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

Hongjian Pu, Xuan Zheng, Xiaoyan Jiang, Hongfeng Mu, Fei Xu, Wen Zhu, Qing Ye, Yunneng Jizhang, T. Kevin Hitchens, Yejie Shi, Xiaoming Hu, Rehana K. Leak, C. Edward Dixon, Michael V.L. Bennett, Jun Chen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)511-529
Number of pages19
JournalJournal of Cerebral Blood Flow and Metabolism
Volume41
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

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

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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