Phagosome-Regulated-mTOR Signaling During Sarcoidosis Granulomagenesis

Crouser, E.D.; Locke, Landon W.; Julian, M.W.; Bicer, Sabahattin; White, Peter; Schlesinger, Larry S.

doi:10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a3102

Cited by 1 publication

(6 citation statements)

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“…Interestingly, hypoxia markedly reduced phagocytosis in controls but not in sarcoidosis, suggesting that macrophage phagocytosis could be maintained under hypoxia in this disease. Previous papers reported that phagocytic activity of macrophages was increased in sarcoidosis and in an in vitro model of granuloma (17,40,41). An enhanced expression of phagocytosis-related genes, but a downregulation of genes involved in proteasome degradation were also observed, suggesting that the accumulation of intracellular phagocytic degradation products could participate in the chronicity of inflammation in sarcoidosis (40).…”

Section: Discussionmentioning

confidence: 94%

“…This score was highly correlated with the range of FVC improvement under further sarcoidosis treatment, a good marker of the lesions reversibility. The choice to specifically study MD-macrophages in these patients was supported by recent works showing that in vitro models of granuloma using PBMCs can mimic sarcoidosis events such as phagosome-regulated mTOR or IL-13 signaling (17,44). In addition, previous studies reported that immune cells constituting recurrent sarcoidosis granulomas in lung transplant allografts originated from the recipient monocyte-macrophage lineage (19,20).…”

Section: Discussionmentioning

confidence: 99%

“…It has been previously reported that phagocytosis, a main function of macrophages, can be modulated by HIF-1 (39) and involved in sarcoidosis pathogenicity (17,40,41). Therefore, phagocytosis was assessed in MD-macrophages exposed to normoxia or 24hrs-hypoxia and challenged with fluospheres (Figures 2A-C).…”

Section: Hypoxia Impaired Phagocytosis In Controls But Not In Sarcoidosis Md-macrophagesmentioning

confidence: 99%

“…Different types of macrophage populations (alveolar and interstitial) derivating from distinct precursors of embryonic/fetal and myeloid origin, reside in the lung (14,15). Notably, upon injury, the myeloid precursors generate monocyte-derived (MD) macrophages, though to play a major role in fibrosis (16) and sarcoidosis (11,(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

“…In the lung of patients, these cells are an important source of TNFa, a major cytokine in the pathogenesis of sarcoidosis (11). Circulating mononuclear cells from sarcoidosis patients are also able to reconstitute granulomas in vitro, and present a specific transcriptional profile compared to other granulomatosis such as tuberculosis (17,18). In addition, analysis of granulomas from sarcoidosis recurrence after lung transplantation demonstrated that constitutive cells derived from recipient blood cells (19,20), indicating that peripheral blood cells are major contributors in granuloma formation.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 94%