دورية أكاديمية
Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis.
| العنوان: | Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis. |
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| المؤلفون: | Gonçales RA; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., Bastos HN; i3S - Instituto de Investigação e Inovação em Saúde.; IBMC - Instituto de Biologia Molecular e Celular.; Department of Pneumology and., Duarte-Oliveira C; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., Antunes D; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., Sokhatska O; Basic and Clinical Immunology, Department of Pathology, Faculty of Medicine, and., Jacob M; Department of Pneumology and., Rolo R; Department of Pneumology, Hospital de Braga, Braga, Portugal., Campos CF; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., Sasaki SD; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.; Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, São Bernardo do Campo, São Paulo, Brazil., Donato A; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy., Mapelli SN; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy., Costa S; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., Moura CS; Department of Pathology, Centro Hospitalar Universitário de São João, Porto, Portugal., Delgado L; Basic and Clinical Immunology, Department of Pathology, Faculty of Medicine, and.; Center for Health Technology and Services Research (CINTESIS@RISE), Faculty of Medicine, University of Porto, Porto, Portugal., Morais A; Department of Pneumology and., Torrado E; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., van de Veerdonk FL; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands., Weichhart T; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria., Lambris JD; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and., Silvestre R; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., Garlanda C; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy., Mantovani A; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.; William Harvey Research Institute, Queen Mary University, London, United Kingdom., Cunha C; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., Carvalho A; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. |
| المصدر: | American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2022 Nov 01; Vol. 206 (9), pp. 1140-1152. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Thoracic Society Country of Publication: United States NLM ID: 9421642 Publication Model: Print Cited Medium: Internet ISSN: 1535-4970 (Electronic) Linking ISSN: 1073449X NLM ISO Abbreviation: Am J Respir Crit Care Med Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2000- : New York, NY : American Thoracic Society Original Publication: New York, NY : American Lung Association, c1994- |
| مواضيع طبية MeSH: | C-Reactive Protein*/metabolism , Macrophage Activation* , Sarcoidosis* , Serum Amyloid P-Component*/genetics , Serum Amyloid P-Component*/metabolism, Animals ; Mice ; Complement System Proteins ; Granuloma ; Inflammation ; Leukocytes, Mononuclear/metabolism ; Humans |
| مستخلص: | Rationale: Sarcoidosis is a multisystemic inflammatory disease characterized by the formation of granulomas in response to persistent stimuli. 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. Objectives: To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis. Methods: 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. Measurements and Main Results: 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. Conclusions: 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. |
| التعليقات: | Comment in: Am J Respir Crit Care Med. 2022 Nov 1;206(9):1064-1065. (PMID: 35820078) |
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| فهرسة مساهمة: | Keywords: complement system proteins; granuloma; humoral immunity; macrophages; sarcoidosis |
| المشرفين على المادة: | 9007-41-4 (C-Reactive Protein) 9007-36-7 (Complement System Proteins) 148591-49-5 (PTX3 protein) 0 (Serum Amyloid P-Component) |
| تواريخ الأحداث: | Date Created: 20220629 Date Completed: 20221104 Latest Revision: 20221220 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC9704840 |
| DOI: | 10.1164/rccm.202112-2771OC |
| PMID: | 35767663 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1535-4970 |
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| DOI: | 10.1164/rccm.202112-2771OC |