Institute of Neurological Sciences and Psychiatry, Hacettepe University, Sıhhiye, Ankara, Turkey.
Biotechnology Institute, Ankara University, Ankara, Turkey.
J Neuroinflammation. 2023 Dec 11;20(1):295. doi: 10.1186/s12974-023-02977-6.
The role of high mobility group box 1 (HMGB1) in inflammation is well characterized in the immune system and in response to tissue injury. More recently, HMGB1 was also shown to initiate an "inflammatory signaling cascade" in the brain parenchyma after a mild and brief disturbance, such as cortical spreading depolarization (CSD), leading to headache. Despite substantial evidence implying a role for inflammatory signaling in prevalent neuropsychiatric disorders such as migraine and depression, how HMGB1 is released from healthy neurons and how inflammatory signaling is initiated in the absence of apparent cell injury are not well characterized. We triggered a single cortical spreading depolarization by optogenetic stimulation or pinprick in naïve Swiss albino or transgenic Thy1-ChR2-YFP and hGFAP-GFP adult mice. We evaluated HMGB1 release in brain tissue sections prepared from these mice by immunofluorescent labeling and immunoelectron microscopy. EzColocalization and Costes thresholding algorithms were used to assess the colocalization of small extracellular vesicles (sEVs) carrying HMGB1 with astrocyte or microglia processes. sEVs were also isolated from the brain after CSD, and neuron-derived sEVs were captured by CD171 (L1CAM). sEVs were characterized with flow cytometry, scanning electron microscopy, nanoparticle tracking analysis, and Western blotting. We found that HMGB1 is released mainly within sEVs from the soma of stressed neurons, which are taken up by surrounding astrocyte processes. This creates conditions for selective communication between neurons and astrocytes bypassing microglia, as evidenced by activation of the proinflammatory transcription factor NF-ĸB p65 in astrocytes but not in microglia. Transmission immunoelectron microscopy data illustrated that HMGB1 was incorporated into sEVs through endosomal mechanisms. In conclusion, proinflammatory mediators released within sEVs can induce cell-specific inflammatory signaling in the brain without activating transmembrane receptors on other cells and causing overt inflammation.
高迁移率族蛋白 B1（HMGB1）在免疫系统和组织损伤反应中的炎症作用已得到充分描述。最近，HMGB1 还被证明在轻度和短暂的干扰后，如皮质扩散性去极化（CSD），在脑实质中引发“炎症信号级联”，导致头痛。尽管有大量证据表明炎症信号在偏头痛和抑郁症等常见神经精神疾病中起作用，但 HMGB1 如何从健康神经元中释放，以及在没有明显细胞损伤的情况下如何引发炎症信号，尚未得到充分描述。我们通过光遗传学刺激或针刺在天真的瑞士白化病或转基因 Thy1-ChR2-YFP 和 hGFAP-GFP 成年小鼠中引发单次皮质扩散性去极化。我们通过免疫荧光标记和免疫电子显微镜评估这些小鼠脑组织切片中 HMGB1 的释放。EzColocalization 和 Costes 阈值算法用于评估携带 HMGB1 的小细胞外囊泡（sEVs）与星形胶质细胞或小胶质细胞过程的共定位。CSD 后也从大脑中分离出 sEVs，并通过 CD171（L1CAM）捕获神经元衍生的 sEVs。通过流式细胞术、扫描电子显微镜、纳米颗粒跟踪分析和 Western blot 对 sEVs 进行了表征。我们发现 HMGB1 主要从应激神经元体释放到 sEVs 中，这些 sEVs 被周围的星形胶质细胞过程摄取。这为神经元和星形胶质细胞之间的选择性通讯创造了条件，这一点可以通过星形胶质细胞中促炎转录因子 NF-ĸB p65 的激活而不是小胶质细胞来证明。透射电镜免疫电镜数据表明，HMGB1 通过内体机制被纳入 sEVs。总之，sEVs 中释放的促炎介质可以在不激活其他细胞上的跨膜受体并引起明显炎症的情况下，在大脑中诱导细胞特异性炎症信号。
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