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The Prolyl Hydroxylase PHD3 Identifies Proinflammatory Macrophages and Its Expression Is Regulated by Activin A

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The Prolyl Hydroxylase PHD3 Identifies Proinflammatory Macrophages and Its Expression Is Regulated by Activin A The Prolyl Hydroxylase PHD3 Identifies Proinflammatory Macrophages and Its Expression Is Regulated by Activin A This information is current as María M. Escribese, Elena Sierra-Filardi, Concha Nieto, of September 25, 2021. Rafael Samaniego, Carmen Sánchez-Torres, Takami Matsuyama, Elisabeth Calderon-Gómez, Miguel A. Vega, Azucena Salas, Paloma Sánchez-Mateos and Angel L. Corbí J Immunol published online 9 July 2012 http://www.jimmunol.org/content/early/2012/07/09/jimmun Downloaded from ol.1201064 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 *average by guest on September 25, 2021 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 9, 2012, doi:10.4049/jimmunol.1201064 The Journal of Immunology The Prolyl Hydroxylase PHD3 Identifies Proinflammatory Macrophages and Its Expression Is Regulated by Activin A Marı´a M. Escribese,* Elena Sierra-Filardi,* Concha Nieto,* Rafael Samaniego,† Carmen Sa´nchez-Torres,‡ Takami Matsuyama,x Elisabeth Calderon-Go´mez,{ Miguel A. Vega,* Azucena Salas,{ Paloma Sa´nchez-Mateos,† and Angel L. Corbı´* Modulation of macrophage polarization underlies the onset and resolution of inflammatory processes, with polarization-specific molecules being actively sought as potential diagnostic and therapeutic tools. Based on their cytokine profile upon exposure to pathogenic stimuli, human monocyte-derived macrophages generated in the presence of GM-CSF or M-CSF are considered as proinflammatory (M1) or anti-inflammatory (M2) macrophages, respectively. We report in this study that the prolyl hydroxylase PHD3-encoding EGLN3 gene is specifically expressed by in vitro-generated proinflammatory M1(GM-CSF) human macrophages at the mRNA and protein level. Immunohistochemical analysis revealed the expression of PHD3 in CD163+ lung macrophages Downloaded from under basal homeostatic conditions, whereas PHD3+ macrophages were abundantly found in tissues undergoing inflammatory responses (e.g., Crohn’s disease and ulcerative colitis) and in tumors. In the case of melanoma, PHD3 expression marked a subset of tumor-associated macrophages that exhibit a weak (e.g., CD163) or absent (e.g., FOLR2) expression of typical M2-polarization markers. EGLN3 gene expression in proinflammatory M1(GM-CSF) macrophages was found to be activin A dependent and could be prevented in the presence of an anti-activin A-blocking Ab or inhibitors of activin receptor-like kinase receptors. Moreover, EGLN3 gene expression was upregulated in response to hypoxia only in M2(M-CSF) macrophages, and the hypoxia-mediated http://www.jimmunol.org/ upregulation of EGLN3 expression was significantly impaired by activin A neutralization. These results indicate that EGLN3 gene expression in macrophages is dependent on activin A both under basal and hypoxic conditions and that the expression of the EGLN3-encoded PHD3 prolyl hydroxylase identifies proinflammatory macrophages in vivo and in vitro. The Journal of Immu- nology, 2012, 189: 000–000. he extreme sensitivity of macrophages to endogenous existence of a plethora of macrophage polarization states is critical (e.g., cytokines) and exogenous (e.g., pathogens) stimuli for the adequate onset, regulation, and resolution of immune and T explains their phenotypic and functional heterogeneity inflammatory responses (2). As a representative example, although by guest on September 25, 2021 under homeostatic and pathological conditions (1). In fact, the GM-CSF and M-CSF contribute to macrophage survival and proliferation, they exert distinct actions on macrophage polariza- tion. GM-CSF gives rise to monocyte-derived macrophages that *Laboratorio de Ce´lulas Mieloides, Centro de Investigaciones Biolo´gicas, Consejo Superior de Investigaciones Cientı´ficas, Madrid 28040, Spain; †Hospital General exhibit high Ag-presenting capacity and produce proinflammatory Universitario Gregorio Maran˜o´n, Madrid 28007, Spain; ‡Departamento de Biomedi- cytokines in response to LPS (3, 4). Conversely, M-CSF generates cina Molecular, Centro de Investigacio´n y de Estudios Avanzados del Instituto Poli- x macrophages with high phagocytic activity and IL-10–producing te´cnico Nacional, Mexico DF 07360, Mexico; Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890- ability