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The long pentraxin PTX3 (pentraxin 3) has emerged as a component of humoral innate immunity with essential functions in the resolution of inflammation, but its role during granuloma formation is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Peripheral blood mononuclear cells obtained from patients with sarcoidosis harboring loss-of-function genetic variants and gene-deleted mice were used to assess the role of PTX3 in experimental models of granuloma formation in vitro and in vivo. The identified mechanisms of granulomatous inflammation were further evaluated in tissue and BAL samples and correlated with the disease course.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>We have identified a molecular link between PTX3 deficiency and the pathogenic amplification of complement activation to promote granuloma formation. Mechanistically, PTX3 deficiency licensed the complement component C5a-mediated activation of the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) and the reprogramming of macrophages toward increased glycolysis to foster their proliferation and aggregation. This process sustained the further recruitment of granuloma-promoting immune cells and the associated proinflammatory microenvironment and influenced the clinical course of the disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results identify PTX3 as a pivotal molecule that regulates complement-mediated signaling cues in macrophages to restrain granulomatous inflammation and highlight the therapeutic potential of this signaling axis in targeting granuloma formation in sarcoidosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202112-2771oc","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T14:11:01Z","timestamp":1656511861000},"page":"1140-1152","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":20,"title":["Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis"],"prefix":"10.1093","volume":"206","author":[{"given":"Relber A.","family":"Gon\u00e7ales","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal"},{"name":"ICVS\/3B\u2019s - PT Government Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"}]},{"given":"Helder Novais","family":"Bastos","sequence":"additional","affiliation":[{"name":"i3S - Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade"},{"name":"IBMC - Instituto de Biologia Molecular e Celular"},{"name":"Department of Pneumology and"}]},{"given":"Cl\u00e1udio","family":"Duarte-Oliveira","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal"},{"name":"ICVS\/3B\u2019s - PT Government Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"}]},{"given":"Daniela","family":"Antunes","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal"},{"name":"ICVS\/3B\u2019s - PT Government Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"}]},{"given":"Oksana","family":"Sokhatska","sequence":"additional","affiliation":[{"name":"Basic and Clinical Immunology, Department of Pathology, Faculty of Medicine, and"}]},{"given":"Maria","family":"Jacob","sequence":"additional","affiliation":[{"name":"Department of Pneumology and"}]},{"given":"Rui","family":"Rolo","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Hospital de Braga, Braga, Portugal"}]},{"given":"Cl\u00e1udia F.","family":"Campos","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal"},{"name":"ICVS\/3B\u2019s - PT Government Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"}]},{"given":"Sergio D.","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal"},{"name":"ICVS\/3B\u2019s - PT Government Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"},{"name":"Centro de Ci\u00eancias Naturais e Humanas, Universidade Federal do ABC, S\u00e3o Bernardo do Campo, S\u00e3o Paulo, Brazil"}]},{"given":"Alessia","family":"Donato","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy"}]},{"given":"Sarah N.","family":"Mapelli","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy"}]},{"given":"Sandra","family":"Costa","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal"},{"name":"ICVS\/3B\u2019s - PT Government Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"}]},{"given":"Concei\u00e7\u00e3o Souto","family":"Moura","sequence":"additional","affiliation":[{"name":"Department of Pathology, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o, Porto, Portugal"}]},{"given":"Lu\u00eds","family":"Delgado","sequence":"additional","affiliation":[{"name":"Basic and Clinical Immunology, Department of Pathology, Faculty of Medicine, and"},{"name":"Center for Health Technology and Services Research (CINTESIS@RISE), Faculty of Medicine, University of Porto, Porto, Portugal"}]},{"given":"Ant\u00f3nio","family":"Morais","sequence":"additional","affiliation":[{"name":"Department of Pneumology and"}]},{"given":"Eg\u00eddio","family":"Torrado","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal"},{"name":"ICVS\/3B\u2019s - PT Government Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1121-4894","authenticated-orcid":false,"given":"Frank L.","family":"van de Veerdonk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands"}]},{"given":"Thomas","family":"Weichhart","sequence":"additional","affiliation":[{"name":"Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria"}]},{"given":"John D.","family":"Lambris","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and"}]},{"given":"Ricardo","family":"Silvestre","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal"},{"name":"ICVS\/3B\u2019s - 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