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

Abstract

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.

Humoral Innate Immunity and Acute-Phase Proteins

“…PTX3 and SAP genetic polymorphisms have been associated with susceptibility to fungal and bacterial infections 38 , 48 , 50 , 51 and to lung granuloma formation in sarcoidosis through regulation of complement. 52 Thus, results of mechanistic analyses, evidence from gene-targeted mice, and findings from analyses of human genetic polymorphisms are consistent with the view that the pentraxin trio of C-reactive protein–SAP–PTX3 plays a role in the amplification of innate resistance to selected pathogens and in the regulation of tissue remodeling.…”

PTX3 in Granuloma Formation and Sarcoidosis: Helping Macrophages Accept a “Complement”

“…In conclusion, the study of Gonçales and colleagues ( 13 ) convincingly depicts the relationship among PTX3, complement activation, and macrophages. Its significance extends beyond this relatively well circumscribed molecular observation to represent a conceptual advance uniting innate immunity, humoral factors, granuloma formation, and sarcoidosis that “complements” the proposed immunopathogenic paradigm of this enigmatic disease.…”

“…In this issue of the Journal , Gonçales and colleagues (pp. 1140–1152 ) present a novel molecular link among PTX3 deficiency, amplified complement activation, and granuloma formation in experimental models and in patients with sarcoidosis ( 13 ). By combining animal studies, cell culture work, and primary human biospecimens, the authors demonstrate that PTX3-deficient mice are prone to exacerbation of the mycobacterium superoxide dismutase A mouse granuloma model in a manner that is rescued by PTX3 administration; that PTX3-deficient macrophages are susceptible to C5a (complement component 5a)–mediated activation of the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) and its associated endpoints of glycolytic reprogramming, proliferation, and aggregation; that genetic variation in the human gene PTX3 augments ex vivo granuloma-like structure formation; and that circulating PTX3 concentrations are associated with disease persistence in patients with sarcoidosis.…”

RNA-sequencing comparison of pneumonectomy and bleomycin reveals anti-fibrotic mechanisms of lung fibroblasts

“…and is associated with poor prognosis in human IPF [39]. Interestingly, PTX3 is a regulator of the complement system [40,41]. ITPKC itself has been linked to in ammatory signaling by quenching activation of the NLRP3 in ammasome, an innate immune complex that results in secretion of the in ammatory cytokines IL-1β and IL-18 [42].…”