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01-04-2012

PTX3 Is Located at the Membrane of Late Apoptotic Macrophages and Mediates the Phagocytosis of Macrophages

Authors: Tangmeng Guo, Li Ke, Benling Qi, Jingjing Wan, Jing Ge, Lijuan Bai, Bei Cheng

Published in: Journal of Clinical Immunology | Issue 2/2012

Abstract

Apoptotic macrophages are removed by neighboring phagocytes (efferocytosis), which is an important event in advanced atherosclerosis. Recent reports have elucidated some key molecular regulators in efferocytosis including complement C1q, MFGE8, and MERTK. However, it remains unknown whether the long pentraxin 3 (PTX3), which is an important molecule that is involved in apoptotic cell clearance in the immune response, plays a part in efferocytosis during advanced atherosclerosis. In this study, we modeled macrophage apoptosis in advanced plaques by incubating macrophages (peritoneal macrophages isolated from C57 mice) with free cholesterol (free cholesterol-induced apoptotic macrophages, FC-AMs). FC-AMs were added to a monolayer of fresh phagocytes to study the engulfment response. We observed that PTX3 was mainly located at the membrane of late apoptotic macrophages. The anti-PTX3 monoclonal Ab 16B5 inhibited the engulfment of late apoptotic macrophages by phagocytes in a dose-dependent manner (from 14.63% inhibition at 5 μg/ml to 26.19% inhibition at 50 μg/ml). These results suggest that PTX3 located at the membrane of late apoptotic macrophages mediates their phagocytosis by phagocytes in a cell model of advanced atherosclerosis.

Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006;6:508–19.PubMedCrossRef

Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol. 2010;10:36–46.PubMedCrossRef

Kravitz MS, Pitashny M, Shoenfeld Y. Protective molecules—C-reactive protein (CRP), serum amyloid P (SAP), pentraxin3 (PTX3), mannose-binding lectin (MBL), and apolipoprotein A1 (Apo A1), and their autoantibodies: prevalence and clinical significance in autoimmunity. J Clin Immunol. 2005;25:582–91.PubMedCrossRef

Rovere P, Peri G, Fazzini F, Bottazzi B, Doni A, Bondanza A, Zimmermann VS, Garlanda C, Fascio U, Sabbadini MG, Rugarli C, Mantovani A, Manfredi AA. The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells. Blood. 2000;96:4300–6.PubMed

van Rossum AP, Fazzini F, Limburg PC, Manfredi AA, Rovere-Querini P, Mantovani A, Kallenberg CG. The prototypic tissue pentraxin PTX3, in contrast to the short pentraxin serum amyloid P, inhibits phagocytosis of late apoptotic neutrophils by macrophages. Arthritis Rheum. 2004;50:2667–74.PubMedCrossRef

Jaillon S, Jeannin P, Hamon Y, Fremaux I, Doni A, Bottazzi B, Blanchard S, Subra JF, Chevailler A, Mantovani A, Delneste Y. Endogenous PTX3 translocates at the membrane of late apoptotic human neutrophils and is involved in their engulfment by macrophages. Cell Death Differ. 2009;16:465–74.PubMedCrossRef

Nebuloni M, Pasqualini F, Zerbi P, Lauri E, Mantovani A, Vago L, Garlanda C. PTX3 expression in the heart tissues of patients with myocardial infarction and infectious myocarditis. Cardiovasc Pathol. 2011;20:e27–35.PubMedCrossRef

Peri G, Introna M, Corradi D, Iacuitti G, Signorini S, Avanzini F, Pizzetti F, Maggioni AP, Moccetti T, Metra M, Cas LD, Ghezzi P, Sipe JD, Re G, Olivetti G, Mantovani A, Latini R. PTX3, A prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans. Circulation. 2000;102:636–41.PubMed

Rolph MS, Zimmer S, Bottazzi B, Garlanda C, Mantovani A, Hansson GK. Production of the long pentraxin PTX3 in advanced atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2002;22:e10–14.PubMedCrossRef

10.

Souza DG, Soares AC, Pinho V, Torloni H, Reis LF, Teixeira MM, Dias AA. Increased mortality and inflammation in tumor necrosis factor-stimulated gene-14 transgenic mice after ischemia and reperfusion injury. Am J Pathol. 2002;160:1755–65.PubMedCrossRef

11.

