Stroke is the leading cause of disability in the US and worldwide. Improvements in acute stroke patient care have resulted in reduced stroke mortality, leaving more survivors with severe disability and a long road of recovery. However, strategies based on acute neuroprotection resulted in recurring translational failures, suggesting the need for a paradigm shift to address the translational efficacy issue and improve this devastating condition. Evidence suggests that stroke initiates metabolic and genetic changes that persist for weeks to months following the ischemic insult, therefore providing a promising realm for intervention in the recovery phase. With a relative paucity in our understanding of the repair and remodeling process in chronic stroke, the current study proposes to identify CD36, a common inflammatory mediator in vascular diseases and obesity, as a potential mediator in stroke recovery. Highly expressed on monocytes/macrophages (MMs), CD36 functions in regulating inflammation, innate immunity, taste, and metabolism. Previous studies in our lab showed that CD36 contributes to acute stroke pathology in normal and hyperlipidemic conditions. Despite the adverse effects of CD36 in acute stroke, evidence has also been presented supporting a beneficial role for CD36 in distinct stroke subtypes via its role in enhancing phagocytosis. These studies indicate that CD36 as an inflammatory as well as pattern recognition receptor displays context-dependent functions. MMs play a major role in tissue repair by clearing up debris and phagocytosis through pattern recognition. Our preliminary results also indicate potential involvement of macrophage CD36 in the chronic phase of stroke recovery: the higher CD36 levels, the greater phagocytic activity in macrophages, ii) a late secondary induction of CD36 at 2-month post-stroke, and iii) persistent infiltration of peripheral macrophages in the injured tissue during recovery phase. These observations led to a hypothesis that CD36 facilitates stroke recovery via MM phagocytosis.
Aim 1 will test whether CD36 promotes functional recovery in chronic stroke. We will assess longitudinal motor/gait functions and expression of CD36 and its associated molecules (thrombospondins, toll-like receptors) in chronic stroke in wild type and CD36 KO mice where their CD36 levels are manipulated by CD36 activator(s) or inhibitor(s).
Aim 2 will determine the impact of CD36 on MM trafficking, MM phagocytosis and macrophage phenotypes in vitro and also in mice treated with CD36 inhibitor or activator. Since we observed CD36 expression is increased in MMs in obese conditions, we will test whether obesity-enhanced CD36 expression in MMs promotes functional recovery.
In Aim 3, we will assess behaviors, phagocytosis, and macrophage phenotype in WT and CD36 KO mice fed a normal and high fat diet. Understanding the context-dependent role of CD36 in the stroke recovery phase, in addition to the acute phase studied during a previous funding cycle, may offer a strategy for stroke-stage specific modulations of CD36 in promoting functional recovery in chronic stroke.
Despite the fact that stroke is the leading cause of disability in the U.S., treatments that reduce post-stroke impairment are very limited due to our lack of understanding of the repair/remodeling process in chronic stroke. The current proposal investigates whether and how CD36, a common inflammatory mediator in vascular diseases and obesity, is involved in functional recovery in chronic stroke. We have several findings that lead to the hypothesis that CD36 facilitates stroke recovery by the action of peripheral immune cells. This study aims to test the function of CD36 in the immune cells relevant to the repair/remodeling process after stroke. Defining the underlying events will provide a potential strategy for promoting functional recovery in stroke patients.
