{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:53:51Z","timestamp":1790650431755,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2018,3,17]],"date-time":"2018-03-17T00:00:00Z","timestamp":1521244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Macrophages play a central role in the pathogenesis of inflammatory and fibrotic lung diseases. However, alveolar macrophages (AM) are poorly available in humans to perform in vitro studies due to a limited access to broncho-alveolar lavage (BAL). In this study, to identify the best alternative in vitro model for human AM, we compared the phenotype of AM obtained from BAL of patients suffering from three lung diseases (lung cancers, sarcoidosis and Systemic Sclerosis (SSc)-associated interstitial lung disease) to human blood monocyte-derived macrophages (MDMs) differentiated with M-CSF or GM-CSF. The expression of eight membrane markers was evaluated by flow cytometry. Globally, AM phenotype was closer to GM-CSF MDMs. However, the expression levels of CD163, CD169, CD204, CD64 and CD36 were significantly higher in SSc-ILD than in lung cancers. Considering the expression of CD204 and CD36, the phenotype of SSc-AM was closer to MDMs, from healthy donors or SSc patients, differentiated by M-CSF rather than GM-CSF. The comparative secretion of IL-6 by SSc-MDMs and SSc-AM is concordant with these phenotypic considerations. Altogether, these results support the M-CSF MDM model as a relevant in vitro alternative to simulate AM in fibrotic disorders such as SSc.<\/jats:p>","DOI":"10.3390\/ijms19030894","type":"journal-article","created":{"date-parts":[[2018,3,20]],"date-time":"2018-03-20T06:57:11Z","timestamp":1521529031000},"page":"894","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Distinct Properties of Human M-CSF and GM-CSF Monocyte-Derived Macrophages to Simulate Pathological Lung Conditions In Vitro: Application to Systemic and Inflammatory Disorders with Pulmonary Involvement"],"prefix":"10.3390","volume":"19","author":[{"given":"Alain","family":"Lescoat","sequence":"first","affiliation":[{"name":"Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)-UMR_S 1085, F-35000 Rennes, France"},{"name":"Department of Internal Medicine, Rennes University Hospital, 35203 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Ballerie","sequence":"additional","affiliation":[{"name":"Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)-UMR_S 1085, F-35000 Rennes, France"},{"name":"Department of Internal Medicine, Rennes University Hospital, 35203 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Augagneur","sequence":"additional","affiliation":[{"name":"Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)-UMR_S 1085, F-35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudie","family":"Morzadec","sequence":"additional","affiliation":[{"name":"Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)-UMR_S 1085, F-35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Vernhet","sequence":"additional","affiliation":[{"name":"Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)-UMR_S 1085, F-35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5657-4255","authenticated-orcid":false,"given":"Olivier","family":"Fardel","sequence":"additional","affiliation":[{"name":"Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)-UMR_S 1085, F-35000 Rennes, France"},{"name":"P\u00f4le Biologie, Rennes University Hospital, 35203 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"J\u00e9go","sequence":"additional","affiliation":[{"name":"Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)-UMR_S 1085, F-35000 Rennes, France"},{"name":"Department of Internal Medicine, Rennes University Hospital, 35203 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1949-3461","authenticated-orcid":false,"given":"St\u00e9phane","family":"Jouneau","sequence":"additional","affiliation":[{"name":"Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)-UMR_S 1085, F-35000 Rennes, France"},{"name":"Department of Respiratory Diseases, Rennes University Hospital, 35203 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Lecureur","sequence":"additional","affiliation":[{"name":"Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)-UMR_S 1085, F-35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nri3073","article-title":"Protective and pathogenic functions of macrophage subsets","volume":"11","author":"Murray","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nri2784","article-title":"Unravelling mononuclear phagocyte heterogeneity","volume":"10","author":"Geissmann","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6533","DOI":"10.4049\/jimmunol.167.11.6533","article-title":"Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1\/type 2 cytokines in vivo: Granulomatous pathology is shaped by the pattern of l-arginine metabolism","volume":"167","author":"Hesse","year":"2001","journal-title":"J. