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Myd88/TICAM Signaling Steady-State Granulopoiesis Via Microbiota-Derived Compounds Drive Steady-State Granulopoiesis via MyD88/TICAM Signaling This information is current as Maria L. Balmer, Christian M. Schürch, Yasuyuki Saito, of October 1, 2021. Markus B. Geuking, Hai Li, Miguelangel Cuenca, Larisa V. Kovtonyuk, Kathy D. McCoy, Siegfried Hapfelmeier, Adrian F. Ochsenbein, Markus G. Manz, Emma Slack and Andrew J. Macpherson J Immunol 2014; 193:5273-5283; Prepublished online 10 October 2014; Downloaded from doi: 10.4049/jimmunol.1400762 http://www.jimmunol.org/content/193/10/5273 http://www.jimmunol.org/ References This article cites 43 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/193/10/5273.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Microbiota-Derived Compounds Drive Steady-State Granulopoiesis via MyD88/TICAM Signaling Maria L. Balmer,* Christian M. Schurch,€ † Yasuyuki Saito,‡ Markus B. Geuking,* Hai Li,* Miguelangel Cuenca,x Larisa V. Kovtonyuk,‡ Kathy D. McCoy,* Siegfried Hapfelmeier,x Adrian F. Ochsenbein,† Markus G. Manz,‡ Emma Slack,*,{ and Andrew J. Macpherson* 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 Downloaded from 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 MyD882/2TICAM12/2 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2014, 193: 5273–5283. n detection of wounding or infection, neutrophils are strates that this rapid response is essential for survival (4). How- recruited and swarm within minutes (1–3). The extreme ever, production of sufficient neutrophils is a costly procedure. An O sensitivity of neutropenic patients to infection demon- adult human produces thousands of neutrophils per second, which during health predominantly senesce (5). The possibility to “tune” by guest on October 1, 2021 the levels of neutrophil production to the level of threat faced by *Division of Gastroenterology, Department of Clinical Research, University Clinic the organism would therefore appear to be beneficial. for Visceral Surgery and Medicine, University of Bern, 3010 Bern, Switzerland; †Department of Clinical Research, Tumor Immunology, University of Bern, 3010 It is well documented that during severe bacterial infection, Bern, Switzerland; ‡Division of Hematology, University Hospital Zurich, 8091 a process referred to as “emergency myelopoiesis” is induced (5, Zurich, Switzerland; xInstitute for Infectious Diseases, University of Bern, 3010 { 6). In this situation, a much greater proportion of multipotent Bern, Switzerland; and Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland progenitor cells are diverted into the myeloid lineage at the ex- Received for publication March 26, 2014. Accepted for publication September 9, pense of lymphopoiesis. This process appears to require sensing 2014. of pathogen-associated molecular patterns in a TLR-dependent A.J.M. was supported by the Swiss National Science Foundation (Grants 310030- manner (7). It is further known that massive production of IFN-g 124732 and 313600-123736), the Canadian Institutes of Health Research, and the can enhance the production of monocytes over granulocytes and Genaxen Foundation. M.L.B. was supported by Oncosuisse and the Swiss National Science Foundation (Grant 313600-123736/1). S.H. and K.D.M. received funding can drive erythropoiesis to start at sites outside the bone marrow from the European Research Council under the European Union’s Seventh Frame- (BM) (8). However, increased production of mature granulocytes work Programme (FP/2007-2013)/European Research Council Grants 281785 and requires hours to days in the human system, and although this 281904, respectively. A.F.O. was supported by the Swiss National Science Founda- tion (Grant 133132), Oncosuisse, and the Bernische Krebsliga. C.M.S. was supported increased production is central to the later control and eradication by the Gertrud-Hagmann-Stiftung fur€ Malignomforschung and the SwissLife of infection, the initial encounter with pathogenic or apathogenic Jubila¨umsstiftung. M.G.M. was supported by the Swiss National Science Foun- dation (Grant 310030_146528/1). E.S. (PZ00P3_136742) and M.B.G. were sup- bacteria requires the immediate action of the homeostatically ported by an Ambizione fellowship from the Swiss National Science Foundation. maintained circulating and marginated granulocyte pools (1, 6). Address correspondence and reprint requests to Prof. Andrew J. Macpherson or We and others have previously noticed that germ-free (GF) mice Dr. Emma Slack, Division of Gastroenterology, Department of Clinical Research, show delayed kinetics of clearance of bacteria given i.v. (9, 10). GF University Clinic for Visceral Surgery and Medicine, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland (A.J.M.) or Institute of Microbiology, HCI G 413, mice are known to have an immature mucosal immune system, Vladimir-Prelog-Weg 1-5/10, CH-8093 Zurich, Switzerland (E.S.). E-mail addresses: including reduced secondary lymphoid tissues, lower levels of [email protected] (A.J.M.) or [email protected] (E.S.) secretory IgA, and fewer intestinal plasma cells (11). In addition, Abbreviations used in this article: BM, bone marrow; CLP, common lymphoid pro- GF mice have lower levels of serum Abs and increased suscepti- genitor; GF, germ-free; GMP, granulocyte-monocyte progenitor; HSPC, hematopoi- etic stem/progenitor cell; IVC, individually ventilated cage; LB, Luria–Bertani bility to infection with a number of bacterial pathogens, both in the (media or agar); LCM, low-complexity microbiota; LSK, lineage2, Sca1+, c-kit intestinal tract and systemically (11). It has been observed previ- “high” cells; MEP, megakaryocyte-erythrocyte progenitor; RT, room temperature; ously that treatment of specific pathogen-free (SPF), but not GF SPF, specific pathogen-free. mice, with the lipid A–binding antibiotic polymyxin B reduces the Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 number of granulocyte-monocyte colonies formed during in vitro www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400762 5274 THE MICROBIOTA DRIVES STEADY-STATE GRANULOPOIESIS culture of BM (12). Decreased numbers of granulocytes have also tubes, with the outside surface kept sterile, and imported into flexible film 10 been observed in the BM of kanamycin-treated mice (13). More isolators, where 500 ml (10 CFU) was gavaged into the stomachs of GF recent studies have identified increased bone mass and decreased C57BL/6 mice. Inoculum samples were then re-exported from the isolators for bacterial quantification by plating on supplemented agar plates. Fecal osteoclast numbers in GF mice (14). Thus, we hypothesized that samples exported from the isolator were bacteriologically analyzed to cross talk between the microbiota and the BM is important to monitor HA107 shedding and bacteriological status of the inoculated mice. regulate the size of the steady-state myeloid cell pool. This regu- BrdU proliferation assay latory network may be implicated in the increased susceptibility to infections observed in GF mice and patients with dysbiosis. GF or separately
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