Interleukin-4 improves white matter integrity and functional recovery after murine traumatic brain injury via oligodendroglial PPARγ. Issue 3 (March 2021)

• Record Type: Journal Article
• Authors: Pu, Hongjian; Zheng, Xuan; Jiang, Xiaoyan; Mu, Hongfeng; Xu, Fei; Zhu, Wen; Ye, Qing; Jizhang, Yunneng; Hitchens, T Kevin; Shi, Yejie; Hu, Xiaoming; Leak, Rehana K; Dixon, C Edward; Bennett, Michael VL; Chen, Jun
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 41:Issue 3(2021)
• Page Start: 511
• Page End: 529
• Publication Date: 2021-03
• Subjects: Traumatic brain injury -- white matter injury/integrity -- OPC differentiation -- oligodendrogenesis -- PPARγ; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X20941393
• Languages: English
• ISSNs: 0271-678X

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.