Xiang Xiaoyu, Feng Zhongxue, Wang Lijun, Wang Denian, Li Tingting, Yang Jing, Wang Siying, Xiao Fei, Zhang Wei
Department of Critical Care Medicine, West China Hospital, Sichuan University and Institute of Critical Care Medicine, Chengdu, Sichuan Province, China.
Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
Int Immunopharmacol. 2025 May 16;155:114628. doi: 10.1016/j.intimp.2025.114628. Epub 2025 Apr 10.
Sepsis, a life-threatening condition driven by dysregulated host responses to infection, is associated with long-term cognitive impairments resembling Alzheimer's disease (AD). However, the molecular mechanisms linking sepsis-induced cognitive dysfunction and AD remain unclear. We hypothesized that shared genetic pathways underlie cognitive deficits in both conditions.
Cecal ligation and puncture (CLP) in C57BL/6 J mice modeled sepsis-induced cognitive decline and amyloid pathology. Brain tissue datasets (GSE33000 for AD; GSE135838 for sepsis) were analyzed via Weighted Gene Co-expression Network Analysis (WGCNA), machine learning, and functional enrichment. Key genes were validated through ROC analysis, immune infiltration profiling, and in vivo/in vitro experiments.
Sepsis accelerated cognitive decline and AD-like pathology in mice. Bioinformatics identified CLIC1 and IFITM2 as co-diagnostic genes linked to immune dysregulation in both sepsis and AD. Immune infiltration revealed reduced neutrophils/NK cells, M1 macrophage polarization, and naïve-to-memory B cell shifts in sepsis versus AD. CLIC1 and IFITM2 were upregulated in CLP mice and cytokine-stimulated human cerebral endothelial cells, aligning with bioinformatics predictions.
CLIC1 and IFITM2, pivotal in immune cell activation, emerged as shared biomarkers of sepsis-related cognitive impairment and AD. These findings highlight immune-driven molecular intersections in cognitive deficits, offering novel targets for mechanistic research and therapeutic development.
脓毒症是一种由宿主对感染的反应失调所驱动的危及生命的病症，与类似于阿尔茨海默病（AD）的长期认知障碍相关。然而，将脓毒症诱导的认知功能障碍与AD联系起来的分子机制仍不清楚。我们假设在这两种情况下，共同的遗传途径是认知缺陷的基础。
C57BL/6 J小鼠的盲肠结扎和穿刺（CLP）模拟了脓毒症诱导的认知衰退和淀粉样病理。通过加权基因共表达网络分析（WGCNA）、机器学习和功能富集分析脑组织数据集（AD用GSE33000；脓毒症用GSE135838）。通过ROC分析、免疫浸润分析和体内/体外实验验证关键基因。
脓毒症加速了小鼠的认知衰退和AD样病理。生物信息学确定CLIC1和IFITM2为与脓毒症和AD中免疫失调相关的共同诊断基因。免疫浸润显示，与AD相比，脓毒症中中性粒细胞/自然杀伤细胞减少、M1巨噬细胞极化以及幼稚B细胞向记忆B细胞转变。CLIC1和IFITM2在CLP小鼠和细胞因子刺激的人脑血管内皮细胞中上调，与生物信息学预测一致。
CLIC1和IFITM2在免疫细胞激活中起关键作用，成为脓毒症相关认知障碍和AD的共同生物标志物。这些发现突出了认知缺陷中免疫驱动的分子交叉点，为机制研究和治疗开发提供了新的靶点。