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the full spectrum of macrophage activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"342","DOI":"10.4049\/jimmunol.175.1.342","article-title":"Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences","volume":"175","author":"Stout","year":"2005","journal-title":"J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1164\/rccm.200609-1279OC","article-title":"Important roles for macrophage colony-stimulating factor, CC chemokine ligand 2, and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis","volume":"176","author":"Baran","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mahoney, J.M., Taroni, J., Martyanov, V., Wood, T.A., Greene, C.S., Pioli, P.A., Hinchcliff, M.E., and Whitfield, M.L. (2015). Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms. PLoS Comput. Biol., 11.","DOI":"10.1371\/journal.pcbi.1004005"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1164\/rccm.200406-788PP","article-title":"Lung inflammation and fibrosis: An alveolar macrophage-centered perspective from the 1970s to 1980s","volume":"171","author":"Reynolds","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s11926-015-0554-8","article-title":"Macrophage Involvement in Systemic Sclerosis: Do We Need More Evidence?","volume":"18","author":"Stifano","year":"2016","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lescoat, A., Coiffier, G., de Carlan, M., Droitcourt, C., Ballerie, A., Cazalets, C., Perdriger, A., and Jego, P. (2017). Combination of capillaroscopic and ultrasonographic evaluations in systemic sclerosis: Results of a cross-sectional study. Arthritis Care Res.","DOI":"10.1136\/annrheumdis-2017-eular.4278"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.cellimm.2013.01.010","article-title":"Polarization profiles of human M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin","volume":"281","author":"Jaguin","year":"2013","journal-title":"Cell Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4560","DOI":"10.1073\/pnas.0400983101","article-title":"Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria","volume":"101","author":"Verreck","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13","DOI":"10.12703\/P6-13","article-title":"The M1 and M2 paradigm of macrophage activation: Time for reassessment","volume":"6","author":"Martinez","year":"2014","journal-title":"F1000Prime Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S1074-7613(00)80063-1","article-title":"The M cell as a portal of entry to the lung for the bacterial pathogen Mycobacterium tuberculosis","volume":"10","author":"Teitelbaum","year":"1999","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1007\/s11882-010-0134-y","article-title":"Immune dysregulation in the pathogenesis of pulmonary alveolar proteinosis","volume":"10","author":"Huston","year":"2010","journal-title":"Curr. Allergy Asthma Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1183\/13993003.00252-2016","article-title":"Association of pulmonary alveolar proteinosis and fibrosis: Patient with GATA2 deficiency","volume":"48","author":"Ballerie","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"R128","DOI":"10.1186\/ar3066","article-title":"Characterization of monocyte\/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis","volume":"12","author":"Jinnin","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1002\/art.22382","article-title":"A macrophage marker, Siglec-1, is increased on circu- lating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists","volume":"56","author":"York","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1002\/art.30318","article-title":"Interferon and alternative activation of monocyte\/macrophages in systemic sclerosis-associated pulmonary arterial hypertension","volume":"63","author":"Christmann","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1002\/art.38288","article-title":"Association of Interferon- and transforming growth factor beta-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis","volume":"66","author":"Christmann","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1136\/annrheumdis-2014-207109","article-title":"Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis","volume":"75","author":"Huang","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1136\/annrheumdis-2016-210823","article-title":"Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis","volume":"76","author":"Huang","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.4049\/jimmunol.1700373","article-title":"A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease","volume":"198","author":"PrabhuDas","year":"2017","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"L186","DOI":"10.1152\/ajplung.00474.2004","article-title":"Scavenger receptor class A type I\/II (CD204) null mice fail to develop fibrosis following silica exposure","volume":"289","author":"Beamer","year":"2005","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/343531a0","article-title":"Type I macrophage scavenger receptor contains-helical and collagen-like coiled coils","volume":"343","author":"Kodama","year":"1990","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1172\/JCI200113903","article-title":"Is the class A macrophage scavenger receptor (SR-A) multifunctional?