in response to pathogens (3, 4). Based on their respective 8544, Japan; and {Institut d’Investigacions Biome`diques August Pi i Sunyer, Centre cytokine profiles, human macrophages generated in the presence Esther Koplowitz, Barcelona 08036, Spain of GM-CSF or M-CSF are representative of the classical or al- Received for publication April 10, 2012. Accepted for publication June 9, 2012. ternative macrophage polarization states, respectively, and are This work was supported by grants from Ministerio de Economı´a y Competitividad considered as proinflammatory or anti-inflammatory macrophages (BFU2008-01493-BMC and SAF2011-23801), Genoma Espan˜a (Molecular and Cel- lular Mechanisms in Chronic Inflammatory and Autoimmune Diseases project), Insti- (3, 5). tuto de Salud Carlos III (Spanish Network for the Research in Infectious Diseases Variation in the levels of oxygen is a parameter that also RD06/0008 and Red de Investigacio´n en SIDA RD06/0006/1016), Comunidad determines the state of macrophage polarization (6). In healthy Auto´noma de Madrid/Fondo Europeo de Desarrollo Regional (Rheumatoid Arthritis: Physiopathology Mechanisms and Identification of Potential Therapeutic Targets tissues, oxygen levels span from 150 mmHg in the lung to 40–100 Program) (to A.L.C.), Grant SAF2010-1602 from the Ministerio de Ciencia e Inno- mmHg in the circulation and 4–20 mmHg in the tissues (7). vacion (to P.S.-M.), and Grant Agreement 229673 from the European Community’s Pathologic hypoxia, commonly found in malignant solid tumors, Seventh Framework Programme (FP7/2009-2013). M.M.E. is supported by a Sara Borrell postdoctoral contract from Instituto de Salud Carlos III (CD09/00386). inflammatory lesions, and healing wounds (8–10), also influences M.M.E., E.-S.F., C.N., R.S., and C.S.-T. performed research and analyzed data; T.M., macrophage polarization and leads to transcriptional and meta- M.A.V., and P.S.-M. contributed vital reagents; and M.M.E. and A.L.C. designed the bolic changes (6) and the acquisition of effector functions to research, analyzed data, and wrote the paper. promote angiogenesis and restore tissue homeostasis (7, 11, 12). Address correspondence and reprint requests to Dr. Marı´a M. Escribese and Dr. Macrophages accumulate in large numbers in damaged hypoxic Angel L. Corbı´, Centro de Investigaciones Biolo´gicas, Consejo Superior de Inves- tigaciones Cientı´ficas, Ramiro de Maeztu 9, Madrid 28040, Spain. E-mail addresses: tissues and respond to hypoxia by altering their gene expression [email protected] and [email protected] program via upregulation of the hypoxia-inducible factor (HIF) 1 Abbreviations used in this article: FRb, folate receptor b; HIF, hypoxia-inducible (HIF1a/HIF1b)andHIF2(HIF2a/HIF1b) transcription factors factor; PHD3, prolyl hydroxylase 3; qRT-PCR, quantitative real-time RT-PCR; TAM, (13, 14). In the presence of oxygen, both a subunits are prolyl- tumor-associated macrophage. hydroxylated, recognized by the von Hippel-Lindau tumor Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 suppressor protein (15–17), and degraded by the ubiquitin- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1201064 2 PHD3 EXPRESSION IN PROINFLAMMATORY MACROPHAGES proteasome pathway (17). The three HIF prolyl hydroxylases medium for 48 h in the absence of GM-CSF, after which the conditioned (PHD1–3) (16, 18) require molecular oxygen as a cosubstrate and, medium was collected. Cells were routinely cultured in 21% O2 and 5% therefore, constitute the link between oxygen availability and HIF- CO2 (normoxic conditions). For hypoxic conditions, cells were placed in an in vivo 400 hypoxia Work Station (Ruskinn Technology) that was in- dependent transcription (19). fused with a mixture of 1% O2,5%CO2, and 94% N2 (Sociedad Espan˜ola The prolyl hydroxylase PHD3 is encoded by the EGLN3 gene, de Carburos Meta´licos) for 24 h and treated or not with the activin for which expression is upregulated in platelet-derived growth receptor-like kinase (ALK)4/5/7 inhibitor SB431542 (Sigma-Aldrich) or factor-stimulated rat fibroblasts (20). PHD3 is involved in nerve- an anti-activin A-blocking Ab (R&D Systems). growth factor-dependent survival of neurons (21), stimulates py- Quantitative real-time RT-PCR ruvate kinase M2 coactivation for HIF1 (22), and also participates Oligonucleotides for selected genes were designed according to the Roche in HIF-independent processes to control cell death, changes in software for quantitative real-time PCR (Roche
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