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Immunity Resolution of Inflammation and Airway Diversity in Expression with Critical Roles in Macrophage Populations Reveals

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Immunity Resolution of Inflammation and Airway Diversity in Expression with Critical Roles in Macrophage Populations Reveals Downloaded from http://www.jimmunol.org/ by guest on September 29, 2021 is online at: average * in Mouse γ The Journal of Immunology , 15 of which you can access for free at: 2012; 189:2614-2624; Prepublished online 1 from submission to initial decision 4 weeks from acceptance to publication Emmanuel L. Gautier, Andrew Chow, Rainer Spanbroek, Genevieve Marcelin, Melanie Greter, Claudia Jakubzick, Milena Bogunovic, Marylene Leboeuf, Nico van Rooijen, Andreas J. Habenicht, Miriam Merad and Gwendalyn J. Randolph August 2012; doi: 10.4049/jimmunol.1200495 http://www.jimmunol.org/content/189/5/2614 Systemic Analysis of PPAR Macrophage Populations Reveals Marked Diversity in Expression with Critical Roles in Resolution of Inflammation and Airway Immunity J Immunol cites 48 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://www.jimmunol.org/content/189/5/2614.full#ref-list-1 http://www.jimmunol.org/content/suppl/2012/08/01/jimmunol.120049 5.DC1 This article Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 29, 2021. The Journal of Immunology Systemic Analysis of PPARg in Mouse Macrophage Populations Reveals Marked Diversity in Expression with Critical Roles in Resolution of Inflammation and Airway Immunity Emmanuel L. Gautier,*,†,‡ Andrew Chow,†,x Rainer Spanbroek,{ Genevieve Marcelin,‖ Melanie Greter,†,x Claudia Jakubzick,*,†,1 Milena Bogunovic,†,x Marylene Leboeuf,†,x Nico van Rooijen,# Andreas J. Habenicht,{ Miriam Merad,†,x and Gwendalyn J. Randolph*,†,‡ Although peroxisome proliferator-activated receptor g (PPARg) has anti-inflammatory actions in macrophages, which macro- Downloaded from phage populations express PPARg in vivo and how it regulates tissue homeostasis in the steady state and during inflammation remains unclear. We now show that lung and spleen macrophages selectively expressed PPARg among resting tissue macrophages. In addition, Ly-6Chi monocytes recruited to an inflammatory site induced PPARg as they differentiated to macrophages. When PPARg was absent in Ly-6Chi–derived inflammatory macrophages, initiation of the inflammatory response was unaffected, but full resolution of inflammation failed, leading to chronic leukocyte recruitment. Conversely, PPARg activation favored resolution of inflammation in a macrophage PPARg-dependent manner. In the steady state, PPARg deficiency in red pulp macrophages did http://www.jimmunol.org/ not induce overt inflammation in the spleen. By contrast, PPARg deletion in lung macrophages induced mild pulmonary inflam- mation at the steady state and surprisingly precipitated mortality upon infection with Streptococcus pneumoniae. This accelerated mortality was associated with impaired bacterial clearance and inability to sustain macrophages locally. Overall, we uncovered critical roles for macrophage PPARg in promoting resolution of inflammation and maintaining functionality in lung macrophages where it plays a pivotal role in supporting pulmonary host defense. In addition, this work identifies specific macrophage pop- ulations as potential targets for the anti-inflammatory actions of PPARg agonists. The Journal of Immunology, 2012, 189: 2614– 2624. by guest on September 29, 2021 eroxisome proliferator-activated receptor g (PPARg)is nedione family, the latter being used clinically to improve insulin a ligand-controlled transcription factor of the nuclear re- sensitivity in type 2 diabetic patients (3). P ceptor family capable of regulating gene expression by The anti-inflammatory role of PPARg came to the forefront in transactivation or transrepression (1). First discovered as the master the late 1990s when 15-deoxy-d-12,14-PG J2 (15d-PGJ2) and thia- regulator of the genetic program supporting adipocyte differenti- zolidinediones were shown to dampen macrophage activation ation, PPARg is involved in the regulation of a number of phys- in vitro by activating PPARg (4, 5). Since then, the anti-inflammatory iological processes such as the response to insulin, cell proliferation, role of PPARg agonists has been extensively documented in vitro cellular lipid metabolism, and inflammation (2). Thus, PPARg and in vivo (1, 6). Indeed, PPARg agonists suppress dextran so- activation is an attractive therapeutic target in a variety of diseases dium sulfate-induced colitis (7), obesity-induced