Cerebral ischemia triggers a powerful innate immunity response initiated by danger associated molecular pattern molecules (DAMPs) released by damaged cells. Engagement of innate immunity receptors on resident brain cells, mainly microglia, triggers production of cytokines and adhesion molecules leading to an inflammatory response that contributes to the acute phase of the injury. Post-ischemic inflammation is considered an attractive therapeutic target, but a deeper understanding of the upstream molecular events is needed to inform therapeutic development. Studies over the previous funding period have demonstrated that the innate immunity receptor CD36 promotes the activation and neurotoxicity of neutrophils, a key effector of the acute damage produced by post-ischemic inflammation, and contributes to ischemic injury. These harmful effects are attributable to CD36 expression in microglia and endothelial cells, not in infiltrating hematogenous cells, but the relative roles that microglial and endothelial CD36 play in post-ischemic inflammation have not been established. IL1?, secreted by microglia, has emerged as a key cytokine involved in the initiation of post-ischemic inflammation. IL1? is produced by the inflammasome, a multimolecular complex that when activated by DAMPs leads to the cleavage of pro-IL1? into the mature cytokine. We hypothesize that CD36 in microglia mediates IL1? production by participating in inflammasome activation. IL1?, in turn, acts on endothelial cells to produce, in concert with CD36, potent neutrophil activators, including CSF3, and triggering neutrophil cytotoxicity. This hypothesis will be tested using a well-established mouse model of transient focal ischemia. In vivo and in vitro approaches, as well as CD36 ?floxed? mice enabling targeted deletion of CD36 in specific cell types will be used. Since stroke is a disease of the aged in both sexes and aging enhances the deleterious effects of microglia and CD36, we will also study aged male and female mice.
Aim 1 will test the hypothesis that CD36 contributes to post-ischemic IL1? production by microglia through the NLRP3 inflammasome.
Aim 2 will test whether microglial IL1? acts on endothelial IL1 receptors to induce CSF3 production and neutrophil activation in concert with endothelial CD36.
Aim 3 will use mice with microglial or endothelial CD36 deletion to assess the impact of the molecular pathways defined in Aims 1 and 2 on the histological and functional outcomes of cerebral ischemia. These studies may unveil a novel microglia-endothelial axis whereby microglial CD36 acts as an upstream ?sensor? regulating IL1? secretion and endothelial CSF3 production through CD36, ultimately leading to neutrophil activation and tissue damage.
Stroke is a highly prevalent and devastating brain disease with limited therapeutic interventions. Targeting post-ischemic inflammation offers the prospect of reducing ischemic brain injury with a wide therapeutic window, while enhancing the beneficial effects of reperfusion therapies. The findings of the proposed studies will provide new insights into the cellular bases of the upstream events activating innate immunity after cerebral ischemia and may provide the rationale for new stroke therapies based on targeting CD36 and its dependent signaling pathways.
|Garcia-Bonilla, Lidia; Brea, David; Benakis, Corinne et al. (2018) Endogenous Protection from Ischemic Brain Injury by Preconditioned Monocytes. J Neurosci 38:6722-6736|
|Brea, David; Poon, Carrie; Murphy, Michelle et al. (2018) Ablation of nasal-associated lymphoid tissue does not affect focal ischemic brain injury in mice. PLoS One 13:e0205470|
|Merkler, Alexander E; Diaz, Ivan; Wu, Xian et al. (2018) Duration of Heightened Ischemic Stroke Risk After Acute Myocardial Infarction. J Am Heart Assoc 7:e010782|
|Anderson, Corey J; Kahl, Anja; Qian, Liping et al. (2018) Prohibitin is a positive modulator of mitochondrial function in PC12 cells under oxidative stress. J Neurochem 146:235-250|
|Navi, Babak B; Howard, George; Howard, Virginia J et al. (2018) New diagnosis of cancer and the risk of subsequent cerebrovascular events. Neurology 90:e2025-e2033|
|Merkler, Alexander E; Gialdini, Gino; Lerario, Michael P et al. (2018) Population-Based Assessment of the Long-Term Risk of Seizures in Survivors of Stroke. Stroke 49:1319-1324|
|Kahl, Anja; Stepanova, Anna; Konrad, Csaba et al. (2018) Critical Role of Flavin and Glutathione in Complex I-Mediated Bioenergetic Failure in Brain Ischemia/Reperfusion Injury. Stroke 49:1223-1231|
|Burstein, Suzanne R; Kim, Hyun Jeong; Fels, Jasmine A et al. (2018) Estrogen receptor beta modulates permeability transition in brain mitochondria. Biochim Biophys Acta Bioenerg 1859:423-433|
|Kahl, Anja; Anderson, Corey J; Qian, Liping et al. (2018) Neuronal expression of the mitochondrial protein prohibitin confers profound neuroprotection in a mouse model of focal cerebral ischemia. J Cereb Blood Flow Metab 38:1010-1020|
|Navi, Babak B; Iadecola, Costantino (2018) Ischemic stroke in cancer patients: A review of an underappreciated pathology. Ann Neurol 83:873-883|
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