Irisin reprograms microglia through activation of STAT6 and prevents cognitive dysfunction after surgery in mice
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.
Authors
- Su Fu (ORCID: https://orcid.org/0000-0002-2882-7638)
- Haojie Sun (ORCID: https://orcid.org/0000-0002-5155-1705)
- Kun Cui (ORCID: https://orcid.org/0000-0002-2944-6773)
- Jianyuan Luo (ORCID: https://orcid.org/0000-0001-6057-2914)
- Guanghao Wu (ORCID: https://orcid.org/0000-0001-7243-6370)
- You Wan (ORCID: https://orcid.org/0000-0001-6110-7192)
- Tingting Gong (ORCID: https://orcid.org/0009-0006-7909-7811)
- Catherine C. L. Wong (ORCID: https://orcid.org/0000-0002-6855-2798)
- Xuetao Qi (ORCID: https://orcid.org/0000-0003-1449-7268)
- Feng‐Yuan Liu (ORCID: https://orcid.org/0000-0001-5520-3268)
- Dong‐Xin Wang (ORCID: https://orcid.org/0000-0002-3205-1836)
- Jianmin Jiang (ORCID: https://orcid.org/0000-0003-3563-4006)
- Shuaixin Gao (ORCID: https://orcid.org/0000-0003-2815-5461)
- Zifang Zhao (ORCID: https://orcid.org/0000-0003-4145-4562)
- Feifei Liao (ORCID: https://orcid.org/0000-0001-7328-3783)
- Yawei Li (ORCID: https://orcid.org/0000-0002-8948-7892)
- Jiaxin Wang (ORCID: https://orcid.org/0000-0003-2327-412X)
- Cheng Wang (ORCID: https://orcid.org/0000-0002-9843-5373)
- Xiaoyan Sun
- Xiaoman Li (ORCID: https://orcid.org/0000-0001-5718-0047)
- Shuang Cui (ORCID: https://orcid.org/0000-0002-0859-3141)
- Li Su (ORCID: https://orcid.org/0000-0001-9590-3402)
- Jie Zheng (ORCID: https://orcid.org/0000-0003-1526-0617)
- Ming Yi (ORCID: https://orcid.org/0000-0002-6397-262X)
- Yue Tian (ORCID: https://orcid.org/0000-0003-1719-0894)
- Chaojuan Yang
- Shan Shao (ORCID: https://orcid.org/0000-0001-5685-0264)
- Xiaoyi Wang
Institutions
- Beijing Institute of Technology (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- Peking Union Medical College Hospital (CN)
- Ministry of Education (ME)
- Peking University First Hospital (CN)
- Peking University Third Hospital (CN)
- University College London (GB)
- Beihang University (CN)
Publication Details
- Journal
- Brain Behavior and Immunity
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1016/j.bbi.2024.12.019
- Citations
- 23
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 5.69