High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experiments diffuse alveolar hemorrhage
High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experiments diffuse alveolar hemorrhage
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DOI：
10.1172/jci.insight.129703
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发表时间：
2019-08-08
期刊：
影响因子：
8
通讯作者：
Nigrovic, Peter A.
中科院分区：
文献类型：
--
作者：
Lee, Pui Y.;Nelson-Maney, Nathan;Nigrovic, Peter A.
弥漫性肺泡出血(DAH)是一种与系统性红斑狼疮、血管炎和干细胞移植相关的危及生命的肺部并发症。对DAH的PAT生理学知之甚少，目前还没有针对性的治疗方法。Pristane在小鼠中的治疗诱导了系统自身免疫和肺出血，这概括了人类DAH的标志性病理特征。利用这一实验模型，我们对DAH中的肺免疫细胞进行了高维分析，采用了质量细胞术和单细胞RNA测序。我们在DAH中发现大量髓系细胞流入肺部，并确定了浸润性单核细胞的基因表达谱。骨髓来源的炎性单核细胞活跃地迁移到肺部，并在血管旁归巢。通过3种单核细胞缺乏症模型和补充性移植研究，我们确定了炎性单核细胞在DAH发生发展中的中心作用。我们进一步发现髓系转录因子干扰素调节因子8对于DAH和I型干扰素依赖的自身免疫的发展是必不可少的。这些发现共同揭示了单核细胞作为DAH潜在治疗靶点的可能性。
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 pat hophysiology 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.