Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis

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 dur...

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Published in:American journal of respiratory and critical care medicine 2022-11, Vol.206 (9), p.1140-1152
Main Authors: Gonçales, Relber A, Bastos, Helder Novais, Duarte-Oliveira, Cláudio, Antunes, Daniela, Sokhatska, Oksana, Jacob, Maria, Rolo, Rui, Campos, Cláudia F, Sasaki, Sergio D, Donato, Alessia, Mapelli, Sarah N, Costa, Sandra, Moura, Conceição Souto, Delgado, Luís, Morais, António, Torrado, Egídio, van de Veerdonk, Frank L, Weichhart, Thomas, Lambris, John D, Silvestre, Ricardo, Garlanda, Cecilia, Mantovani, Alberto, Cunha, Cristina, Carvalho, Agostinho
Format: Article
Language:English
Subjects:
Animals
C-Reactive Protein - metabolism
Complement System Proteins
Cytokines
Granuloma
Granulomas
Humans
Inflammation
Leukocytes, Mononuclear - metabolism
Macrophage Activation
Mice
Original
Pathogenesis
Proteins
Sarcoidosis
Serum Amyloid P-Component - genetics
Serum Amyloid P-Component - metabolism
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Summary: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. To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis. 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 and . The identified mechanisms of granulomatous inflammation were further evaluated in tissue and BAL samples and correlated with the disease course. 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. 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.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.202112-2771OC