Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus
Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus
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DOI：
10.1073/pnas.1908576116
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发表时间：
2019-12-10
影响因子：
11.1
通讯作者：
Kaplan, Mariana J.
中科院分区：
文献类型：
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作者：
Mistry, Pragnesh;Nakabo, Shuichiro;Kaplan, Mariana J.
系统性红斑狼疮（SLE）的发病机制涉及神经元失调。SLE的特征在于称为低密度粒细胞（LDG）的致病性中性粒细胞亚群的水平升高。LDG的起源和表型、功能和致病异质性仍有待系统地确定。通过批量和单细胞RNA测序以及转座酶可及染色质测序分析，对狼疮LDG、自体正常密度中性粒细胞和健康对照中性粒细胞进行转录组学和表观遗传学评估。在中性粒细胞亚群中比较功能读数。SLE LDG显示出显著的转录和表观遗传异质性，包括2个中成熟和未成熟中性粒细胞亚群，具有不同程度的染色质可及性和转录因子基序分析的差异。在LDG亚群中，中性粒细胞胞外陷阱（NET）形成、氧化线粒体DNA释放、趋化性、吞噬作用、脱粒作用、损害内皮的能力以及对I型干扰素（IFN）刺激的反应的差异是明显的。与其他免疫细胞亚群相比，LDG显示IFN诱导基因的最高表达。不同的LDG亚群与狼疮的特定临床特征以及冠状动脉疾病的存在和严重程度相关。表型、功能和致病性中性粒细胞异质性在SLE中普遍存在，并可能促进免疫失调和这种疾病的显著血管损伤特征。
Neutrophil dysregulation is implicated in the pathogenesis of systemic lupus erythematosus (SLE). SLE is characterized by elevated levels of a pathogenic neutrophil subset known as low-density granulocytes (LDGs). The origin and phenotypic, functional, and pathogenic heterogeneity of LDGs remain to be systematically determined. Transcriptomics and epigenetic assessment of lupus LDGs, autologous normal-density neutrophils, and healthy control neutrophils was performed by bulk and single-cell RNA sequencing and assay for transposase-accessible chromatin sequencing. Functional readouts were compared among neutrophil subsets. SLE LDGs display significant transcriptional and epigenetic heterogeneity and comprise 2 subpopulations of intermediate-mature and immature neutrophils, with different degrees of chromatin accessibility and differences in transcription factor motif analysis. Differences in neutrophil extracellular trap (NET) formation, oxidized mitochondrial DNA release, chemotaxis, phagocytosis, degranulation, ability to harm the endothelium, and responses to type I interferon (IFN) stimulation are evident among LDG subsets. Compared with other immune cell subsets, LDGs display the highest expression of IFN-inducible genes. Distinct LDG subsets correlate with specific clinical features of lupus and with the presence and severity of coronary artery disease. Phenotypic, functional, and pathogenic neutrophil heterogeneity are prevalent in SLE and may promote immune dysregulation and prominent vascular damage characteristic of this disease.