Wang Jiaxin, Gao Shuaixin, Fu Su, Li Yawei, Su Li, Li Xiaoman, Wu Guanghao, Jiang Jiankuo, Zhao Zifang, Yang Chaojuan, Wang Xiaoyi, Cui Kun, Sun Xiaoyan, Qi Xuetao, Wang Cheng, Sun Haojie, Shao Shan, Tian Yue, Gong Tingting, Luo Jianyuan, Zheng Jie, Cui Shuang, Liao Feifei, Liu Fengyu, Wang Dongxin, Wong Catherine C L, Yi Ming, Wan You
Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China; Human Nutrition Program, Department of Human Sciences & James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Brain Behav Immun. 2025 Mar;125:68-91. doi: 10.1016/j.bbi.2024.12.019. Epub 2024 Dec 17.
Postoperative cognitive dysfunction (POCD) is common in the aged population and associated with poor clinical outcomes. Irisin, an endogenous molecule that mediates the beneficial effects of exercise, has shown neuroprotective potential in several models of neurological diseases. Here we show that preoperative serum level of irisin is reduced in dementia patients over the age of 70. Comprehensive proteomics analysis reveals that deletion of irisin affects the nervous and immune systems, and reduces the expression of complement proteins. Systemically administered irisin penetrates the blood-brain barrier in mice, targets the microglial integrin αVβ5 receptor, activates signal transducer and activator of transcription 6 (STAT6), induces microglia reprogramming to the M2 phenotype, and improves immune microenvironment in LPS-induced neuroinflammatory mice. Finally, prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction. Our findings provide new insights into the direct regulation of the immune microenvironment by irisin, and reveal that recombinant irisin holds great promise as a novel therapy for preventing POCD and other neuroinflammatory disorders. SUMMARY: Our findings reveal molecular and cellular mechanisms of irisin on neuroinflammation, and show that prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction.
术后认知功能障碍（POCD）在老年人群中很常见，且与不良临床结局相关。鸢尾素是一种介导运动有益作用的内源性分子，在多种神经疾病模型中已显示出神经保护潜力。在此我们表明，70岁以上痴呆患者术前血清鸢尾素水平降低。综合蛋白质组学分析显示，鸢尾素缺失会影响神经和免疫系统，并降低补体蛋白的表达。全身性给予鸢尾素可穿透小鼠血脑屏障，作用于小胶质细胞整合素αVβ5受体，激活信号转导子和转录激活子6（STAT6），诱导小胶质细胞重编程为M2表型，并改善脂多糖诱导的神经炎症小鼠的免疫微环境。最后，预防性给予鸢尾素可预防类似POCD的行为，尤其是早期认知功能障碍。我们的研究结果为鸢尾素对免疫微环境的直接调节提供了新见解，并表明重组鸢尾素作为预防POCD和其他神经炎症性疾病的新型疗法具有巨大潜力。总结：我们的研究结果揭示了鸢尾素对神经炎症的分子和细胞机制，并表明预防性给予鸢尾素可预防类似POCD的行为，尤其是早期认知功能障碍。
