Intranasal delivery of interleukin-4 attenuates chronic cognitive deficits via beneficial microglial responses in experimental traumatic brain injury. Issue 11 (November 2021)

• Record Type: Journal Article
• Authors: Pu, Hongjian; Ma, Cheng; Zhao, Yongfang; Wang, Yangfan; Zhang, Wenting; Miao, Wanying; Yu, Fang; Hu, Xiaoming; Shi, Yejie; Leak, Rehana K; Hitchens, T Kevin; Dixon, C Edward; Bennett, Michael VL; Chen, Jun
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 41:Issue 11(2021)
• Page Start: 2870
• Page End: 2886
• Publication Date: 2021-11
• Subjects: Cognitive function -- microglia polarization -- long-term potentiation -- PPARγ -- DTI; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X211028680
• Languages: English
• ISSNs: 0271-678X

Abstract

Traumatic brain injury (TBI) is commonly followed by long-term cognitive deficits that severely impact the quality of life in survivors. Recent studies suggest that microglial/macrophage (Mi/MΦ) polarization could have multidimensional impacts on post-TBI neurological outcomes. Here, we report that repetitive intranasal delivery of interleukin-4 (IL-4) nanoparticles for 4 weeks after controlled cortical impact improved hippocampus-dependent spatial and non-spatial cognitive functions in adult C57BL6 mice, as assessed by a battery of neurobehavioral tests for up to 5 weeks after TBI. IL-4-elicited enhancement of cognitive functions was associated with improvements in the integrity of the hippocampus at the functional ( e.g., long-term potentiation) and structural levels (CA3 neuronal loss, diffusion tensor imaging of white matter tracts, etc .). Mechanistically, IL-4 increased the expression of PPARγ and arginase-1 within Mi/MΦ, thereby driving microglia toward a global inflammation-resolving phenotype. Notably, IL-4 failed to shift microglial phenotype after TBI in Mi/MΦ-specific PPARγ knockout (mKO) mice, indicating an obligatory role for PPARγ in IL-4-induced Mi/MΦ polarization. Accordingly, post-TBI treatment with IL-4 failed to improve hippocampal integrity or cognitive functions in PPARγ mKO mice. These results demonstrate that administration of exogenous IL-4 nanoparticles stimulates PPARγ-dependent beneficial Mi/MΦ responses, and improves hippocampal function after TBI.