Infection regulates pro-resolving mediators that lower antibiotic requirements

摘要

Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown1"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, cf.u.), the dominant SPMs identified were resolvin (Rv) D5 and protectin Dl (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 RvDl and PD1 levels higher than in conventional mice. RvDl 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 macro-phages, RvDl, RvD5 and PD1 each directly enhanced phagocytosis of E. coli, and RvD5 counter-regulated a panel of pro-inflammatory genes, including NF-kB and TNF-a. RvD5 activated the RvDl receptor, GPR32, to enhance phagocytosis. With self-limited E. coli infections, RvDl and the antibiotic ciprofloxacin accelerated resolution, each shortening resolution intervals (R_i). Host-directed RvDl actions enhanced ciprofloxacin's therapeutic actions. In 107 cf.u. E. coli infections, SPMs (RvDl, 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.