Circulating Pro-Inflammatory Exosomes Worsen Stroke Outcomes in Aging.
Circulating Pro-Inflammatory Exosomes Worsen Stroke Outcomes in Aging.
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DOI：
10.1161/circresaha.121.318897
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发表时间：
2021-09-17
影响因子：
20.1
通讯作者：
Jin K
中科院分区：
文献类型：
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作者：
Zhang H;Lin S;McElroy CL;Wang B;Jin D;Uteshev VV;Jin K
全身性炎症环境在与年龄相关的功能完整性下降中起重要作用，但其对与年龄相关的疾病（例如，中风）仍然是未知的。确定全身炎症环境在缺血性卒中中的作用。在这里，我们报告说，从年轻大鼠（Y-exo）到老年缺血大鼠的血清外泌体全身给药改善缺血性中风后的短期和长期功能结果，并减少突触丢失。相比之下，将来自老年大鼠的血清外泌体（O-exo）类似地注射到老年缺血大鼠中，通过由于过度的小胶质细胞吞噬作用（初级吞噬作用）导致的突触功能障碍的恶化而使感觉运动缺陷恶化。我们的蛋白质组学分析进一步揭示，CD 46，一个C3 b/C4 b失活因子，在Y-exo中的表达高于O-exo。而血清外泌体中促炎介质（C1 q、C3 a和C3 b）的患病率随着年龄的增长而增加。与Y-exo和溶剂组相比，O-exo处理后小胶质细胞C3 a/B和C3 aR的表达增加。给予选择性C3 aR抑制剂或小胶质细胞耗竭可减轻与O-exo治疗相关的突触功能障碍，并改善卒中后功能恢复。我们的数据表明，血清外泌体中促炎介质的水平随着年龄的增长而增加，并与过度C3 aR依赖性小胶质细胞吞噬作用导致的卒中结局恶化相关。调节这一过程可能是治疗中风和其他与年龄有关的脑部疾病的一种有前途的方法。循环外泌体可作为全身性炎症的神经炎症介质，并导致与年龄相关的功能完整性下降。然而，它们在缺血性卒中中的作用仍有待研究。在这项研究中，我们发现衰老的血液外泌体逐渐积累外周促炎介质，并可以通过C3 aR依赖性机制穿过BBB以引发和过度激活小胶质细胞。缺血性卒中促进了这一过程，导致突触损伤、突触功能降低以及感觉运动和认知缺陷增加。通过用年轻的外泌体取代老化的外泌体，有可能逆转突触和神经功能的下降，并在中风后提供治疗益处。因此，外周和中枢免疫系统通过补体-小胶质细胞相互作用参与连续的串扰，并且它们的调节可以作为缺血性中风和其他年龄相关性脑疾病的有前途的治疗工具。
The systemic inflammatory milieu plays an important role in the age-related decline in functional integrity, but its contribution to age-related disease (e.g., stroke) remains largely unknown. To determine the role of systemic inflammatory milieu in ischemic stroke. Here, we report that systemic administration of serum exosomes from young rats (Y-exo) into aged ischemic rats improved short- and long-term functional outcomes after ischemic stroke and reduced synaptic loss. By contract, similar injections of serum exosomes from aged rats (O-exo) into aged ischemic rats worsened sensorimotor deficits through exacerbation of synaptic dysfunction due to excessive microglial phagoptosis (primary phagocytosis). Our proteomic analysis further revealed that the expression of CD46, a C3b/C4b-inactivating factor, was higher in Y-exo, compared to O-exo. Whereas the prevalence of pro-inflammatory mediators (C1q, C3a and C3b) in serum exosomes increased with age. Microglial expression of C3a/b and C3aR increased after O-exo treatment, compared with Y-exo and vehicle groups. Administration of a selective C3aR inhibitor or microglial depletion attenuated synaptic dysfunction associated with O-exo treatment and improved post-stroke functional recovery. Our data suggest that the levels of pro-inflammatory mediators in serum exosomes increase with age and are associated with worsened stroke outcomes through excessive C3aR-dependent microglial phagoptosis. Modulation of this process may serve as a promising therapy for stroke and other age-related brain disorders. Circulating exosomes could act as a neuroinflammatory mediators in systemic inflammation and contribute to age-related decline in functional integrity. However, their role in ischemic stroke remains unexplored. In this study, we found that aging blood exosomes progressively accumulate peripheral pro-inflammatory mediators and could cross the BBB to prime and excessively activate microglia via a C3aR-dependent mechanism. This process is facilitated by ischemic stroke resulting in synaptic damage, reduced synaptic function, and elevated sensorimotor and cognitive deficits. By replacing aging exosomes with young exosomes, it is possible to reverse the decline of synaptic and neurological functions and deliver therapeutic benefits after stroke. Thus, the peripheral and central immune systems are engaged in a continuous crosstalk via complement-microglial interactions and their modulation may serve as a promising therapeutic tool in ischemic stroke and other age-related brain diseases.
DOI：
10.1016/j.trsl.2010.12.013
发表时间：
2011-04
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Dorn GW 2nd
通讯作者：
Dorn GW 2nd