insulin resistance such as type 2 diabetes, cancer, atherosclerosis, and immune (8), and the progression of atherosclerosis (9). By contrast, dele- disorders. Activation of PPARg can be achieved by natural fatty tion of PPARg in macrophages exacerbates the development of acid derivatives as well as synthetic ligands from the thiazolidi- atherosclerosis (10, 11), colitis (12), and obesity-induced insulin *Department of Developmental and Regenerative Biology, Mount Sinai School of (10POST4160140), and A.C. is funded by a fellowship from the National Institutes Medicine, New York, NY 10029; †Immunology Institute, Mount Sinai School of of Health, National Heart, Lung, and Blood Institute 5F30HL099028-02. Medicine, New York, NY 10029; ‡Department of Pathology and Immunology, Wash- x The datasets presented in this article have been submitted to the National Center for ington University, St. Louis, MO 63110; Department of Oncological Sciences, { Biotechnology Information/Gene Expression Omnibus (http://www.ncbi.nlm.nih. Mount Sinai School of Medicine, New York, NY 10029; Institute for Vascular gov/geo/) under accession numbers GSE15907 and GSE32034. Medicine, Friedrich Schiller University of Jena, Jena University Hospital, 07743 Jena, Germany; ‖Albert Einstein College of Medicine, Bronx, NY 10461; Address correspondence and reprint requests to Dr. Emmanuel L. Gautier and and #Department of Molecular Cell Biology, Free University Medical Center, 1007 Dr. Gwendalyn J. Randolph, Department of Pathology and Immunology, Washington Amsterdam, The Netherlands University, 660 South Euclid Avenue, Campus Box 8118, St. Louis, MO 63110. E-mail addresses: [email protected] (E.L.G.) and [email protected]. 1Current address: Integrated Department of Immunology, National Jewish Health, edu (G.J.R.) University of Colorado, Denver, CO. The online version of this article contains supplemental material. Received for publication February 9, 2012. Accepted for publication July 4, 2012. Abbreviations used in this article: DC, dendritic cell; 15d-PGJ , 15-deoxy-d-12,14-PG This work was supported by National Institutes of Health Grants AI061741 and 2 J2; FABP4, fatty acid binding protein 4; PAP, pulmonary alveolar proteinosis; PPAR, AI049653 and American Heart Association Established Investigator Award peroxisome proliferator-activated receptor. 0740052 (to G.J.R.), National Institutes of Health Grant HL086899 (to M.M.), Deut- sche Forschungsgemeinschaft Project Grant SP71314-1 (to R.S.), and Deutsche Ó Forschungsgemeinschaft Project Grants Ha 1083/16-1 and Ha 1083/15-1 (to A.J.H.). Copyright 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 E.L.G. is supported by a fellowship from the American Heart Association www.jimmunol.org/cgi/doi/10.4049/jimmunol.1200495 The Journal of Immunology 2615 resistance (13). On the basis of these studies, a model emerges subsets were CD11c+MHC II+ cells that differentially expressed CD4 + + 2 2 2 + wherein macrophages are universally central targets of PPARg (CD11b CD4 CD8 ) or CD8 (CD11b CD4 CD8 ) (21). RNA was pre- modulation. However, it is not known whether all monocyte/ pared from sorted populations from C57BL/6J mice after sorting directly into TRIzol reagent, amplified, and hybridized on the Affymetrix Mouse macrophage populations express PPARg or rely on its activation Gene 1.0 ST. For data analysis using ImmGen datasets, raw data for all to maintain homeostasis or to carry out their functions in different populations were normalized using the robust multiarray averaging algo- organs during inflammation. Ultimately, the design and develop- rithm. Extensive quality control documents are available on the Immgen ment of therapeutic strategies based on the use of PPARg agonists Web site. All datasets have been deposited at the National Center for Biotechnology Information/Gene Expression Omnibus under accession to combat inflammatory diseases would benefit from the identifi- number GSE15907 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc= cation of the specific macrophage populations potentially respon- GSE15907). Microarrays on blood monocytes treated with a PPARg ag- sive to these agonists. onist were performed as previously described (15) using Affymetrix GeneChip In this context, we decided to profile the expression of PPARg 430 2.0 arrays. Corresponding datasets have been deposited at National in a range of macrophage populations extracted from different Center for Biotechnology Information/Gene Expression Omnibus under accession number GSE32034 (http://www.ncbi.nlm.nih.gov/geo/query/acc.
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