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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.

Background and Purpose Type-2 diabetes mellitus (T2DM) is a major comorbidity that exacerbates ischemic brain injury and worsens functional outcome after stroke. T2DM is known to aggravate white matter impairment but the underlying mechanism is not completely understood. This study was designed to test the hypothesis that T2DM impedes post-stroke white matter recovery by suppressing both oligodendrogenesis and beneficial microglia/macrophage responses. Methods Permanent distal middle cerebral artery occlusion was performed in wild-type, homozygous diabetic db/db, and heterozygous db/+ mice. The adhesive removal, open field, and Morris water maze tests were used to assess neurobehavioral outcomes. Neuronal tissue loss, white matter damage, oligodendrogenesis, and microglia/macrophage responses were evaluated up to 35d after stroke. The functional integrity of white matter was measured by electrophysiology. Primary microglia-oligodendrocyte co-cultures were used for additional mechanistic studies. Results T2DM exacerbated structural damage and impaired conduction of compound action potentials in white matter 35d after stroke. The deterioration in white matter integrity correlated with poor sensorimotor performance. Furthermore, T2DM impaired the proliferation of oligodendrocyte precursor cells (OPCs) and the generation of new myelinating oligodendrocytes. T2DM also promoted a shift of microglia/macrophage phenotype toward the pro-inflammatory modality. Co-culture studies confirmed that microglia/macrophage polarization toward the pro-inflammatory phenotype under high glucose conditions suppressed OPC differentiation. Conclusions Deterioration of white matter integrity and impairments in oligodendrogenesis after stroke are associated with poor long-term functional outcomes in experimental diabetes mellitus. High glucose concentrations may shift microglia/macrophage polarization toward a pro-inflammatory phenotype, significantly impairing OPC differentiation and white matter repair.

Transforming growth factor α (TGF-α) has been reported to play important roles in neurogenesis and angiogenesis in the injured brain. The present study characterizes a novel role for TGFα in oligodendrocyte lineage cell survival and white matter integrity after ischemic stroke. Three days after transient (60 min) middle cerebral artery occlusion (tMCAO), TGFα expression was significantly increased in microglia/macrophages and neurons. Expression of the receptor of TGFα—epidermal growth factor receptor (EGFR)—was increased in glial cells after ischemia, including in oligodendrocyte lineage cells. TGFα knockout enlarged brain infarct volumes and exacerbated cell death in oligodendrocyte precursor cells (OPCs) and oligodendrocytes three days after tMCAO. TGFα-deficient mice displayed long-term exacerbation of sensorimotor deficits after tMCAO, and these functional impairments were accompanied by loss of white matter integrity and impaired oligodendrocyte replacement. In vitro studies confirmed that 5 or 10 ng/mL TGFα directly protected OPCs and oligodendrocytes against oxygen and glucose deprivation (OGD)-induced cell death, but exerted no effects on OPC differentiation. Further studies identified STAT3 as a key transcription factor mediating the effects of TGFα on OPCs and oligodendrocytes. In conclusion, TGFα provides potent oligodendrocyte protection against cerebral ischemia, thereby maintaining white matter integrity and improving neurological recovery after stroke.