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Jimmunol.1502690.Full.Pdf Changes in Gene Expression during G-CSF− Induced Emergency Granulopoiesis in Humans This information is current as Corinna C. Pedersen, Rehannah Borup, Anne of September 29, 2021. Fischer-Nielsen, Helena Mora-Jensen, Anna Fossum, Jack B. Cowland and Niels Borregaard J Immunol published online 1 August 2016 http://www.jimmunol.org/content/early/2016/07/30/jimmun ol.1502690 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/07/30/jimmunol.150269 Material 0.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 1, 2016, doi:10.4049/jimmunol.1502690 The Journal of Immunology Changes in Gene Expression during G-CSF–Induced Emergency Granulopoiesis in Humans Corinna C. Pedersen,* Rehannah Borup,† Anne Fischer-Nielsen,‡ Helena Mora-Jensen,* Anna Fossum,x Jack B. Cowland,*,1 and Niels Borregaard*,1 Emergency granulopoiesis refers to the increased production of neutrophils in bone marrow and their release into circulation in- duced by severe infection. Several studies point to a critical role for G-CSF as the main mediator of emergency granulopoiesis. However, the consequences of G-CSF stimulation on the transcriptome of neutrophils and their precursors have not yet been in- vestigated in humans. In this work, we examine the changes in mRNA expression induced by administration of G-CSF in vivo, as a model of emergency granulopoiesis in humans. Blood samples were collected from healthy individuals after 5 d of G-CSF admin- istration. Neutrophil precursors were sorted into discrete stages of maturation by flow cytometry, and RNAwas subjected to micro- array analysis. mRNA levels were compared with previously published expression levels in corresponding populations of neutrophil Downloaded from precursors isolated from bone marrow of untreated, healthy individuals. One thousand one hundred and ten mRNAs were differ- entially expressed >2-fold throughout terminal granulopoiesis. Major changes were seen in pathways involved in apoptosis, cytokine signaling, and TLR pathways. In addition, G-CSF treatment reduced the levels of four of five measured granule proteins in mature neutrophils, including the proantibacterial protein hCAP-18, which was completely deficient in neutrophils from G-CSF–treated donors. These results indicate that multiple biological processes are altered to satisfy the increased demand for neutrophils during G-CSF–induced emergency granulopoiesis in humans. The Journal of Immunology, 2016, 197: 000–000. http://www.jimmunol.org/ eutrophils are the most abundant leukocytes in human important of these is G-CSF, the principal cytokine controlling neu- blood (1). They play an essential role in innate immunity trophil development and function (8–12). The effect of G-CSF is N by combating invading microorganisms. Their impor- propagated exclusively via its cell membrane–bound receptor (8), tance is illustrated by qualitative and quantitative neutrophil G-CSFR, through several distinct pathways, which affect processes deficiencies that predispose to severe infections and increased such as proliferation, differentiation, survival, and migration (13, 14). mortality (2–4). Lack of G-CSF or its receptor results in severe neutropenia (9, 15). Neutrophils are normally produced at a steady rate in the bone The boost in production and release of neutrophils into circulation marrow (BM), where they remain for several days before transit to induced by severe infection is termed emergency granulopoiesis (16– by guest on September 29, 2021 blood (5). Microbial infections elicit production of cytokines that 18). Several studies in mice and humans point to a critical role for augment the production and survival of neutrophils (6, 7). The most G-CSF as the main mediator of emergency granulopoiesis (9, 17–19). G-CSF exerts its effects via different G-CSF–responsive transcription factors: C/EBPa during steady state and C/EBPb during emergency *Granulocyte Research Laboratory, Department of Hematology, National Uni- versity Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark; granulopoiesis (18–22). The effect of such switch in use of essential †Center for Genomic Medicine, National University Hospital, DK-2100 Copenhagen, transcription factors on expression of genes important for neutrophil Denmark; ‡Department of Clinical Immunology, Cell Therapy Facility, National x maturation and function has not been examined systematically. University Hospital, DK-2100 Copenhagen, Denmark; and Biotech and Research Innovation Centre, University of Copenhagen, DK-2100 Copenhagen, Denmark This study examines the effects of emergency granulopoiesis 1J.B.C. and N.B. are cosenior authors. elicited by G-CSF on the neutrophil transcriptional program. We have ORCIDs: 0000-0001-8838-6777 (C.C.P.); 0000-0002-9050-0601 (H.M.-J.); 0000- previously characterized the transcriptional program during steady- 0002-7429-5388 (J.B.C.). state granulopoiesis (23). In this state, only mature neutrophils are Received for publication December 29, 2015. Accepted for publication June 27, released from BM, whereas neutrophil precursors are also released 2016. during emergency granulopoiesis. G-CSF is used for mobilization of This work was supported by grants from Rigshospitalet, Copenhagen University hematopoietic stem cells from BM to circulation from where they Hospital, the University of Copenhagen, and the Danish Medical Research Council. can be harvested and deployed for stem cell transplantation. C.C.P., N.B., J.B.C., and H.M.-J. conceived and designed the experiments; C.C.P., We isolated neutrophils and their precursors from blood of healthy H.M.-J., and A.F. performed experiments; C.C.P., R.B., N.B., J.B.C., and A.F. analyzed the data; A.F.-N. contributed samples; C.C.P. drafted the manuscript; N.B., J.B.C., G-CSF–treated donors of hematopoietic stem cells. We compared R.B., and A.F.-N. contributed to the writing of the manuscript. the gene expression profiles at different stages of maturation with Address correspondence and reprint requests to Dr. Niels Borregaard and Dr. Jack gene expression profiles of normal BM neutrophil precursors at B. Cowland, Granulocyte Research Laboratory, Department of Hematology, National corresponding stages of maturation. This showed that G-CSF has a University Hospital, 9322, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail addresses: [email protected] (N.B.) and [email protected] (J.B.C.) substantial effect on gene expression during granulopoiesis and on The online version of this article contains supplemental material. the content of essential granule proteins in mature neutrophils. Abbreviations used in this article: BC, band cell; BM, bone marrow; GPCR, G protein– coupled receptor; LPM, late promyelocyte; MB, myeloblast; MM, metamyelocyte; MPO, myeloperoxidase; MY, myelocyte; NE, neutrophil elastase; NGAL, neutrophil Materials and Methods gelatinase-associated lipocalin; PC, principal component; PMN, polymorphonuclear Ethics statement neutrophil; rhG-CSF, human rG-CSF; SCN, severe congenital neutropenia. All donors gave informed consent. The study was approved by the local Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 Ethics Committee of the Capital Region (H-1-2011-165 and H-1-2013-075). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1502690 2 G-CSF–INDUCED HUMAN EMERGENCY GRANULOPOIESIS Isolation of neutrophil precursors and PMNs from peripheral Sorting and cell cycle analysis blood and BM Five cell populations representing successive stages of terminal neutrophil Healthy donors were treated s.c. with 10 mg/kg human rG-CSF (rhG-CSF; differentiation from G-CSF–treated donors and BM neutrophils and blood Neupogen Novum, Amgen) daily for 5 d, including the day of leukaphe- PMNs from rhG-CSF–naive individuals were stained with fluorochrome- resis. Blood was drawn just prior to leukapheresis, and polymorphonuclear conjugated mAbs: CD11b PE-Cy7 (eBioscience), CD16 Pacific Blue (used neutrophils (PMNs) and their precursors were isolated, as described pre- for sorting), CD16 PE (used for cell cycle analysis), CD33 PE-CF594, CD49d viously (24). Following sedimentation of erythrocytes by 2% Dextran FITC (all BD Biosciences), and streptavidin PE-Cy5 (BioLegend). Cells were T-500 in saline, cells from the leukocyte-rich supernatant were pelleted. sorted, as described previously (25), into 1.5-ml tubes containing 300 mlPBS/ Remaining erythrocytes were removed by hypotonic lysis. BM from rhG- 3% FCS (cytospins) or 300 ml RNEasy RLT buffer (Qiagen) with 2-ME CSF–naive individuals was aspirated and anticoagulated, as described (RNA) using the FACSAria cell sorter (BD Biosciences). The gating strategy is
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