title: Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling.
abstract: Neutropenia is probably the strongest known predisposition to infection with otherwise harmless environmental or microbiota-derived species. Because initial swarming of neutrophils at the site of infection occurs within minutes, rather than the hours required to induce "emergency granulopoiesis," the relevance of having high numbers of these cells available at any one time is obvious. We observed that germ-free (GF) animals show delayed clearance of an apathogenic bacterium after systemic challenge. In this article, we show that the size of the bone marrow myeloid cell pool correlates strongly with the complexity of the intestinal microbiota. The effect of colonization can be recapitulated by transferring sterile heat-treated serum from colonized mice into GF wild-type mice. TLR signaling was essential for microbiota-driven myelopoiesis, as microbiota colonization or transferring serum from colonized animals had no effect in GF MyD88(-/-)TICAM1(-/-) mice. Amplification of myelopoiesis occurred in the absence of microbiota-specific IgG production. Thus, very low concentrations of microbial Ags and TLR ligands, well below the threshold required for induction of adaptive immunity, sets the bone marrow myeloid cell pool size. Coevolution of mammals with their microbiota has probably led to a reliance on microbiota-derived signals to provide tonic stimulation to the systemic innate immune system and to maintain vigilance to infection. This suggests that microbiota changes observed in dysbiosis, obesity, or antibiotic therapy may affect the cross talk between hematopoiesis and the microbiota, potentially exacerbating inflammatory or infectious states in the host.
authors.affiliation: Division of Gastroenterology, Department of Clinical Research, University Clinic for Visceral Surgery and Medicine, University of Bern, 3010 Bern, Switzerland;
authors.forename: Maria L
authors.initials: ML
authors.lastname: Balmer
authors.affiliation: Department of Clinical Research, Tumor Immunology, University of Bern, 3010 Bern, Switzerland;
authors.forename: Christian M
authors.initials: CM
authors.lastname: Schürch
authors.affiliation: Division of Hematology, University Hospital Zurich, 8091 Zurich, Switzerland;
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Division of Gastroenterology, Department of Clinical Research, University Clinic for Visceral Surgery and Medicine, University of Bern, 3010 Bern, Switzerland;
authors.forename: Markus B
authors.initials: MB
authors.lastname: Geuking
authors.affiliation: Division of Gastroenterology, Department of Clinical Research, University Clinic for Visceral Surgery and Medicine, University of Bern, 3010 Bern, Switzerland;
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute for Infectious Diseases, University of Bern, 3010 Bern, Switzerland; and.
authors.forename: Miguelangel
authors.initials: M
authors.lastname: Cuenca
authors.affiliation: Division of Hematology, University Hospital Zurich, 8091 Zurich, Switzerland;
authors.forename: Larisa V
authors.initials: LV
authors.lastname: Kovtonyuk
authors.affiliation: Division of Gastroenterology, Department of Clinical Research, University Clinic for Visceral Surgery and Medicine, University of Bern, 3010 Bern, Switzerland;
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.affiliation: Institute for Infectious Diseases, University of Bern, 3010 Bern, Switzerland; and.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hapfelmeier
authors.affiliation: Department of Clinical Research, Tumor Immunology, University of Bern, 3010 Bern, Switzerland;
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Ochsenbein
authors.affiliation: Division of Hematology, University Hospital Zurich, 8091 Zurich, Switzerland;
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.affiliation: Division of Gastroenterology, Department of Clinical Research, University Clinic for Visceral Surgery and Medicine, University of Bern, 3010 Bern, Switzerland; Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland andrew.macpherson@insel.ch emma.slack@micro.biol.ethz.ch.
authors.forename: Emma
authors.initials: E
authors.lastname: Slack
authors.affiliation: Division of Gastroenterology, Department of Clinical Research, University Clinic for Visceral Surgery and Medicine, University of Bern, 3010 Bern, Switzerland; andrew.macpherson@insel.ch emma.slack@micro.biol.ethz.ch.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Macpherson
mesh_terms: D056704:Adaptive Immunity; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D005075:Biological Evolution; D001854:Bone Marrow Cells / Q000276:immunology / Q000382:microbiology; D005786:Gene Expression Regulation; D005856:Germ-Free Life; D007113:Immunity, Innate; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology* / Q000382:microbiology; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D038042:Myelopoiesis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000942:Antigens, Bacterial; D053594:Myeloid Differentiation Factor 88; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse