Departments of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
Mol Neurobiol. 2020 Sep;57(9):3875-3890. doi: 10.1007/s12035-020-01994-3. Epub 2020 Jul 1.
Activation of microglia and mitochondrial dysfunction are two major contributors to the pathogenesis of sepsis-associated brain dysfunction. Mitochondrial dysfunction can alter the immunological profile of microglia favoring to a pro-inflammatory phenotype. Mitochondrial transplantation, as an emerging mitochondria-targeted therapy, possesses considerable therapeutic potential in various central nervous system injuries or diseases. However, the effects of mitochondrial transplantation on microglial polarization and neuroprotection after sepsis remain unclear. In this study, lipopolysaccharide (LPS)/interferon-γ (IFN-γ) and interleukin-4 (IL-4)/interleukin-13 (IL-13) were used to induce different phenotypes of BV2 microglial cells. We observed that mitochondrial content and function were enhanced in IL-4-/IL-13-stimulated microglia. In vitro, mitochondria treatment conferred neuroprotection by enhancing microglial polarization from the M1 phenotype to the M2 phenotype and suppressing microglial-derived inflammatory cytokine release. Furthermore, microglial phenotypes and behavior tests were assessed after mice were subjected to sepsis by cecal ligation and puncture (CLP) followed by intracerebroventricular injection of exogenous functional mitochondria. We found that mitochondrial transplantation induced microglial M2 rather than M1 response 24 h after sepsis. Mitochondrial transplantation improved behavioral deficits by increasing the latency time in inhibitory avoidance test and decreasing the number of crossing and rearing in the test session of open field test 10 days after CLP onset. These findings indicate that mitochondrial transplantation promotes the phenotypic conversion of microglia and improves cognitive impairment in sepsis survivors, supporting the potential use of exogenous mitochondrial transplantation therapy that may be a potential therapeutic opportunity for sepsis-associated brain dysfunction.
小胶质细胞的激活和线粒体功能障碍是导致脓毒症相关脑功能障碍发病机制的两个主要因素。线粒体功能障碍可以改变小胶质细胞的免疫表型，使其偏向促炎表型。线粒体移植作为一种新兴的线粒体靶向治疗方法，在各种中枢神经系统损伤或疾病中具有相当大的治疗潜力。然而，线粒体移植对脓毒症后小胶质细胞极化和神经保护的影响尚不清楚。在这项研究中，脂多糖（LPS）/干扰素-γ（IFN-γ）和白细胞介素-4（IL-4）/白细胞介素-13（IL-13）被用来诱导 BV2 小胶质细胞的不同表型。我们观察到，IL-4-/IL-13 刺激的小胶质细胞中线粒体含量和功能增强。在体外，线粒体处理通过增强小胶质细胞从 M1 表型向 M2 表型的极化和抑制小胶质细胞衍生的炎症细胞因子释放来发挥神经保护作用。此外，在通过盲肠结扎和穿孔（CLP）后对小鼠进行脓毒症，并通过侧脑室注射外源性功能性线粒体后，评估了小胶质细胞表型和行为测试。我们发现，线粒体移植在脓毒症后 24 小时诱导小胶质细胞 M2 而不是 M1 反应。线粒体移植通过增加抑制性回避测试中的潜伏期时间，以及减少开放场测试中第 10 天 CLP 发作后的穿越和站立次数，改善了行为缺陷。这些发现表明，线粒体移植促进了小胶质细胞的表型转化，并改善了脓毒症幸存者的认知障碍，支持外源性线粒体移植治疗的潜在应用，这可能是脓毒症相关脑功能障碍的潜在治疗机会。
