title: Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis.
abstract: Maintenance of myeloid cell homeostasis requires continuous turnover of phagocytes from the bloodstream, yet whether environmental signals influence phagocyte longevity in the absence of inflammation remains unknown. Here, we show that the gut microbiota regulates the steady-state cellular lifespan of neutrophils and inflammatory monocytes, the 2 most abundant circulating myeloid cells and key contributors to inflammatory responses. Treatment of mice with broad-spectrum antibiotics, or with the gut-restricted aminoglycoside neomycin alone, accelerated phagocyte turnover and increased the rates of their spontaneous apoptosis. Metagenomic analyses revealed that neomycin altered the abundance of intestinal bacteria bearing γ-d-glutamyl-meso-diaminopimelic acid, a ligand for the intracellular peptidoglycan sensor Nod1. Accordingly, signaling through Nod1 was both necessary and sufficient to mediate the stimulatory influence of the flora on myeloid cell longevity. Stimulation of Nod1 signaling increased the frequency of lymphocytes in the murine intestine producing the proinflammatory cytokine interleukin 17A (IL-17A), and liberation of IL-17A was required for transmission of Nod1-dependent signals to circulating phagocytes. Together, these results define a mechanism through which intestinal microbes govern a central component of myeloid homeostasis and suggest perturbations of commensal communities can influence steady-state regulation of cell fate.
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Hergott
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Aoife M
authors.initials: AM
authors.lastname: Roche
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Department of Ophthalmology, Otorhinolaryngology, and Head and Neck Surgery, Ribeirao Preto School of Medicine, University of São Paulo, São Paulo, Brazil;
authors.forename: Edwin
authors.initials: E
authors.lastname: Tamashiro
authors.affiliation: Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom;
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Clarke
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Aubrey G
authors.initials: AG
authors.lastname: Bailey
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Alice
authors.initials: A
authors.lastname: Laughlin
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and Department of Microbiology, New York University School of Medicine, New York, NY.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weiser
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D020296:Animals, Congenic; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000502:physiology*; D005856:Germ-Free Life; D006706:Homeostasis; D020381:Interleukin-17 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D009504:Neutrophils / Q000166:cytology; D053474:Nod1 Signaling Adaptor Protein / Q000172:deficiency / Q000502:physiology; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency / Q000502:physiology; D010457:Peptidoglycan / Q000494:pharmacology*; D010586:Phagocytes / Q000166:cytology* / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; C098680:Il17a protein, mouse; D020381:Interleukin-17; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D010457:Peptidoglycan; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D003960:Diaminopimelic Acid; C034331:N(2)-(gamma-D-glutamyl)-meso-2,2'-diaminopimelic acid