High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhage
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ABSTRACT:
PROVIDER: PRJNA549920 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9331940_1.fastq.gz | Fastqsanger.gz | |||
| SRR9331940_2.fastq.gz | Fastqsanger.gz | |||
| SRR9331941_1.fastq.gz | Fastqsanger.gz | |||
| SRR9331941_2.fastq.gz | Fastqsanger.gz | |||
| SRR9331942_1.fastq.gz | Fastqsanger.gz |
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Project description:Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication associated with systemic lupus erythematous and other autoimmune diseases. Little is known about the pathophysiology of DAH and no targeted therapy is currently available. Pristane treatment in mice induces systemic autoimmunity and lung hemorrhage that recapitulates hallmark pathologic features of human DAH. Using this experimental model, we performed high dimensional analysis of lung immune cells in DAH by mass cytometry and single cell RNA sequencing. We found a large influx of myeloid cells to the lungs in DAH and defined the gene expression profile of infiltrating monocytes. Using three models of monocyte deficiency and complementary transfer studies, we established a central role of inflammatory monocytes in the development of DAH. We further found that the myeloid transcription factor interferon regulatory factor 8 (Irf8) is essential to the development of both DAH and type-I interferon-dependent autoimmunity. These findings collectively reveal monocytes as a potential treatment target in DAH.
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Project description:Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication associated with systemic lupus erythematosus, vasculitis, and stem cell transplant. Little is known about the pathophysiology of DAH, and no targeted therapy is currently available. Pristane treatment in mice induces systemic autoimmunity and lung hemorrhage that recapitulates hallmark pathologic features of human DAH. Using this experimental model, we performed high-dimensional analysis of lung immune cells in DAH by mass cytometry and single-cell RNA sequencing. We found a large influx of myeloid cells to the lungs in DAH and defined the gene expression profile of infiltrating monocytes. Bone marrow-derived inflammatory monocytes actively migrated to the lungs and homed adjacent to blood vessels. Using 3 models of monocyte deficiency and complementary transfer studies, we established a central role of inflammatory monocytes in the development of DAH. We further found that the myeloid transcription factor interferon regulatory factor 8 is essential to the development of both DAH and type I interferon-dependent autoimmunity. These findings collectively reveal monocytes as a potential treatment target in DAH.
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Project description:Diffuse alveolar hemorrhage is an uncommon, yet often fatal, complication of systemic lupus erythematosus (SLE). Advances in the treatment of alveolar hemorrhage have been hampered because of the heterogeneity of clinical findings and the lack of suitable animal models. A single intraperitoneal injection of pristane induces a lupus-like syndrome characterized by lupus-related autoantibodies and glomerulonephritis in non-autoimmune-prone strains of mice. In addition, C57BL/6 (B6) mice frequently develop alveolar hemorrhage within a few weeks of pristane injection. Immunopathogenesis of pristane-induced alveolar hemorrhage was investigated in the present study. Early (2-4 weeks after injection) mortality due to hemorrhage was unique to C57BL/6 and C57BL/10 strains of mice. Recruitment of the macrophages and neutrophils preceded the hemorrhage by several days, and hemorrhage started 3-7 days after pristane injection in some mice, peaked at 2 weeks (84% in B6) and then resolved by 4 weeks in a majority of mice. Alveolar hemorrhage was independent of MyD88 (myeloid differentiation factor 88), or TLR7 pathways, in contrast to autoantibody production and glomerulonephritis, and was also independent of Fc?R or Fas. Rag1(-/-) mice had a reduced prevalence of alveolar hemorrhage compared with B6 (P=0.01) congenics. However, T-cell receptor-deficient mice developed alveolar hemorrhage at a rate comparable to wild-type controls, whereas B6 Ig?(-/-) mice surprisingly had a strikingly reduced prevalence (7% vs 84% in B6, P<0.0001). Reconstitution of B6 Ig?(-/-) mice with wild-type B cells increased the prevalence to 50% (P=0.028). Pristane-induced alveolar hemorrhage is a useful model to study the pathogenesis and develop new therapy for this underappreciated and often life-threatening complication of SLE.
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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: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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