title: Neutrophil ageing is regulated by the microbiome.
abstract: Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases. Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow. Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow, with feedback inhibition of neutrophil production via the IL-17/G-CSF axis, and rhythmic modulation of the haematopoietic stem-cell niche. The aged subset also expresses low levels of L-selectin. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties. Here, using in vivo ageing analyses in mice, we show that neutrophil pro-inflammatory activity correlates positively with their ageing whilst in circulation. Aged neutrophils represent an overly active subset exhibiting enhanced αMβ2 integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptor and myeloid differentiation factor 88-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle-cell disease or endotoxin-induced septic shock. These results identify a role for the microbiota in regulating a disease-promoting neutrophil subset.
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Dachuan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Deepa
authors.initials: D
authors.lastname: Manwani
authors.affiliation: Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.|The Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Mortha
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Chunliang
authors.initials: C
authors.lastname: Xu
authors.affiliation: The Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.|The Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Jeremiah J
authors.initials: JJ
authors.lastname: Faith
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burk
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kunisaki
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Jang
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheiermann
authors.affiliation: Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.|The Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000382:microbiology / Q000473:pathology; D000818:Animals; D016922:Cellular Senescence / Q000276:immunology*; D004195:Disease Models, Animal; D004913:Erythrocytes, Abnormal / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D064307:Microbiota / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology*; D012772:Shock, Septic / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D016177:Macrophage-1 Antigen; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors