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Gene Expression During the Generation and Activation of Mouse Neutrophils: Implication of Novel Functional and Regulatory Pathways

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Gene Expression During the Generation and Activation of Mouse Neutrophils: Implication of Novel Functional and Regulatory Pathways Gene Expression during the Generation and Activation of Mouse Neutrophils: Implication of Novel Functional and Regulatory Pathways Jeffrey A. Ericson1, Pierre Duffau2, Kei Yasuda2, Adriana Ortiz-Lopez1, Katherine Rothamel1, Ian R. Rifkin2, Paul A. Monach2*, ImmGen Consortium" 1 Division of Immunology, Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, United States of America, 2 Department of Medicine, Boston University School of Medicine, Boston, MA, United States of America Abstract As part of the Immunological Genome Project (ImmGen), gene expression was determined in unstimulated (circulating) mouse neutrophils and three populations of neutrophils activated in vivo, with comparison among these populations and to other leukocytes. Activation conditions included serum-transfer arthritis (mediated by immune complexes), thioglycollate-induced peritonitis, and uric acid-induced peritonitis. Neutrophils expressed fewer genes than any other leukocyte population studied in ImmGen, and down-regulation of genes related to translation was particularly striking. However, genes with expression relatively specific to neutrophils were also identified, particularly three genes of unknown function: Stfa2l1, Mrgpr2a and Mrgpr2b. Comparison of genes up-regulated in activated neutrophils led to several novel findings: increased expression of genes related to synthesis and use of glutathione and of genes related to uptake and metabolism of modified lipoproteins, particularly in neutrophils elicited by thioglycollate; increased expression of genes for transcription factors in the Nr4a family, only in neutrophils elicited by serum-transfer arthritis; and increased expression of genes important in synthesis of prostaglandins and response to leukotrienes, particularly in neutrophils elicited by uric acid. Up-regulation of genes related to apoptosis, response to microbial products, NFkB family members and their regulators, and MHC class II expression was also seen, in agreement with previous studies. A regulatory model developed from the ImmGen data was used to infer regulatory genes involved in the changes in gene expression during neutrophil activation. Among 64, mostly novel, regulatory genes predicted to influence these changes in gene expression, Irf5 was shown to be important for optimal secretion of IL-10, IP-10, MIP-1a, MIP-1b, and TNF-a by mouse neutrophils in vitro after stimulation through TLR9. This data-set and its analysis using the ImmGen regulatory model provide a basis for additional hypothesis-based research on the importance of changes in gene expression in neutrophils in different conditions. Citation: Ericson JA, Duffau P, Yasuda K, Ortiz-Lopez A, Rothamel K, et al. (2014) Gene Expression during the Generation and Activation of Mouse Neutrophils: Implication of Novel Functional and Regulatory Pathways. PLoS ONE 9(10): e108553. doi:10.1371/journal.pone.0108553 Editor: Arun Rishi, Wayne State University, United States of America Received February 19, 2014; Accepted August 30, 2014; Published October 3, 2014 Copyright: ß 2014 Ericson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work received support from R24 AI072073 from NIH/NIAID to the ImmGen consortium; Arthritis Investigator Award from the Arthritis Foundation to P.A.M.; P01 AR050256 from NIH/NIAMS to I.R.R.; 1K01AR060857 from NIH/NIAMS to K.Y.; and grants from Socie´te´ Franc¸aise de Me´decine Interne and CHU de Bordeaux to P.D. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: [email protected] " Membership of the ImmGen Consortium is provided in the Acknowledgments. Introduction for host survival in a normal environment. However, ‘‘acute’’ neutrophilic inflammation is also characteristic of diverse non- The Immunological Genome Project (ImmGen) is a consortium infectious disease states such as inflammatory arthritis, neutro- of immunologists and computational biologists who aim to philic dermatoses, and vascultis. produce a comprehensive description of gene expression and a Unstimulated neutrophils are short-lived, and many of the best- model of its regulation in the immune system of the mouse [1–11]. known functions of activated neutrophils involve pre-formed In this context, we analyzed gene expression in neutrophils, in mediators. However, over the past 25 years it has become clear order to determine gene expression patterns that distinguish that activated neutrophils have prolonged survival, that