Hypoxia Promotes a Mixed Inflammatory-Fibrotic Macrophages Phenotype in Active Sarcoidosis

Abstract

BackgroundMacrophages are pivotal cells in sarcoidosis. Monocytes-derived (MD) macrophages have recently been demonstrated to play a major role especially in pulmonary sarcoidosis. From inflammatory tissues to granulomas, they may be exposed to low oxygen tension environments. As hypoxia impact on sarcoidosis immune cells has never been addressed, we designed the present study to investigate MD-macrophages from sarcoidosis patients in this context. We hypothesized that hypoxia may induce functional changes on MD-macrophages which could have a potential impact on the course of sarcoidosis.MethodsWe studied MD-macrophages, from high active sarcoidosis (AS) (n=26), low active or inactive sarcoidosis (IS) (n=24) and healthy controls (n=34) exposed 24 hours to normoxia (21% O2) or hypoxia (1.5% O2). Different macrophage functions were explored: hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-κB) activation, cytokines secretion, phagocytosis, CD80/CD86/HLA-DR expression, profibrotic response.ResultsWe observed that hypoxia, with a significantly more pronounced effect in AS compared with controls and IS, increased the HIF-1α trans-activity, promoted a proinflammatory response (TNFα, IL1ß) without activating NF-κB pathway and a profibrotic response (TGFß1, PDGF-BB) with PAI-1 secretion associated with human lung fibroblast migration inhibition. These results were confirmed by immunodetection of HIF-1α and PAI-1 in granulomas observed in pulmonary biopsies from patients with sarcoidosis. Hypoxia also decreased the expression of CD80/CD86 and HLA-DR on MD-macrophages in the three groups while it did not impair phagocytosis and the expression of CD36 expression on cells in AS and IS at variance with controls.ConclusionsHypoxia had a significant impact on MD-macrophages from sarcoidosis patients, with the strongest effect seen in patients with high active disease. Therefore, hypoxia could play a significant role in sarcoidosis pathogenesis by increasing the macrophage proinflammatory response, maintaining phagocytosis and reducing antigen presentation, leading to a deficient T cell response. In addition, hypoxia could favor fibrosis by promoting profibrotic cytokines response and by sequestering fibroblasts in the vicinity of granulomas.

Exome Sequencing Reveals Genetic Variability and Identifies Chronic Prognostic Loci in Chinese Sarcoidosis Patients

“…PAI-1, also called "serpin family E member 1 (SERPINE1)," a member of the serine proteinase inhibitor (serpin) superfamily, has been shown to promote fibrosis in multiple organ systems and function as a component of innate antiviral immunity. Florence Jeny et al identified that hypoxia increased the profibrotic response with PAI-1 secretion associated with human lung fibroblast migration inhibition in monocyte-derived (MD) macrophages among highly active sarcoidosis patients (56).…”

“…Florence Jeny et al. identified that hypoxia increased the profibrotic response with PAI-1 secretion associated with human lung fibroblast migration inhibition in monocyte-derived (MD) macrophages among highly active sarcoidosis patients ( 56 ).…”

Novel insights in fibrotic pulmonary sarcoidosis

“…Hypoxia, as recent studies suggest, may promote a mixed inflammatory/fibrosing response of macrophages involved in the development and persistence of granulomas in active sarcoidosis and fibrosis surrounding granulomas by reducing their antigen presentation capacities that results in a deficient T cell response [29 ▪ ]. Hypoxia could have a significant impact in patients with highly active disease and the HIF pathway and PAI-1 can represent new therapeutic targets of active sarcoidosis.…”

Hypoxia in Aging and Aging-Related Diseases: Mechanism and Therapeutic Strategies

“…In the context of respiratory viral diseases, such as influenza and COVID-19 patients, researchers have found that patients with these lower respiratory viral infections often develop hypoxemia, primarily because crosstalk between lung inflammation and a hypoxic microenvironment may impair pulmonary ventilation [ 35 ]. Hypoxia may also promote tissue inflammation–fibrosis [ 36 ]. In active nodular diseases, hypoxia promotes fibrosis through a pro-fibrotic cytokine response.…”