The interleukin-4/PPARγ signaling axis promotes oligodendrocyte differentiation and remyelination after brain injury

Qingxiu Zhang,Yejie Shi,Wei Cai,Ligen Shi,T Kevin Hitchens,Fang Yu,Jun Chen,Fei Xu,Rehana K Leak,Xiangrong Liu,Wen Zhu,Lesley M Foley,Hongfeng Mu,Jie Chen,Xiaoming Hu,Yanqin Gao,Xuejiao Dai,Richard Daneman

doi:10.1371/journal.pbio.3000330

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.

Highlights

The primary focus of stroke research has traditionally been on neuronal damage within gray matter, but emerging evidence reveals a robust correlation between white matter injury and long-term sensorimotor and cognitive deficits after stroke [1]
Cellular fate mapping studies have demonstrated the differentiation of oligodendrocyte progenitor cell (OPC) toward the oligodendrocyte lineage in the ischemic brain, but the majority of these cells fail to develop into mature, functional oligodendrocytes [11,12,13]
Consistent with previous reports [15, 21], IL-4 receptor α (IL-4Rα) was expressed on CD45−CD11b−glial fibrillary acidic protein (GFAP)+ astrocytes, CD45−CD11b−NeuN+ neurons, CD45intermediateCD11b+ microglia, CD45highCD11b+ macrophages, and other infiltrated immune cells (CD45+CD11b−) 3 d after 60-min middle cerebral artery occlusion (MCAO) (Fig 1A and 1B)

Summary

Introduction

The primary focus of stroke research has traditionally been on neuronal damage within gray matter, but emerging evidence reveals a robust correlation between white matter injury and long-term sensorimotor and cognitive deficits after stroke [1]. White matter accounts for approximately 60% of total brain volume in humans It is composed mostly of bundled axons and glial cells, including myelin-producing oligodendrocytes, astrocytes, and microglia. Remyelination is a process whereby new myelin sheaths are generated around demyelinated axons in the adult central nervous system (CNS) after injuries. It is one of the critical regenerative mechanisms for white matter repair after brain injuries. Therapeutic interventions to promote the differentiation of OPCs into mature oligodendrocytes and enhance the remyelination of axons are promising strategies to achieve successful white matter repair and functional recovery after stroke [11]

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Results

Conclusion