Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea.
Medical Research Center, Inha University School of Medicine, Inchon, Republic of Korea.
Cell Death Dis. 2018 Apr 1;9(4):426. doi: 10.1038/s41419-018-0438-8.
Post-stroke infection (PSI) is known to worsen functional outcomes of stroke patients and accounts to one-third of stroke-related deaths in hospital. In our previous reports, we demonstrated that massive release of high-mobility group box protein 1 (HMGB1), an endogenous danger signal molecule, is promoted by N-methyl-D-aspartic acid-induced acute damage in the postischemic brain, exacerbating neuronal damage by triggering delayed inflammatory processes. Moreover, augmentation of proinflammatory function of lipopolysaccharides (LPS) by HMGB1 via direct interaction has been reported. The aim of this study was to investigate the role of HMGB1 in aggravating inflammation in the PSI by exacerbating the function of LPS. PSI animal model was produced by administrating a low-dose LPS at 24 h post-middle cerebral artery occlusion (MCAO). Profound aggravations of inflammation, deterioration of behavioral outcomes, and infarct expansion were observed in LPS-injected MCAO animals, in which serum HMGB1 surge, especially disulfide type, occurred immediately after LPS administration and aggravated brain and systemic inflammations probably by acting in synergy with LPS. Importantly, blockage of HMGB1 function by delayed administrations of therapeutic peptides known to inhibit HMGB1 (HMGB1 A box, HPep1) or by treatment with LPS after preincubation with HMGB1 A box significantly ameliorated damages observed in the rat PSI model, demonstrating that HMGB1 plays a crucial role. Furthermore, administration of Rhodobacter sphaeroides LPS, a selective toll-like receptor 4 antagonist not only failed to exert these effects but blocked the effects of LPS, indicating its TLR4 dependence. Together, these results indicated that alarmin HMGB1 mediates potentiation of LPS function, exacerbating TLR4-dependent systemic and brain inflammation in a rat PSI model and there is a positive-feedback loop between augmentation of LPS function by HMGB1 and subsequent HMGB1 release/serum. Therefore, HMGB1 might be a valuable therapeutic target for preventing post-stroke infection.
中风后感染（PSI）已知会使中风患者的功能预后恶化，并且占医院中风相关死亡人数的三分之一。在我们之前的报告中，我们证明了 N-甲基-D-天冬氨酸诱导的缺血后大脑急性损伤会促进高迁移率族蛋白 1（HMGB1）的大量释放，这种内源性危险信号分子通过触发延迟性炎症过程加剧神经元损伤。此外，已经报道 HMGB1 通过直接相互作用增强脂多糖（LPS）的促炎功能。本研究的目的是通过增强 LPS 的促炎功能来研究 HMGB1 在加重 PSI 炎症中的作用。PSI 动物模型是通过在大脑中动脉闭塞（MCAO）后 24 小时给予低剂量 LPS 产生的。在 LPS 注射 MCAO 动物中观察到炎症明显加重、行为结果恶化和梗死扩大，其中血清 HMGB1 激增，尤其是二硫键型，在 LPS 给药后立即发生，并可能通过与 LPS 协同作用加重脑和全身炎症。重要的是，通过延迟给予已知抑制 HMGB1 的治疗性肽（HMGB1 A 盒，HPep1）或在用 HMGB1 A 盒预先孵育后用 LPS 进行治疗来阻断 HMGB1 功能，可显著改善大鼠 PSI 模型中观察到的损伤，表明 HMGB1 发挥了关键作用。此外，施用 Rhodobacter sphaeroides LPS，一种选择性 Toll 样受体 4 拮抗剂，不仅未能发挥这些作用，反而阻断了 LPS 的作用，表明其依赖 TLR4。综上所述，这些结果表明警报素 HMGB1 介导 LPS 功能的增强，在大鼠 PSI 模型中加剧 TLR4 依赖性全身和脑炎症，并且 HMGB1 增强 LPS 功能与随后的 HMGB1 释放/血清之间存在正反馈回路。因此，HMGB1 可能是预防中风后感染的有价值的治疗靶点。
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