Stroke is one of the major medical concerns for United States military veterans. The classically neurocentric view of the brain in stroke research may have hindered the development of effective therapies. White matter (WM) injury, characterized by loss of myelin and myelin-producing oligodendrocytes (OLs), is a major cause of functional disability after stroke but has not been widely appreciated until recently. Strategies that are able to alleviate both gray matter and WM pathophysiology are needed to achieve full brain protection and long-term neurological recovery. Accumulating evidence suggests that the different functional phenotypes of microglia/ macrophages contribute considerably to the regulation of inflammatory status of injured brain and ultimately impact the brain integrity. Specifically, M2-like phenotype is essential for tissue preservation and brain repair because M2 cells resolve local inflammation, clear cell debris, and provide protective factors. Interleukin-33 (IL-33) is a multifunctional cytokine that involves in a wide range of immune responses, including potentiating M2-like responses in macrophages. Interestingly, both IL-33 and its receptor, which consists of ST2 and IL-1 receptor accessory protein, are expressed in the CNS. The precise roles of IL-33/ST2 signaling in the ischemic brain, however, are not well-characterized and the underlying mechanisms of action remain unknown. Our preliminary results show that ST2 knockout (KO) mice exhibited enlarged brain infarct, deteriorated WM injury and worse sensorimotor deficits after transient middle cerebral artery occlusion (tMCAO). In contrast, intranasal infusion of IL-33 1h after tMCAO attenuates brain infarct. Remarkably, ST2 KO mice showed reduced expression of M2-like markers and increased expression of M1-like markers in the ischemic brain. We have found in vitro that IL-33 potentiates M2 polarization, especially IL-10 production in primary microglia. Furthermore, IL-33 treatment enhanced neuronal and OL survival against oxygen glucose deprivation (OGD) in neuron-glia mixed culture, which can be abolished by IL-10 neutralizing antibody. This proposal will further explore the protective effect of IL-33/ST2 signaling after ischemic brain injury with the hope of developing IL-33 into a novel, clinically feasible therapeutic strategy to ameliorate post-stroke brain damage. We will test the overarching hypothesis that the activation of IL-33/ST2 signaling protects against cerebral ischemia by enhancing microglia/macrophage polarization toward a protective M2 phenotype, which in turn restricting neuronal and WM injury after stroke.
The Specific Aims to be tested are:
Aim 1 : Test the hypothesis that IL-33 post-treatment protects against focal cerebral ischemia in both young and aged mice.
Aim 2 : Test the hypothesis that IL-33/ST2 signaling ameliorates ischemic neuronal and OL damage via shifting microglia toward a protective phenotype.
Aim 3 : Test the hypothesis that IL-10 is an essential protective factor released by IL-33-treated microglia. The success of this study will shed light on IL-33 as a potential therapeutic strategy for both gray matter and WM protection and long-term recovery after stroke.

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 33 (IL-33) as a promising immune therapy for ischemic stroke. We will investigate whether and how nasal delivery of IL-33 into the ischemic brain protects against ischemic brain injury and improves long-term neurological outcomes after experimental stroke. This information will be valuable for future development of new therapy for stroke and, possibly, other neurological disorders.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX003651-02
Application #
9815352
Study Section
Neurobiology C (NURC)
Project Start
2018-10-01
Project End
2022-09-30
Budget Start
2019-10-01
Budget End
2020-09-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
033127569
City
Pittsburgh
State
PA
Country
United States
Zip Code
15240