Targeting the Immune System for Ischemic Stroke

Stroke is the leading cause of death and disability globally. Two-thirds of stroke survivors are left disabled, requiring assistance in daily living tasks. Currently, treatments for ischemic stroke are limited to clot lysis and/or mechanical removal within a few hours of stroke onset. In addition to the brain injury and cell death that occurs rapidly due to severe cerebral ischemia, a secondary phase of infarct growth is driven by inflammation for several days. There are complex contributions from the innate and adaptive immune systems, but an improved understanding of this process may yield new therapeutic targets to limit stroke injury. Stroke is responsible for almost 6 million deaths and more than 10% of all mortalities each year, and two-thirds of stroke survivors remain disabled. With treatments for ischemic stroke still limited to clot lysis and/or mechanical removal, new therapeutic targets are desperately needed. In this review, we provide an overview of the complex mechanisms of innate and adaptive immune cell-mediated inflammatory injury, that exacerbates infarct development for several days after stroke. We also highlight the features of poststroke systemic immunodepression that commonly leads to infections and some mortalities, and argue that safe and effective therapies will need to balance pro- and anti-inflammatory mechanisms in a time-sensitive manner, to maximize the likelihood of an improved long-term outcome. Stroke is responsible for almost 6 million deaths and more than 10% of all mortalities each year, and two-thirds of stroke survivors remain disabled. With treatments for ischemic stroke still limited to clot lysis and/or mechanical removal, new therapeutic targets are desperately needed. In this review, we provide an overview of the complex mechanisms of innate and adaptive immune cell-mediated inflammatory injury, that exacerbates infarct development for several days after stroke. We also highlight the features of poststroke systemic immunodepression that commonly leads to infections and some mortalities, and argue that safe and effective therapies will need to balance pro- and anti-inflammatory mechanisms in a time-sensitive manner, to maximize the likelihood of an improved long-term outcome. the process of accumulation and activation of immune cells in injured or infected issues. Inflammation involving innate and adaptive immune cells is complex and occurs over several days, but exerts an overall detrimental effect in augmenting the brain infarct volume. region of brain tissue with critical blood flow reduction (typically <20% of normal blood flow) from which an infarct (volume of dead tissue) will develop. one extreme of the simplified macrophage activation spectrum, usually identified by production of IFN-γ, LPS, and reactive oxygen species. M1-polarized macrophages are responsible for inflammatory response and pathogen clearance. Sometimes referred to as classical activated macrophages. the other extreme of the simplified macrophage activation spectrum, usually identified by production of arginase-I, IL-10, and TGF-β. M2 macrophages are responsible for anti-inflammatory effects and promoting tissue repair and regeneration. type of innate immune cell responsible for phagocytosis of pathogens and apoptotic cells. They are differentiated from monocytes, which circulate in the blood, and extravasate into infected or affected tissues. also known as brain resident macrophages. Microglia constantly survey the brain and spinal cord. They act as the first line of defense against foreign antigen or autoantigen within the CNS. similar to M1 cells, are considered proinflammatory and secrete TNF-α and IL-12, promote blood brain barrier breakdown and are anti-tumorigenic. similar to M2 cells, are considered anti-inflammatory but promote tumor growth. an abundant type of circulating multigranular innate immune cell that is among the first cell types to respond to and migrate toward a site of tissue inflammation. brain region adjacent to the ischemic core which is subjected to a less severe blood flow reduction, typically 20–40 % of normal blood flow, provided by collateral vessels. In acute stroke, the penumbra remains metabolically active but functionally silent. It may recover function but is susceptible to infarct development due to persistent ischemia and inflammation-driven injury. a special T cell subset that suppress immune responses by secreting IL-10 and TGF-β. T helper (Th) 1 cells form part of T cell mediated immunity and secrete the inflammatory cytokines IL-2, IL-6, IL-12, IL-18, and IFN-γ. Th1 immunity is essential for protection from intracellular bacterial and viral infection. T helper (Th) 2 cells form part of humoral immunity and secrete cytokines IL-4, IL-5, IL-13, and IL-33. Th2 immunity is important for large extracellular antigens such as parasites, but is also responsible for allergic reactions. Th1 immune responses can be counteracted by Th2 immune responses, which in the case of stroke, can serve an anti-inflammatory purpose. a separate T cell lineage promoting tissue inflammation by secreting IL-17 and IL-22.