{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T12:55:15Z","timestamp":1793105715043,"version":"4.5.0"},"reference-count":66,"publisher":"SAGE Publications","issue":"11","license":[{"start":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T00:00:00Z","timestamp":1626220800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Cereb Blood Flow Metab"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:p>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\u03a6) 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\u2009weeks 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\u2009weeks 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\u03b3 and arginase-1 within Mi\/M\u03a6, thereby driving microglia toward a global inflammation-resolving phenotype. Notably, IL-4 failed to shift microglial phenotype after TBI in Mi\/M\u03a6-specific PPAR\u03b3 knockout (mKO) mice, indicating an obligatory role for PPAR\u03b3 in IL-4-induced Mi\/M\u03a6 polarization. Accordingly, post-TBI treatment with IL-4 failed to improve hippocampal integrity or cognitive functions in PPAR\u03b3 mKO mice. These results demonstrate that administration of exogenous IL-4 nanoparticles stimulates PPAR\u03b3-dependent beneficial Mi\/M\u03a6 responses, and improves hippocampal function after TBI.<\/jats:p>","DOI":"10.1177\/0271678x211028680","type":"journal-article","created":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T07:12:35Z","timestamp":1626246755000},"page":"2870-2886","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":39,"title":["Intranasal delivery of interleukin-4 attenuates chronic cognitive deficits via beneficial microglial responses in experimental traumatic brain injury"],"prefix":"10.1177","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5435-7070","authenticated-orcid":false,"given":"Hongjian","family":"Pu","sequence":"first","affiliation":[{"name":"Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 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