Denver Paul, Cunningham Colm
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.
Neuropharmacology. 2025 Apr 1;267:110285. doi: 10.1016/j.neuropharm.2024.110285. Epub 2024 Dec 31.
Sepsis is characterised by dysregulated immune responses to infection, leading to multi-organ dysfunction and high rates of mortality. With increasing survival rates in recent years long-term neurological and psychiatric consequences have become more apparent in survivors. Many patients develop sepsis associated encephalopathy (SAE) which encompasses the profound but usually transient neuropsychiatric syndrome delirium but also new brain injury that emerges in the months and years post-sepsis. It is now clear that systemic inflammatory signals reach the brain during sepsis and that very significant neuroinflammation ensues. The major brain resident immune cell population, the microglia, has been implicated in acute and chronic cognitive dysfunction in animal models of sepsis based on a growing number of studies using bacterial endotoxin and in polymicrobial sepsis models such as cecal ligation and puncture. The current review explores the effects of sepsis on the brain, focussing on how systemic insults translate to microglial activation and neuroinflammation and how this disrupts neuronal function and integrity. We examine what has been demonstrated specifically with respect to microglial activation, revealing robust evidence for a role for neuroinflammation in sepsis-induced brain sequelae but less clear information on the extent of the specific microglial contribution to this, arising from findings using global knockout mice, non-selective drugs and treatments that equally target peripheral and central compartments. There is, nonetheless, clear evidence that microglia do become activated and do contribute to brain consequences of sepsis thus arguing for improved understanding of these neuroinflammatory processes toward the prevention and treatment of sepsis-induced brain dysfunction.
脓毒症的特征是对感染的免疫反应失调，导致多器官功能障碍和高死亡率。近年来，随着生存率的提高，长期的神经和精神后果在幸存者中变得更加明显。许多患者会发展为脓毒症相关性脑病（SAE），其中包括严重但通常是短暂的神经精神综合征谵妄，以及在脓毒症后的数月和数年中出现的新的脑损伤。现在很清楚，在脓毒症期间全身炎症信号会到达大脑，并随之引发非常显著的神经炎症。基于越来越多使用细菌内毒素的研究以及在诸如盲肠结扎和穿刺等多微生物脓毒症模型中，主要的脑内驻留免疫细胞群体——小胶质细胞，已被认为与脓毒症动物模型中的急性和慢性认知功能障碍有关。本综述探讨了脓毒症对大脑的影响，重点关注全身损伤如何转化为小胶质细胞激活和神经炎症，以及这如何破坏神经元功能和完整性。我们研究了关于小胶质细胞激活的具体证据，揭示了神经炎症在脓毒症诱导的脑后遗症中起作用的有力证据，但关于小胶质细胞对此具体贡献程度的信息尚不清楚，这是由于使用全球基因敲除小鼠、非选择性药物以及同样针对外周和中枢部分的治疗方法所得到的研究结果。然而，有明确证据表明小胶质细胞确实会被激活，并确实对脓毒症的脑后果有影响，因此主张更好地理解这些神经炎症过程，以预防和治疗脓毒症诱导的脑功能障碍。