Salio M, Chimenti S, De Angelis N, Molla F, Maina V, Nebuloni M, Pasqualini F, Latini R, Garlanda C, Mantovani A. Cardioprotective function of the long pentraxin PTX3 in acute myocardial infarction. Circulation. 2008;117:1055–64.PubMedCrossRef

12.

Brugger-Andersen T, Ponitz V, Kontny F, Staines H, Grundt H, Sagara M, Nilsen DW. The long pentraxin 3 (PTX3): a novel prognostic inflammatory marker for mortality in acute chest pain. Thromb Haemost. 2009;102:555–63.PubMed

13.

Kume N, Mitsuoka H, Hayashida K & Tanaka M: Pentraxin 3 as a biomarker for acute coronary syndrome: comparison with biomarkers for cardiac damage. J Cardiol. 2011

14.

Maekawa Y, Nagai T & Anzai A: Pentraxins: CRP and PTX3 and cardiovascular disease. Inflamm Allergy Drug Targets. 2011

15.

Matsubara J, Sugiyama S, Nozaki T, Sugamura K, Konishi M, Ohba K, Matsuzawa Y, Akiyama E, Yamamoto E, Sakamoto K, Nagayoshi Y, Kaikita K, Sumida H, Kim-Mitsuyama S, Ogawa H. Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction. J Am Coll Cardiol. 2011;57:861–9.PubMedCrossRef

16.

Jenny NS, Arnold AM, Kuller LH, Tracy RP. & Psaty BM:Associations of pentraxin 3 with cardiovascular disease and all-cause death: the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 2009;29:594–9.PubMedCrossRef

17.

Lee DH, Jeon HK, You JH, Park MY, Lee SJ, Kim SS, Shim BJ, Choi YS, Shin WS, Lee JM, Park CS, Youn HJ, Chung WS, Kim JH. Pentraxin 3 as a novel marker predicting congestive heart failure in subjects with acute coronary syndrome. Korean Circ J. 2010;40:370–6.PubMedCrossRef

18.

Matsui S, Ishii J, Kitagawa F, Kuno A, Hattori K, Ishikawa M, Okumura M, Kan S, Nakano T, Naruse H, Tanaka I, Nomura M, Hishida H, Ozaki Y. Pentraxin 3 in unstable angina and non-ST-segment elevation myocardial infarction. Atherosclerosis. 2010;210:220–5.PubMedCrossRef

19.

Atzeni F, Turiel M, Hollan I, Meroni P, Sitia S, Tomasoni L, Sarzi-Puttini P. Usefulness of cardiovascular biomarkers and cardiac imaging in systemic rheumatic diseases. Autoimmun Rev. 2010;9:845–8.PubMedCrossRef

20.

Thorp EB. Mechanisms of failed apoptotic cell clearance by phagocyte subsets in cardiovascular disease. Apoptosis. 2010;15:1124–36.PubMedCrossRef

21.

Yano Y, Matsuda S, Hatakeyama K, Sato Y, Imamura T, Shimada K, Kodama T, Kario K, Asada Y. Plasma pentraxin 3, but not high-sensitivity C-reactive protein, is a useful inflammatory biomarker for predicting cognitive impairment in elderly hypertensive patients. J Gerontol A Biol Sci Med Sci. 2010;65:547–52.PubMedCrossRef

22.

Li Y, Ge M, Ciani L, Kuriakose G, Westover EJ, Dura M, Covey DF, Freed JH, Maxfield FR, Lytton J, Tabas I. Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages. J Biol Chem. 2004;279:37030–9.PubMedCrossRef

23.

Li Y, Gerbod-Giannone MC, Seitz H, Cui D, Thorp E, Tall AR, Matsushima GK, Tabas I. Cholesterol-induced apoptotic macrophages elicit an inflammatory response in phagocytes, which is partially attenuated by the Mer receptor. J Biol Chem. 2006;281:6707–17.PubMedCrossRef

24.

Gaipl US, Kuenkele S, Voll RE, Beyer TD, Kolowos W, Heyder P, Kalden JR, Herrmann M. Complement binding is an early feature of necrotic and a rather late event during apoptotic cell death. Cell Death Differ. 2001;8:327–34.PubMedCrossRef

25.

