Mitochondrial reverse electron transport in myeloid cells perpetuates neuroinflammation

Sustained smouldering, or low grade, activation of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct metabolic and mitochondrial features of myeloid cells guide diverse functional states. How these features act to perpetuate neuroinflammation is currently unknown. Using a multiomics approach, we identify a new molecular signature that perpetuates the activation of microglia by the reverse electron transport through complex I and the subsequent production of reactive oxygen species. Blocking reverse electron transport in pro-inflammatory myeloid cells protects against neurotoxic damage and improves functional outcomes in animal disease models in vivo. Our data show that reverse electron transport in myeloid cells is a potential new therapeutic target to foster neuroprotection in smouldering inflammatory central nervous system diseases. Resident microglia and infiltrating myeloid cells were isolated via FACS from a Cx3cr1-fate mapping mouse line at the peak or chronic phase of EAE, as well as healthy controls. Cells were then analysed via scRNAseq.

持续迁延性、低活性的髓系细胞活化是包括多发性硬化在内的多种慢性神经系统疾病的常见病理特征。髓系细胞独特的代谢与线粒体特征，决定了其多样化的功能表型。目前学界尚未阐明此类特征如何驱动神经炎症的持续进展。本研究通过多组学策略，鉴定出一条全新的分子特征：该特征通过复合物I介导的逆向电子传递及后续活性氧（reactive oxygen species, ROS）生成，维持小胶质细胞的活化状态。在促炎髓系细胞中阻断逆向电子传递，可减轻神经毒性损伤，并在体内动物疾病模型中改善功能预后。本研究数据表明，髓系细胞中的逆向电子传递可作为潜在新型治疗靶点，为迁延性炎症性中枢神经系统疾病的神经保护治疗提供新方向。本研究从处于实验性自身免疫性脑脊髓炎（Experimental Autoimmune Encephalomyelitis, EAE）发病峰值期或慢性期的Cx3cr1命运示踪小鼠品系，以及健康对照组小鼠体内，通过荧光激活细胞分选术（Fluorescence-Activated Cell Sorting, FACS）分离原位小胶质细胞与浸润性髓系细胞，随后采用单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）对细胞进行分析。