Interleukin-4 improves white matter integrity and functional recovery after murine traumatic brain injury via oligodendroglial PPARγ

DOI

10.1177/0271678X20941393

Hongjian Pu, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Xuan Zheng, Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
Xiaoyan Jiang, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Hongfeng Mu, Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
Fei Xu, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Wen Zhu, Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
Qing Ye, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Yunneng Jizhang, Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
T Kevin Hitchens, Animal Imaging Center, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Yejie Shi, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Xiaoming Hu, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
Rehana K. Leak, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, 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

3-1-2021

Publication Title

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

Volume

41

Issue

3

First Page

511

Last Page

529

Keywords

OPC differentiation, PPARγ, Traumatic brain injury, oligodendrogenesis, white matter injury/integrity

Abstract

Long-term neurological recovery after severe traumatic brain injury (TBI) is strongly linked to the repair and functional restoration of injured white matter. Emerging evidence suggests that the anti-inflammatory cytokine interleukin-4 (IL-4) plays an important role in promoting white matter integrity after cerebral ischemic injury. Here, we report that delayed intranasal delivery of nanoparticle-packed IL-4 boosted sensorimotor neurological recovery in a murine model of controlled cortical impact, as assessed by a battery of neurobehavioral tests for up to five weeks. Post-injury IL-4 treatment failed to reduce macroscopic brain lesions after TBI, but preserved the structural and functional integrity of white matter, at least in part through oligodendrogenesis. IL-4 directly facilitated the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-producing oligodendrocytes in primary cultures, an effect that was attenuated by selective PPARγ inhibition. IL-4 treatment after TBI in vivo also failed to stimulate oligodendrogenesis or improve white matter integrity in OPC-specific PPARγ conditional knockout (cKO) mice. Accordingly, IL-4-afforded improvements in sensorimotor neurological recovery after TBI were markedly impaired in the PPARγ cKO mice compared to wildtype controls. These results support IL-4 as a potential novel neurorestorative therapy to improve white matter functionality and mitigate the long-term neurological consequences of TBI.

Open Access

Green Final

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