TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation.
Ontology highlight
ABSTRACT:
SUBMITTER: Wakabayashi A
PROVIDER: S-EPMC8616552 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The generation of CD138+ phagocytic macrophages with an alternative (M2) phenotype that clear apoptotic cells from tissues is defective in lupus. Liver X receptor-alpha (LXR?) is an oxysterol-regulated transcription factor that promotes reverse cholesterol transport and alternative (M2) macrophage activation. Conversely, hypoxia-inducible factor 1-? (HIF1?) promotes classical (M1) macrophage activation. The objective of this study was to see if lupus can be treated by enhancing the generation of M2-like macrophages using LXR agonists. Peritoneal macrophages from pristane-treated mice had an M1 phenotype, high HIF?-regulated phosphofructokinase and TNF? expression (quantitative PCR, flow cytometry), and low expression of the LXR?-regulated gene ATP binding cassette subfamily A member 1 (Abca1) and Il10 vs. mice treated with mineral oil, a control inflammatory oil that does not cause lupus. Glycolytic metabolism (extracellular flux assays) and Hif1a expression were higher in pristane-treated mice (M1-like) whereas oxidative metabolism and LXR? expression were higher in mineral oil-treated mice (M2-like). Similarly, lupus patients' monocytes exhibited low LXR?/ABCA1 and high HIF1? vs. CONTROLS:The LXR agonist T0901317 inhibited type I interferon and increased ABCA1 in lupus patients' monocytes and in murine peritoneal macrophages. In vivo, T0901317 induced M2-like macrophage polarization and protected mice from diffuse alveolar hemorrhage (DAH), an often fatal complication of lupus. We conclude that end-organ damage (DAH) in murine lupus can be prevented using an LXR agonist to correct a macrophage differentiation abnormality characteristic of lupus. LXR agonists also decrease inflammatory cytokine production by human lupus monocytes, suggesting that these agents may be have a role in the pharmacotherapy of lupus.
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Project description:Diffuse alveolar hemorrhage is a condition with high morbidity and mortality. The majority of cases are caused by pulmonary capillaritis associated with systemic vasculitis. Infection disease has also been associated with this condition. A 62-year-old woman with a history of chronic alcohol abuse presented with shortness of breath, hemoptysis, constipation, and icterus. Chest x-rays on admission showed diffuse patchy opacities concerning for diffuse alveolar hemorrhage. The patient quickly developed acute respiratory failure requiring intubation. PCR identified human metapneumovirus and bronchoalveolar lavage confirmed alveolar hemorrhage. Despite all efforts, the patient ultimately developed multi-organ failure and died. Human metapneumovirus is usually associated with mild upper and lower respiratory tract infections in young children. Nevertheless, clinicians should recognize that this virus has recently emerged as a significant pathogen, particularly in adult patients with underlying conditions and the elderly population.
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Project description:An 80-year-old man was admitted to the hospital because of fever, bloody sputum and exertional dyspnea of 3 days. Laboratory tests showed anemia and increase of the C-reactive protein level. A chest computed tomography scan revealed diffuse bilateral ground-glass opacities. Bronchoalveolar lavage confirmed the clinical diagnosis of diffuse alveolar hemorrhage (DAH). After methylprednisolone pulse therapy, Enterococcus faecalis was detected in the blood cultures. A diagnosis of infective endocarditis was made according to the Modified Duke's criteria. The causes of DAH are certainly diverse; however, we should consider infective endocarditis as one of the etiologies of DAH.
