Irisin ameliorates cognitive impairment in a lipopolysaccharide- induced neuroinflammation mouse model by inhibiting the NLRP3 inflammasome pathway in microglia

Da-Qi Zhang; Ge Li; Zong-Dong Fu; Yu-Sheng Huang; Xiao-Li Feng; Li-Jun Chen; Rong Wang; Wen-Jie Zhao; Qifu Li

doi:10.1016/j.neuropharm.2025.110572

Irisin ameliorates cognitive impairment in a lipopolysaccharide- induced neuroinflammation mouse model by inhibiting the NLRP3 inflammasome pathway in microglia

Neuropharmacology. 2025 Jun 23:110572. doi: 10.1016/j.neuropharm.2025.110572. Online ahead of print.

Authors

Da-Qi Zhang¹, Ge Li², Zong-Dong Fu³, Yu-Sheng Huang², Xiao-Li Feng², Li-Jun Chen³, Rong Wang⁴, Wen-Jie Zhao², Qifu Li⁵

Affiliations

¹ Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou 570102, China; Key Laboratory of Emergency and Trauma of Ministry of Education, The First Affiliated Hospital, Hainan Medical University, Haikou 570102, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Haikou 571199, China.
² Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou 570102, China.
³ Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou 570102, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Haikou 571199, China.
⁴ Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Collaborative Innovation Center of One Health, Hainan University, Haikou, 570228, China.
⁵ Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou 570102, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Haikou 571199, China. Electronic address: lee-chief@163.com.

PMID: 40562230
DOI: 10.1016/j.neuropharm.2025.110572

Abstract

Neuroinflammation is implicated in the development of neurodegenerative diseases. Irisin was first identified as an exercise-induced skeletal muscle-secreted glycosylated protein. The main physiological functions of irisin were initially thought to include the promotion of angiogenesis; improvement of oxidative metabolism; and regulation of glucose, lipid, and mitochondrial metabolism. However, despite its demonstrated neuroprotective effects in Alzheimer's disease, the precise role of irisin in neuroinflammation, particularly in lipopolysaccharide (LPS)-induced cognitive impairment, remains unclear. This study was performed to investigate the protective effects and mechanisms of irisin on LPS-induced inflammatory cognitive impairment both in vivo and in vitro. We induced cognitive impairment in mice using LPS and evaluated cognitive function by employing the Morris water maze test. Further, we used immunofluorescence staining and flow cytometry to assess microglial activation and polarization in the cortex and hippocampus, two brain regions involved in cognitive behaviors. Western blotting was used to detect the levels of proteins related to the NLRP3 signaling pathway. Furthermore, we measured tumor necrosis factor -α, interleukin (IL)-6, CCL2, IL-4 and IL-10 levels in BV2 cells using a mouse enzyme-linked immunosorbent assay kit and characterized M1 and M2 polarization using flow cytometry. Irisin administration improved learning and cognitive abilities but inhibited microglial activation and M1 polarization in LPS-treated mice. Irisin significantly decreased the expression of NLRP3 inflammasome signaling pathway molecules in LPS-treated mice. Further, irisin suppressed microglial activation and reduced the production of proinflammatory cytokines in BV2 cells. Moreover, irisin protected PC12 cells from LPS-activated BV2 microglia-induced neurotoxicity and inhibited apoptosis in PC12 cells induced by BV2 conditioned medium. Irisin mitigated inflammatory cognitive dysfunction and suppressed microglial activation and M1-type polarization by inhibiting the NLRP3 signaling pathway.

Keywords: NLRP3; cognitive function; irisin; lipopolysaccharide; microglia.