White matter (WM) injury, characterized by demyelination and loss of axonal integrity, is an important cause of long-term sensorimotor and cognitive deficits after stroke. A persistent pro-inflammatory microenvironment after stroke is considered one underlying mechanism that hinders oligodendrocyte precursor cell (OPCs) differentiation and maturation into myelinating oligodendrocytes (OLs). Accumulating recent evidence suggests that the different functional phenotypes of microglia/macrophages contribute considerably to the regulation of inflammatory status of injured WM and ultimately impact the WM integrity. Specifically, alternatively activated M2 microglia are essential for remyelination and WM repair because they resolve local inflammation, clear broken myelin sheath or cellular debris, and provide trophic factors that promote OPC differentiation. Interleukin-4 (IL-4) is thus far the best characterized inducer for M2 polarization of microglia/macrophages; however, its role in microglia regulation in WM and long term stroke outcomes is not known. We have discovered that IL-4 is a novel endogenous protectant against WM injury and that it promotes WM repair. Our preliminary results show that IL-4 knockout (KO) mice exhibit worse sensorimotor deficits over 14 days after tMCAO. Remarkably, IL-4 KO mice display deteriorated WM injury. Moreover, IL-4 KO mice show markedly reduced numbers of M2 microglia/macrophages in WM-enriched brain regions, including the corpus callosum and striatum after tMCAO. In contrast, intraventricular infusion of IL-4 for 14 days beginning 6h after MCAO attenuates long-term sensorimotor and cognitive deficits and improves WM integrity. In addition to promoting M2 polarization, we have found that IL-4 directly induces the differentiation of primary OPCs into mature OLs at nanomolar concentrations and that this effect of IL-4 on OPCs is mediated through the activation of PPAR?. In this proposal, we will focus on the novel action of IL-4 on WM integrity and explore the underlying mechanisms. We will test the overarching hypothesis that IL-4 promotes WM integrity and long-term neurological recovery after stroke by dual mechanisms, in that it 1) promotes OPC differentiation/maturation via PPAR? activation and 2) potentiates microglia/macrophage polarization toward the beneficial M2 phenotype, which is essential for remyelination and WM repair in demyelinating brains.
The Specific Aims to be tested are:
Aim 1 : Test the hypothesis that post-ischemia IL-4 treatment enhances WM integrity and long-term neurological recovery after stroke. IL-4 will be delivered into the brain by repeated intranasal administrations after reperfusion. The endpoints for assessment include neurological outcomes and various markers for WM integrity.
Aim 2 : Test the hypothesis that IL-4 induces OPC differentiation into mature OLs and promotes axonal remyelination via PPAR? activation.
Aim 3 : Test the hypothesis that IL-4 potentiates microglia/macrophage polarization into the inflammation-resolving, tissue repair-enhancing M2 phenotype and restores a healthy microenvironment for efficient WM repair.

Public Health Relevance

Stroke is a devastating disease as currently no therapy is available to alleviate post-stroke neurological deficits. The proposed study will explore interleukin 4 (IL-4) as a promising recovery-enhancing treatment for ischemic stroke. We will investigate whether and how delayed delivery of IL-4 into the ischemic brain promotes white matter integrity and improves long-term neurological outcomes after experimental stroke. This information will be valuable for future development of new restorative therapy for stroke and, possibly, other neurological disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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University of Pittsburgh
Schools of Medicine
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Zhang, Haiyue; Xia, Yuguo; Ye, Qing et al. (2018) In Vivo Expansion of Regulatory T Cells with IL-2/IL-2 Antibody Complex Protects against Transient Ischemic Stroke. J Neurosci 38:10168-10179
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