Abstract 55: Interleukin 4 Improves White Matter Repair After Stroke By Promoting Oligodendrocyte Differentiation

Abstract

Introduction: White matter (WM) injury is an important cause of long-term deficits after stroke. This study explores a novel action of IL-4 on promoting WM integrity after stroke and elucidates the underlying mechanisms. Hypothesis: IL-4 promotes WM repair and enhances long-term neurological recovery after ischemic stroke by targeting both OPC differentiation and microglial polarization. Methods: Cerebral ischemia was induced by transient (60 min) middle cerebral artery occlusion (tMCAO) in wild type, IL-4 knockout and oligodendrocyte precursor cell (OPC)-specific PPARγ KO mice. The animals were then randomly assigned to vehicle or IL-4 treatment. IL-4 was delivered intranasally 6h after stroke and repeated every day at 1-7d, 14d, 21d, and 28d after tMCAO. Sensorimotor deficits were determined by adhesive removal, rotarod test and corner test. Cognitive deficits were determined by water maze test. A combined approach including cell-specific depletion, immunohistology staining, electron microscopy (EM), diffusion tensor imaging (DTI) and electrophysiology, was applied to evaluate WM integrity. Results: IL-4 knockout (KO) mice exhibited worse sensorimotor deficits and deteriorated WM injury over 14 days after tMCAO. In contrast, intraventricular infusion of IL-4 beginning 6h after MCAO attenuated long-term sensorimotor and cognitive deficits and improved WM integrity, as revealed by immunohistology staining, EM, DTI and electrophysiology. In addition to promoting microglia/macrophage M2 polarization, IL-4 treatment enhanced OPC differentiation in the ischemic brain and in organotypic cultures. Interestingly, IL-4-afforded oligodendrogenesis was still potent in microglia depleted (with PLX5662) mice. In vitro study confirmed that IL-4 directly induced the differentiation of primary OPCs into mature oligodendrocytes. This effect was mediated through the activation of PPARγ. The therapeutic efficacy of IL-4 on OPC differentiation and white matter protection was significantly reduced in OPC-specific PPARγ KO mice. Conclusions: IL-4 promotes oligodendrogenesis and white matter repair in an PPARγ-dependent manner. IL-4 may represent a novel recovery-enhancing strategy to promote functional recovery after ischemic stroke.