Person:

Oh, Sungwhan

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 (E. coli) infections with temporal identification of pro-inflammatory (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPM). In self-resolving E. coli exudates ((10^5) CFU), the dominant SPM identified were resolvin (Rv) D5 and protectin D1 (PD1), which at 12 h were significantly greater than levels in exudates from higher titer E. coli ((10^7) CFU) challenged mice. Germ-free mice displayed endogenous RvD1 and PD1 levels higher than in conventional mice. RvD1 and RvD5 (ng/mouse) each reduced bacterial titers in blood and exudates, E. coli-induced hypothermia and increased survival, demonstrating the first actions of RvD5. With human polymorphonuclear neutrophils (PMN) 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 (10^7) CFU E. coli infections, SPM (RvD1, RvD5, PD1) together with ciprofloxacin also heightened host antimicrobial responses. In skin infections, SPM enhanced vancomycin clearance of Staphylococcus aureus. These results demonstrate that specific SPM are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance.

Epidemiological and experimental data implicate branched chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms underlying this link remain unclear.1–3 Insulin resistance in skeletal muscle stems from excess accumulation of lipid species4, a process that requires blood-borne lipids to first traverse the blood vessel wall. Little is known, however, of how this trans-endothelial transport occurs or is regulated. Here, we leverage PGC-1α, a transcriptional coactivator that regulates broad programs of FA consumption, to identify 3-hydroxy-isobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a novel paracrine regulator of trans-endothelial fatty acids (FA) transport. 3-HIB is secreted from muscle cells, activates endothelial FA transport, stimulates muscle FA uptake in vivo, and promotes muscle lipid accumulation and insulin resistance in animals. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the promotion of endothelial FA uptake. 3-HIB levels are elevated in muscle from db/db mice and from subjects with diabetes. These data thus unveil a novel mechanism that regulates trans-endothelial flux of FAs, revealing 3-HIB as a new bioactive signaling metabolite that links the regulation of FA flux to BCAA catabolism and provides a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.

Although maternal antibodies protect newborns from infection, little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice lacking the capacity to produce IgG are protected by maternal natural IgG antibodies to the enteric pathogen enterotoxigenic Escherichia coli (ETEC) when antibodies are delivered either trans-placentally or through milk. By challenging pups fostered on either maternal antibody¬–sufficient or –deficient dams, we found that milk-derived IgG was critical for protection against ETEC-induced disease. Pups utilize the neonatal Fc receptor (FcRn) to transfer IgG from milk into serum, and this IgG provides protection against systemic and mucosal E. coli infection. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by ETEC and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers ETEC protection in pups. The surprising role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defense mechanism against neonatal infection.