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- Title
The interleukin-4/PPARγ signaling axis promotes oligodendrocyte differentiation and remyelination after brain injury.
- Authors
Zhang, Qingxiu; Zhu, Wen; Xu, Fei; Dai, Xuejiao; Shi, Ligen; Cai, Wei; Mu, Hongfeng; Hitchens, T. Kevin; Foley, Lesley M.; Liu, Xiangrong; Yu, Fang; Chen, Jie; Shi, Yejie; Leak, Rehana K.; Gao, Yanqin; Chen, Jun; Hu, Xiaoming
- Abstract
The repair of white matter damage is of paramount importance for functional recovery after brain injuries. Here, we report that interleukin-4 (IL-4) promotes oligodendrocyte regeneration and remyelination. IL-4 receptor expression was detected in a variety of glial cells after ischemic brain injury, including oligodendrocyte lineage cells. IL-4 deficiency in knockout mice resulted in greater deterioration of white matter over 14 d after stroke. Consistent with these findings, intranasal delivery of IL-4 nanoparticles after stroke improved white matter integrity and attenuated long-term sensorimotor and cognitive deficits in wild-type mice, as revealed by histological immunostaining, electron microscopy, diffusion tensor imaging, and electrophysiology. The selective effect of IL-4 on remyelination was verified in an ex vivo organotypic model of demyelination. By leveraging primary oligodendrocyte progenitor cells (OPCs), microglia-depleted mice, and conditional OPC-specific peroxisome proliferator-activated receptor gamma (PPARγ) knockout mice, we discovered a direct salutary effect of IL-4 on oligodendrocyte differentiation that was mediated by the PPARγ axis. Our findings reveal a new regenerative role of IL-4 in the central nervous system (CNS), which lies beyond its known immunoregulatory functions on microglia/macrophages or peripheral lymphocytes. Therefore, intranasal IL-4 delivery may represent a novel therapeutic strategy to improve white matter integrity in stroke and other brain injuries.
- Subjects
OLIGODENDROGLIA; BRAIN injuries; DIFFUSION tensor imaging; PEROXISOME proliferator-activated receptors; NEUROGLIA; CENTRAL nervous system
- Publication
PLoS Biology, 2019, Vol 17, Issue 6, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000330