Intranasal delivery of interleukin-4 attenuates chronic cognitive deficits via beneficial microglial responses in experimental traumatic brain injury.
Intranasal delivery of interleukin-4 attenuates chronic cognitive deficits via beneficial microglial responses in experimental traumatic brain injury.
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DOI：
10.1177/0271678x211028680
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Chen J
中科院分区：
文献类型：
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作者：
Pu H;Ma C;Zhao Y;Wang Y;Zhang W;Miao W;Yu F;Hu X;Shi Y;Leak RK;Hitchens TK;Dixon CE;Bennett MV;Chen J
创伤性脑损伤（TBI）通常伴随着长期的认知缺陷，严重影响幸存者的生活质量。最近的研究表明，小胶质细胞/巨噬细胞（Mi/MΦ）极化可能对TBI后的神经功能结局产生多方面的影响。在这里，我们报告说，反复鼻内递送白细胞介素-4（IL-4）纳米粒子4周后，控制皮质的影响，改善了成年C57 BL 6小鼠的视皮层依赖的空间和非空间认知功能，作为评估电池的神经行为测试后5周TBI。IL-4引起的认知功能的增强与功能性海马体完整性的改善相关（例如，长时程增强）和结构水平（CA 3神经元损失、白色物质束的扩散张量成像等）。从机制上讲，IL-4增加了Mi/MΦ内的PPARγ和过氧化物酶-1的表达，从而驱动小胶质细胞向全局炎症消退表型发展。值得注意的是，在Mi/MΦ特异性PPARγ敲除（mKO）小鼠中，IL-4在TBI后未能改变小胶质细胞表型，表明PPARγ在IL-4诱导的Mi/MΦ极化中的强制性作用。因此，TBI后IL-4治疗未能改善PPARγ mKO小鼠的海马完整性或认知功能。这些结果表明，外源性IL-4纳米颗粒的施用刺激了TBI后的PPARγ依赖性有益Mi/MΦ应答，并改善了海马功能。
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.