- 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. 2008;12:R159.
- Stables MJ, et al. Priming innate immune responses to infection by cyclooxygenase inhibition kills antibiotic-susceptible and -resistant bacteria. Blood. 2010;116:2950–2959.
- World Health Organization Antibiotics Resistance. 2011 Feb; Factsheet No. 194. 2011, doi:
- Seki H, et al. The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury. J. Immunol. 2010;184:836–843. doi:doi: 10.4049/jimmunol.0901809.
- 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. 2009;180:311–319.
- Prescott D, McKay DM. Aspirin-triggered lipoxin enhances macrophage phagocytosis of bacteria while inhibiting inflammatory cytokine production. Am. J. Physiol. Gastrointest. Liver Physiol. 2011;301:G487–G497.
- Yang R, Chiang N, Oh SF, Serhan CN. Metabolomics-lipidomics of eicosanoids and docosanoids generated by phagocytes. Curr. Protoc. Immunol. 2011;95:14.26.11–14.26.26.
- Winyard PG, Willoughby DA, editors. Inflammation Protocols. Humana; 2003.
Source: PubMed