Chen T, Xu Y, Guo H, Liu Y, Hu P, Yang X, Li X, Ge S, Velu SE, Nadkarni DH, Wang W, Zhang R, Wang H. Experimental therapy of ovarian cancer with synthetic makaluvamine analog: in vitro and in vivo anticancer activity and molecular mechanisms of action. PLoS One. 2011;6:e20729.PubMedCrossRef

26.

Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol. 1992;148:2207–16.PubMed

27.

Steinberg D, Lewis A. Conner Memorial Lecture. Oxidative modification of LDL and atherogenesis. Circulation. 1997;95:1062–71.PubMed

28.

Kinscherf R, Claus R, Wagner M, Gehrke C, Kamencic H, Hou D, Nauen O, Schmiedt W, Kovacs G, Pill J, Metz J, Deigner HP. Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent. FASEB J. 1998;12:461–7.PubMed

29.

Tabas I. Apoptosis and plaque destabilization in atherosclerosis: the role of macrophage apoptosis induced by cholesterol. Cell Death Differ. 2004;11(1):S12–16.PubMedCrossRef

30.

Tabas I. Consequences of cellular cholesterol accumulation: basic concepts and physiological implications. J Clin Invest. 2002;110:905–11.PubMed

31.

Yao PM, Tabas I. Free cholesterol loading of macrophages induces apoptosis involving the fas pathway. J Biol Chem. 2000;275:23807–13.PubMedCrossRef

32.

Alles VV, Bottazzi B, Peri G, Golay J, Introna M, Mantovani A. Inducible levelsion of PTX3, a new member of the pentraxin family, in human mononuclear phagocytes. Blood. 1994;84:3483–93.PubMed

33.

Majai G, Sarang Z, Csomos K, Zahuczky G, Fesus L. PPARgamma-dependent regulation of human macrophages in phagocytosis of apoptotic cells. Eur J Immunol. 2007;37:1343–54.PubMedCrossRef

34.

Klouche M, Peri G, Knabbe C, Eckstein HH, Schmid FX, Schmitz G, Mantovani A. Modified atherogenic lipoproteins induce levelsion of pentraxin-3 by human vascular smooth muscle cells. Atherosclerosis. 2004;175:221–8.PubMedCrossRef

35.

Jaillon S, Peri G, Delneste Y, Fremaux I, Doni A, Moalli F, Garlanda C, Romani L, Gascan H, Bellocchio S, Bozza S, Cassatella MA, Jeannin P, Mantovani A. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med. 2007;204:793–804.PubMedCrossRef

36.

Nauta AJ, Bottazzi B, Mantovani A, Salvatori G, Kishore U, Schwaeble WJ, Gingras AR, Tzima S, Vivanco F, Egido J, Tijsma O, Hack EC, Daha MR, Roos A. Biochemical and functional characterization of the interaction between pentraxin 3 and C1q. Eur J Immunol. 2003;33:465–73.PubMedCrossRef

37.

Baruah P, Dumitriu IE, Peri G, Russo V, Mantovani A, Manfredi AA, Rovere-Querini P. The tissue pentraxin PTX3 limits C1q-mediated complement activation and phagocytosis of apoptotic cells by dendritic cells. J Leukoc Biol. 2006;80:87–95.PubMedCrossRef

38.

Baruah P, Propato A, Dumitriu IE, Rovere-Querini P, Russo V, Fontana R, Accapezzato D, Peri G, Mantovani A, Barnaba V, Manfredi AA. The pattern recognition receptor PTX3 is recruited at the synapse between dying and dendritic cells, and edits the cross-presentation of self, viral, and tumor antigens. Blood. 2006;107:151–8.PubMedCrossRef

Title: PTX3 Is Located at the Membrane of Late Apoptotic Macrophages and Mediates the Phagocytosis of Macrophages
Authors: Tangmeng Guo
Li Ke
Benling Qi
Jingjing Wan
Jing Ge
Lijuan Bai
Bei Cheng
Publication date: 01-04-2012
Publisher: Springer US
Published in: Journal of Clinical Immunology / Issue 2/2012
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-011-9615-6

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