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.

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 后神经学结果产生多维影响。在这里，我们报告了在受控皮质影响后 4 周内重复鼻内递送白细胞介素 4 (IL-4) 纳米颗粒改善了成年 C57BL6 小鼠的海马依赖性空间和非空间认知功能，正如通过一系列神经行为测试评估的那样TBI 后最多 5 周。IL-4 引起的认知功能增强与功能区海马体完整性的改善有关（例如，长时程增强）和结构水平（CA3 神经元丢失、白质束扩散张量成像等）。从机制上讲，IL-4 增加了 Mi/MΦ 中 PPARγ 和精氨酸酶-1 的表达，从而将小胶质细胞推向全局炎症解决表型。值得注意的是，在 Mi/MΦ 特异性 PPARγ 敲除 (mKO) 小鼠中，IL-4 未能在 TBI 后改变小胶质细胞表型，表明 PPARγ 在 IL-4 诱导的 Mi/MΦ 极化中具有强制性作用。因此，用 IL-4 进行 TBI 后治疗未能改善 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 纳米颗粒的给药会刺激 PPARγ 依赖性有益的 Mi/MΦ 反应，并改善 TBI 后的海马功能。