Intranasal delivery of interleukin-4 attenuates chronic cognitive deficits via beneficial microglial responses in experimental traumatic brain injury

DOI

10.1177/0271678X211028680

Hongjian Pu, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Cheng Ma, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Yongfang Zhao, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Yangfan Wang, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Wenting Zhang, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Wanying Miao, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Fang Yu, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Xiaoming Hu, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Yejie Shi, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Rehana K. Leak, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
T Kevin Hitchens, Animal Imaging Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
C Edward Dixon, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Michael Vl Bennett, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
Jun Chen, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.

Document Type

Journal Article

Publication Date

11-1-2021

Publication Title

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

Volume

41

Issue

11

First Page

2870

Last Page

2886

Keywords

Cognitive function, DTI, PPARγ, long-term potentiation, microglia polarization

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 ( long-term potentiation) and structural levels (CA3 neuronal loss, diffusion tensor imaging of white matter tracts, .). 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.

Open Access

Green Final

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