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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2022

Autores

Goncales, RA (Autor) Outra; Bastos, HN (Autor) FMUP; Duarte-Oliveira, C (Autor) Outra; Antunes, D (Autor) Outra; Sokhatska, O (Autor) Outra; Jacob, M (Autor) Outra; Rolo, R (Autor) Outra; Campos, CF (Autor) Outra; Sasaki, SD (Autor) Outra; Donato, A (Autor) Outra; Mapelli, SN (Autor) Outra; Costa, S (Autor) Outra; Moura, CS (Autor) Outra; Delgado, L (Autor) FMUP; Morais, A (Autor) Outra; Torrado, E (Autor) Outra; van de Veerdonk, FL (Autor) Outra; Weichhart, T (Autor) Outra; Lambris, JD (Autor) Outra; Silvestre, R (Autor) Outra; Garlanda, C (Autor) Outra; Mantovani, A (Autor) Outra; Cunha, C (Autor) Outra; Carvalho, A (Autor) Outra

Revista

Título: American Journal of Respiratory and Critical Care Medicine

Vol. 206

Páginas: 1140-1152

ISSN: 1073-449X

Editora: American Thoracic Society

Indexação

ISI Web of Knowledge - 8 Citações

Scopus - 13 Citações

Outras Informações

ID Authenticus: P-00X-3W5

DOI: 10.1164/rccm.202112-2771oc

Abstract (EN): 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 granulomapromoting 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 13