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Project description:Hutchinson Gilford progeria syndrome (HGPS) is a devastating accelerated aging disease caused by LMNA gene mutation. The truncated lamin A protein produced "progerin" has a dominant toxic effect in cells, causing disruption of nuclear architecture and chromatin structure, genomic instability, gene expression changes, oxidative stress, and premature senescence. It was previously shown that progerin-induced genomic instability involves replication stress (RS), characterized by replication fork stalling and nuclease-mediated degradation of stalled forks. RS is accompanied by activation of cGAS/STING cytosolic DNA sensing pathway and STAT1-regulated interferon (IFN)-like response. It is also found that calcitriol, the active hormonal form of vitamin D, rescues RS and represses the cGAS/STING/IFN cascade. Here, the mechanisms underlying RS in progerin-expressing cells and the rescue by calcitriol are explored. It is found that progerin elicits a marked downregulation of RAD51, concomitant with increased levels of phosphorylated-RPA, a marker of RS. Interestingly, calcitriol prevents RS and activation of the cGAS/STING/IFN response in part through maintenance of RAD51 levels in progerin-expressing cells. Thus, loss of RAD51 is one of the consequences of progerin expression that can contribute to RS and activation of the IFN response. Stabilization of RAD51 helps explain the beneficial effects of calcitriol in these processes.
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Project description:Diffuse alveolar hemorrhage (DAH) is a fatal complication in patients with lupus. DAH can be induced in B6 mice by an intraperitoneal injection of pristane. Since human alpha-1-antitrypsin (hAAT) is an anti-inflammatory and immuno-regulatory protein, we investigated the protective effect of hAAT against pristane-induced DAH in B6 mice and hAAT transgenic (hAAT-Tg) mice. We first showed that hAAT Tg expression lowers TNF-α production in B cells, as well as CD4+ T cells in untreated mice. Conversely, the frequency of regulatory CD4+CD25+ and CD4+CD25-IL-10+ cells was significantly higher in hAAT-Tg than in B6 mice. This confirmed the anti-inflammatory effect of hAAT that was observed even at steady state. One week after a pristane injection, the frequency of peritoneal Ly6Chi inflammatory monocytes and neutrophils in hAAT-Tg mice was significantly lower than that in B6 mice. Importantly, pristane-induced DAH was completely prevented in hAAT-Tg mice and this was associated with a modulation of anti- to pro-inflammatory myeloid cell ratio/balance. We also showed that treatment with hAAT decreased the severity of DAH in B6 mice. These results showed for the first time that hAAT has a therapeutic potential for the treatment of DAH.
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Project description:BackgroundDiffuse alveolar hemorrhage (DAH) occurs during the course of autoimmune disease and may be life threatening. The objective was to assess characteristics and prognosis factors of DAH who required intensive care unit (ICU) admission in patients with autoimmune diseases.MethodsFrench multicenter retrospective study including patients presenting DAH related to autoimmune diseases requiring ICU admission from 2000 to 2016.ResultsOne hundred four patients (54% of men) with median age of 56 [32-68] years were included with 79 (76%) systemic vasculitis and 25 (24%) connective tissue disorders. All patients received steroids, and 72 (69%), 12 (11.5%), and 57 (55%) patients had cyclophosphamide, rituximab, and plasma exchanges, respectively. During ICU stay, 52 (50%), 36 (35%), and 55 (53%) patients required mechanical ventilation, vasopressor use, and renal replacement therapy, respectively. Factors associated with mechanical ventilation weaning were age (HR [95%CI] 0.97 [0.96-0.99] per 10?years, p?<?0.0001), vasculitis-related DAH (0.52 [0.27-0.98], p?=?0.04), and time from dyspnea onset to ICU admission (0.99 [0.99-1] per day, p?=?0.03). ICU mortality was 15%. Factors associated with alive status at ICU discharge were chronic cardiac failure (HR [95%CI] 0.37 [0.15-0.94], p?=?0.04), antiphospholipid syndrome-related DAH (3.17 [1.89-5.32], p?<?0.0001), SAPS II (0.98 [0.97-0.99], p?=?0.007), and oxygen flow at ICU admission (0.95 [0.91-0.99] per liter/min, p?=?0.04).ConclusionDAH in autoimmune diseases is a life-threatening complication which requires mechanical ventilation in half of the cases admitted to ICU.
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