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Mitochondrial Transplantation Attenuates Brain Dysfunction in Sepsis by Driving Microglial M2 Polarization.
Molecular Neurobiology ( IF 5.1 ) Pub Date : 2020-07-01 , DOI: 10.1007/s12035-020-01994-3
Chaoying Yan 1 , Zhi Ma 1 , Hongli Ma 1 , Qing Li 1 , Qian Zhai 1 , Tao Jiang 1 , Zhanqin Zhang 1 , Qiang Wang 1
Affiliation  

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.



中文翻译:

线粒体移植通过驱动小胶质细胞M2极化减轻败血症中的脑功能障碍。

小胶质细胞的激活和线粒体功能障碍是与脓毒症相关的脑功能障碍的发病机制的两个主要因素。线粒体功能障碍可改变小胶质细胞的免疫学特征,有利于促炎表型。线粒体移植作为一种针对线粒体的新兴疗法,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,线粒体移植对败血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)和白介素4(IL-4)/白介素13(IL-13)被用来诱导BV2小胶质细胞的不同表型。我们观察到在IL-4- / IL-13刺激的小胶质细胞中线粒体含量和功能得到增强。体外,线粒体治疗通过增强小胶质细胞从M1型到M2型的极化并抑制小胶质源性炎症细胞因子的释放而赋予神经保护作用。此外,通过盲肠结扎和穿刺(CLP)对小鼠进行败血症治疗,然后脑室内注射外源功能性线粒体,评估小胶质细胞表型和行为测试。我们发现线粒体移植在败血症后24 h引起小胶质细胞M2而非M1反应。线粒体移植通过增加抑制性回避测试中的潜伏时间并减少CLP发作后10天的开放视野测试的测试阶段的交叉和饲养次数,从而改善了行为缺陷。

更新日期:2020-07-01
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