Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
Immunity. 2021 Nov 9;54(11):2632-2649.e6. doi: 10.1016/j.immuni.2021.10.004. Epub 2021 Oct 12.
The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and in vitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.
与欧洲血统个体相比，非洲血统个体的败血症发病率和严重程度更高。我们发现，仅存在于非洲血统个体中的溶组织因子载脂蛋白 L1（APOL1）的遗传风险变异（RV）与败血症发病率和严重程度增加相关。血清 APOL1 水平与败血症和 COVID-19 的严重程度相关，人类肾脏的单细胞测序显示内皮细胞中 APOL1 高表达。对内皮细胞特异性表达 RV APOL1 的小鼠进行分析和体外研究表明，RV APOL1 干扰了线粒体自噬，导致线粒体 DNA 向细胞质释放并激活了炎症小体（NLRP3）和细胞质核苷酸感应途径（STING）。NLRP3 和 STING 的基因缺失或药理学抑制可保护小鼠免受 RV APOL1 引起的败血症通透性缺陷和促炎内皮变化的影响。我们的研究确定了炎症小体和 STING 途径作为减少败血症和 COVID-19 中与 APOL1 相关的健康差异的潜在靶点。