they neutrophils from other leukocytes, compare expression patterns undergo prominent changes in gene expression, and that they among neutrophils activated by different stimuli in vivo, and infer synthesize and secrete proteins [12–15], indicating that studies of regulators of gene expression during neutrophil activation using gene expression are biologically relevant. Gene expression the ImmGen regulatory model. profiling of neutrophils has been reported in multiple studies, Neutrophils are highly differentiated cells of the myeloid lineage mostly for human cells, sometimes ex vivo comparing disease and are produced in large numbers in the bone marrow. They are states [16–19] but more often in vitro after stimulation with then released into the circulation, from which they extravasate in lipopolysaccharide, GM-CSF, or bacteria [19–24]. In all of these response to a variety of inflammatory stimuli. Neutrophils are studies, numerous changes in gene expression were seen with specialized for defense against bacterial infection and are essential PLOS ONE | www.plosone.org 1 October 2014 | Volume 9 | Issue 10 | e108553 Gene Expression Profiling of Mouse Neutrophils neutrophil activation. Two findings noted in multiple studies have For experiments using neutrophils in vitro, C57BL/6 wild-type been up-regulation of anti-apoptotic genes [17,18,23,24] and mice were purchased from the Jackson Laboratory. Irf52/2 mice genes for pro-inflammatory cytokines and chemokines (backcrossed 8 generations to C57BL/6) were provided by Dr. T. [17,18,20,21,24]. Some authors have focused on other changes, Taniguchi (University of Tokyo, Tokyo, Japan) and Dr. T. Mak such as in genes for transcription factors [22] or related to antigen (University of Toronto, Toronto, Canada) [34] and then presentation [19], and these papers have also reported differences backcrossed a further 7 generations to C57BL/6 mice from the among different stimuli in vitro [19,22]. We are aware of only one Jackson Laboratory. Mice were maintained at the Boston study of gene expression in mouse neutrophils, in which University School of Medicine Laboratory Animal Sciences neutrophils activated in vivo by thioglycollate-induced peritonitis Center and used under IACUC-approved protocol 14794. were found to express many genes previously thought to be specific to macrophages [25]. Mouse neutrophils activated in vivo by Inflammatory Stimuli and Collection of Cells different stimuli have not been compared to each other, nor to Arthritis was induced using serum from K/BxN mice, 0.15 ml non-activated neutrophils. intraperitoneally (i.p.) on day 0 and day 2. Synovial fluid was The importance of particular regulators of gene expression has collected on day 7 by puncture of the medial or lateral ankle with a been established most conclusively for the differentiation of 21-gauge needle, recovery of the fluid with a micropipet, and neutrophils; for example, PU.1, CEBP/a, CEBP/e, and Gfi-1 immediate dilution in cold DMEM (without Phenol Red) are essential for normal granulopoiesis [26–29]. During neutrophil containing 5% FBS, 0.1% sodium azide (DMEM/FBS/azide), activation, studied using human cells in vitro, evidence for and 20 mM EDTA. Peritonitis was induced by i.p. injection of involvement of STAT proteins, NFkB isoforms (specifically the 1 ml autoclaved 3% thioglycollate FTG medium (Sigma), or canonical pathway involving NFkB1/p50 and RelA), and CEBP/ 0.1 ml of 10% uric acid (Sigma, non-crystalline) in 0.8% NaCl a has been obtained [26,30]. that had been sonicated and stored at RT overnight to allow In the current study, we obtained gene expression profiles from crystals to form [35]. Peritoneal exudate cells were recovered unstimulated mouse neutrophils (bone marrow and blood) and 18 hr later by lavage with 9 ml cold DMEM/FBS/azide. Blood three disease states that involve extravasation and activation, in was collected by cardiac puncture and immediately diluted into order to identify genes that distinguish neutrophils from other cold DMEM/FBS/azide also containing 20 mM EDTA. Bone leukocytes, to identify changes in gene expression that are shared marrow cells from femurs were extruded directly into cold among activated states, and to identify changes characteristic of a DMEM/FBS/azide. particular stimulus. Uric acid (UA) crystals elicit inflammation in the peritoneal cavity–a model for the human arthritic disease Purification of Neutrophils, Flow Cytometry gout–and initiate pro-inflammatory signals in leukocytes through In most cases, samples from two mice were pooled before the NLRP3 inflammasome [31]. Thioglycollate broth (TG) elicits purification of neutrophils for gene expression studies. The neutrophilic and then macrophage inflammation
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