\u2014The mouse\u2019s tale","volume":"108","author":"Platt","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Stahl, M., Schupp, J., J\u00e4ger, B., Schmid, M., Zissel, G., M\u00fcller-Quernheim, J., and Prasse, A. (2013). Lung collagens perpetuate pulmonary fibrosis via CD204 and M2 macrophageactivation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0081382"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1513\/AnnalsATS.201303-069FR","article-title":"Pulmonary fibrosis in sarcoidosis. Clinical features and outcomes","volume":"10","author":"Patterson","year":"2013","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/S0140-6736(13)60680-7","article-title":"Sarcoidosis","volume":"383","author":"Valeyre","year":"2014","journal-title":"Lancet"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/1465-9921-11-121","article-title":"No evidence of altered alveolar macrophage polarization, but reduced expression of TLR2, in bronchoalveolar lavage cells in sarcoidosis","volume":"11","author":"Idali","year":"2010","journal-title":"Respir. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1183\/09031936.00131713","article-title":"Serum CCL18 is predictive for lung disease progression and mortality in systemic sclerosis","volume":"43","author":"Schupp","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3899\/jrheum.150474","article-title":"Monocytic Angiotensin and Endothelin Receptor Imbalance Modulate Secretion of the Profibrotic Chemokine Ligand 18","volume":"43","author":"Rademacher","year":"2016","journal-title":"J. Rheumatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13073-017-0417-1","article-title":"A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis","volume":"9","author":"Taroni","year":"2017","journal-title":"Genome Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1007\/s10067-017-3597-6","article-title":"CD16-positive circulating monocytes and fibrotic manifestations of systemic sclerosis","volume":"36","author":"Lescoat","year":"2017","journal-title":"Clin. Rheumatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.4049\/jimmunol.1302269","article-title":"In vivo characterization of alveolar and interstitial lung macrophages in rhesus macaques: Implications for understanding lung disease in humans","volume":"192","author":"Cai","year":"2014","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/nrrheum.2017.190","article-title":"Systemic sclerosis: STAT3\u2014A key integrator of profibrotic signalling","volume":"13","author":"McHugh","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_37","first-page":"263","article-title":"Much More than M1 and M2 Macrophages, There are also CD169(+) and TCR(+) Macrophages","volume":"6","author":"Olleros","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1007\/s00262-017-2052-5","article-title":"Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression","volume":"66","author":"Fu","year":"2017","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2630","DOI":"10.1016\/S0140-6736(16)00232-4","article-title":"Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): A phase 2, randomised, controlled trial","volume":"387","author":"Khanna","year":"2016","journal-title":"Lancet"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1136\/annrheumdis-2011-200955","article-title":"Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis","volume":"71","author":"Khan","year":"2012","journal-title":"Ann. Rheum. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1002\/art.1780400422","article-title":"Cytokine concentrations in bronchoalveolar lavage fluid of patients with systemic sclerosis","volume":"40","author":"Bolster","year":"1997","journal-title":"Arthritis Rheum."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5752","DOI":"10.4049\/jimmunol.1103426","article-title":"Defining GM-CSF- and macrophage-CSF-dependent macrophage responses by in vitro models","volume":"188","author":"Lacey","year":"2012","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jim.2015.08.001","article-title":"Impact of Detachment Methods on M2 Macrophage Phenotype and Function","volume":"426","author":"Chen","year":"2015","journal-title":"J. Immunol. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/3\/894\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:57:31Z","timestamp":1760194651000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/3\/894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,17]]},"references-count":43,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,3]]}},"alternative-id":["ijms19030894"],"URL":"https:\/\/doi.org\/10.3390\/ijms19030894","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,17]]}}}