Intranasal Delivery Of Interleukin-4 Attenuates Chronic Cognitive Deficits Via Beneficial Microglial Responses In Experimental Traumatic Brain Injury

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/M phi) 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 PPAR gamma and arginase-1 within Mi/M phi, thereby driving microglia toward a global inflammation-resolving phenotype. Notably, IL-4 failed to shift microglial phenotype after TBI in Mi/M phi-specific PPAR gamma knockout (mKO) mice, indicating an obligatory role for PPAR gamma in IL-4-induced Mi/M phi polarization. Accordingly, post-TBI treatment with IL-4 failed to improve hippocampal integrity or cognitive functions in PPAR gamma mKO mice. These results demonstrate that administration of exogenous IL-4 nanoparticles stimulates PPAR gamma-dependent beneficial Mi/M phi responses, and improves hippocampal function after TBI.