Stroke-induced brain injury has been viewed mainly from a neurocentric perspective, with much attention given to the primary injury site and its penumbra. However, an important notion derived from recent studies, including our own, favor a view that the peripheral inflammatory state influences the outcome of primary injury. The goal of this proposal is to investigate the mechanism(s) by which peripheral immunity may be regulated by cerebral ischemia and how this contributes to CNS damage in stroke. Specifically, we propose that spleen monocytes play a critical role in stroke-mediated injury through a novel CD36 mechanism. Stroke induces infiltration of peripheral monocytes into primary injury sites. The monocyte trafficking is a tightly controlled event that involves sequential recruitment of monocyte subsets that either express or do not express the pro-inflammatory chemokine receptor CCR2. Hyperlipidemia expands the CCR2+ monocyte subset in the spleen and accelerates the progression of cardio- and cerebrovascular diseases. We recently made an exciting observation that links the spleen to stroke pathology;the larger the injury associated with hyperlipidemia, the greater the reduction in spleen weight, and the higher the expression of CCR2 in the post- ischemic brain. This led us to hypothesize that the spleen CCR2+ monocytes contribute to stroke-induced brain injury in hyperlipidemic conditions. Furthermore, we identified CD36 as an inflammatory mediator that contributes to stroke induced brain injury. CD36 deficiency in mice reversed the hyperlipidemia-associated phenotype and resulted in reduced CCR2 expression in the brain and a smaller infarct. These observations led to the subsequent hypotheses that CD36 regulates the mobilization of spleen CCR2+ monocytes to the infarct. Therefore, targeting CD36 is neuroprotective.
Aim 1 will determine the role of spleen CCR2+ monocytes in injury following stroke. We will establish temporal changes of CCR2+ monocyte subsets in the brain and spleen following stroke. The necessity and sufficiency of spleen monocytes will be investigated in mice that have undergone a splenectomy and in splenectomized mice that have received exogenous spleen monocytes via adoptive transfer.
Aim 2 will determine if CD36 regulates CCR2 monocyte trafficking to infarct. We will assess CCR2+ monocytes in the spleen and brain of CD36-expressing and -deficient mice after stroke. Monocyte trafficking will be evaluated in vivo by adoptively transferred GFP+ monocytes. Additional in vitro study will determine the effect of CD36 deficiency on CCR2+ monocyte subsets and their ability to acquire the CCR2+ phenotype in circulation.
Aim 3 will utilize several approaches to inhibit CD36. To selectively inhibit monocyte CD36, CD36-deficient monocytes will used. Additional pharmacological approaches using a CD36 inhibitor for acute post-ischemic treatment and chronic preventive treatment will complement the genetic cell- based approach. Understanding of peripheral monocyte influence on the primary injury may open the door to the therapeutic application of neuro-immune modulation for stroke and a host of inflammatory diseases.
Elevated plasma lipid levels are associated with peripheral inflammation and accelerate the progression of cardio- and cerebrovascular diseases. The current proposal investigates how the spleen, once thought to be a dispensable peripheral organ of the immune system, can amend the outcome of stroke-induced brain injury in the hyperlipidemic condition. Understanding the underlying events will give rise to novel therapeutic strategies to block or slow down the inflammatory disease progression.
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