Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury.
Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury.
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DOI：
10.1186/s12974-017-0819-4
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发表时间：
2017-03-15
影响因子：
9.3
通讯作者：
Faden AI
中科院分区：
文献类型：
--
作者：
Kumar A;Stoica BA;Loane DJ;Yang M;Abulwerdi G;Khan N;Kumar A;Thom SR;Faden AI
局部和全身炎症反应在创伤性脑损伤（TBI）后早期启动，并可能在导致神经元丢失和神经功能缺损的继发性损伤过程中发挥关键作用。然而，负责神经炎症的快速扩张及其长期进展的机制尚未阐明。在这里，我们调查的作用微粒（MP），细胞外囊泡家族的成员，在脑免疫细胞之间的促炎分子的交换，以及它们的转移到体循环，作为脑创伤后炎症传播的关键途径。使成年雄性C57 BL/6小鼠经受受控皮质撞击TBI 24小时，并在血液中分离富集的MP，同时在TBI皮质中评估神经炎症。采用流式细胞术对MP进行表征，并使用促炎介质的基因和蛋白标记物测定MP含量。将与BV 2或原代小胶质细胞共培养的富集MP用于免疫增殖测定。将来自BV 2小胶质细胞或来自TBI脑的CD 11b阳性小胶质细胞的富集MP立体定向地注射到未损伤小鼠的皮质中，以评价体内神经炎症的MP相关播种。由于TBI后大脑中的神经炎症反应正在发展，小胶质细胞衍生的MP被释放到循环中。来自TBI动物的循环富集的MP可以在体外激活小胶质细胞。脂多糖刺激可增加体外小胶质细胞释放MP，并增加其促炎性介质白细胞介素-1 β和microRNA-155的含量。来自体外活化小胶质细胞的富集MP或来自离体TBI脑的CD 11b分离的小胶质细胞/巨噬细胞足以在注射到幼稚（未损伤）动物的皮质中后引发神经炎症。这些数据为TBI后神经炎症的发展和传播机制提供了进一步的见解。MP装载有最初由小胶质细胞在创伤后释放的促炎分子，可以激活额外的小胶质细胞，这可能有助于受伤大脑中的进行性神经炎症反应，以及刺激全身免疫反应。由于它们能够独立地引发炎症反应，源自活化的小胶质细胞的MP可为其它神经系统疾病提供潜在的治疗靶点，其中神经炎症可能是促成因素。
Local and systemic inflammatory responses are initiated early after traumatic brain injury (TBI), and may play a key role in the secondary injury processes resulting in neuronal loss and neurological deficits. However, the mechanisms responsible for the rapid expansion of neuroinflammation and its long-term progression have yet to be elucidated. Here, we investigate the role of microparticles (MP), a member of the extracellular vesicle family, in the exchange of pro-inflammatory molecules between brain immune cells, as well as their transfer to the systemic circulation, as key pathways of inflammation propagation following brain trauma. Adult male C57BL/6 mice were subjected to controlled cortical impact TBI for 24 h, and enriched MP were isolated in the blood, while neuroinflammation was assessed in the TBI cortex. MP were characterized by flow cytometry, and MP content was assayed using gene and protein markers for pro-inflammatory mediators. Enriched MP co-cultured with BV2 or primary microglial cells were used for immune propagation assays. Enriched MP from BV2 microglia or CD11b-positive microglia from the TBI brain were stereotactically injected into the cortex of uninjured mice to evaluate MP-related seeding of neuroinflammation in vivo. As the neuroinflammatory response is developing in the brain after TBI, microglial-derived MP are released into the circulation. Circulating enriched MP from the TBI animals can activate microglia in vitro. Lipopolysaccharide stimulation increases MP release from microglia in vitro and enhances their content of pro-inflammatory mediators, interleukin-1β and microRNA-155. Enriched MP from activated microglia in vitro or CD11b-isolated microglia/macrophage from the TBI brain ex vivo are sufficient to initiate neuroinflammation following their injection into the cortex of naïve (uninjured) animals. These data provide further insights into the mechanisms underlying the development and dissemination of neuroinflammation after TBI. MP loaded with pro-inflammatory molecules initially released by microglia following trauma can activate additional microglia that may contribute to progressive neuroinflammatory response in the injured brain, as well as stimulate systemic immune responses. Due to their ability to independently initiate inflammatory responses, MP derived from activated microglia may provide a potential therapeutic target for other neurological disorders in which neuroinflammation may be a contributing factor.