Innate immunity and ischemic stroke

Veterans Health Administration, Decatur PA

Investigators

Abstract

Abstract The immune system is closely involved in all stages of ischemic stroke-induced brain damage and tissue repair. However, treatments aimed at modulating inflammation have not been successfully translated into the clinical settings yet. Therefore, the development of new anti‐ inflammatory therapies, especially those targeting upstream inflammatory signaling in ischemic stroke is necessary and urgent. Transposable Elements (TEs) alter gene expression via transposition. Dysregulation of TEs plays a critical role in pathogenesis of neuroinflammation. TE RNA activity is regulated by adenosine deaminase acting on RNA 1 (ADAR1) which is the “Editor- in-Chief” of cytoplasmic innate immunity and thus plays a key role in regulating innate immunity to dampen interferon-mediated response. Our preliminary data indicate that brain ischemia caused ADAR1 dysfunction, leading to TE RNA editing alteration. Dysregulated TE RNAs activated RNA sensing molecules which in turn triggered interferon-stimulating genes (ISG). ADAR1 mutation triggered a robust production of MDA5 and activation of ISG signaling and aggravated brain damage and neuroinflammation in murine ischemic model of middle cerebral artery occlusion (MCAO). Bocking RNA sensing signaling by deleting MDA5 effectively prevented inflammation. This specific innate immune pathway connects ADAR1 to the dysregulated TE RNAs and neuroinflammation following brain ischemia. The central hypothesis to be tested is that ADAR1 protects against ischemic brain injury by suppressing neuroinflammation through blocking the RNA sensing signaling pathway of innate immunity. The following three Aims are proposed: Aim 1: Characterize ADAR1 RNA editing profile in brain injury in MCAO model. Aim2: Test whether ADAR1 protects against ischemic brain injury by suppressing neuroinflammation through blocking MDA5/IRF7/IFN signaling pathway in MCAO model. Aim 3: Test whether targeting ADAR1 signaling can ameliorate neuroinflammation and brain injury and rescue behavioral abnormalities in MCAO model. The role of ADAR1 in brain ischemia has never been investigated. This study is the first to link RNA editing and neuroinflammation in the context of brain ischemia and will provide new insights on the role of innate immunity in ischemic brain injury. Our proposal paves a foundation to a new concept of targeting upstream inflammatory signaling to treat ischemic stroke and neurological diseases that involve inflammation.