The immunology of stroke: from mechanisms to translation Stroke, a leading cause of death worldwide, involves complex interactions between the immune system and the brain. Immune responses, particularly inflammation, play a critical role in both the damage caused by ischemia and the subsequent recovery. While the immune system contributes to brain damage, the damaged brain also exerts immunosuppressive effects that increase the risk of infections and worsen outcomes. Inflammatory signaling is involved in all stages of the ischemic cascade, from the initial damage caused by arterial occlusion to the regenerative processes following tissue repair. Recent research indicates that both innate and adaptive immunity are involved in stroke, but adaptive immunity triggered by newly exposed brain antigens does not significantly impact the acute phase of damage. However, modulation of adaptive immunity can protect the ischemic brain and offer new therapeutic opportunities. Despite this, immunomodulation can have harmful side effects, and understanding the interaction between the immune system and the ischemic brain is essential for maximizing the therapeutic potential of immunology in stroke. Inflammation after stroke is characterized by a sequence of events involving the brain, its vessels, circulating blood, and lymphoid organs. The inflammatory process begins immediately after arterial occlusion, with hypoxia, changes in shear stress, and reactive oxygen species (ROS) triggering the coagulation cascade and activating complement, platelets, and endothelial cells. Intravascular fibrin formation traps platelets and leukocytes, leading to microvascular occlusions. Adhesion molecules like P-selectin are translocated to the surface of platelets and endothelial cells, promoting inflammatory signals. Oxidative stress reduces the bioavailability of nitric oxide, exacerbating intravascular plugging and worsening ischemic damage. Oxidative stress also alters the permeability of the blood-brain barrier, facilitating the entry of leukocytes into the brain. Cell death during ischemia activates innate immunity and sets the stage for adaptive immunity. Danger signals released by dying cells activate the immune system, including the release of ATP and neurotransmitters. ATP activates P2X7 receptors in microglia, leading to the release of pro-inflammatory mediators. Neurotransmitters can counteract the inflammatory response by downregulating microglial cytokine, ROS, and NO production. The loss of immunosuppressive mechanisms, such as CD200 and CX3CL1, promotes microglial activation, contributing to post-ischemic inflammation. Antigen presentation by damaged cells leads to the development of cellular and humoral immunity against the antigens. This adaptive immune response has the potential to induce autoimmunity against the organ where cell death occurred, as seen in conditions like Dressler's syndrome, sympathetic ophthalmia, and diabetes. Adaptive immunity is also well established in multiple sclerosis and autoimmune demyelination. However, the role of adaptive immunity in stroke is not fully understood, as the temporal profile of T-cell involvement in brain damageThe immunology of stroke: from mechanisms to translation Stroke, a leading cause of death worldwide, involves complex interactions between the immune system and the brain. Immune responses, particularly inflammation, play a critical role in both the damage caused by ischemia and the subsequent recovery. While the immune system contributes to brain damage, the damaged brain also exerts immunosuppressive effects that increase the risk of infections and worsen outcomes. Inflammatory signaling is involved in all stages of the ischemic cascade, from the initial damage caused by arterial occlusion to the regenerative processes following tissue repair. Recent research indicates that both innate and adaptive immunity are involved in stroke, but adaptive immunity triggered by newly exposed brain antigens does not significantly impact the acute phase of damage. However, modulation of adaptive immunity can protect the ischemic brain and offer new therapeutic opportunities. Despite this, immunomodulation can have harmful side effects, and understanding the interaction between the immune system and the ischemic brain is essential for maximizing the therapeutic potential of immunology in stroke. Inflammation after stroke is characterized by a sequence of events involving the brain, its vessels, circulating blood, and lymphoid organs. The inflammatory process begins immediately after arterial occlusion, with hypoxia, changes in shear stress, and reactive oxygen species (ROS) triggering the coagulation cascade and activating complement, platelets, and endothelial cells. Intravascular fibrin formation traps platelets and leukocytes, leading to microvascular occlusions. Adhesion molecules like P-selectin are translocated to the surface of platelets and endothelial cells, promoting inflammatory signals. Oxidative stress reduces the bioavailability of nitric oxide, exacerbating intravascular plugging and worsening ischemic damage. Oxidative stress also alters the permeability of the blood-brain barrier, facilitating the entry of leukocytes into the brain. Cell death during ischemia activates innate immunity and sets the stage for adaptive immunity. Danger signals released by dying cells activate the immune system, including the release of ATP and neurotransmitters. ATP activates P2X7 receptors in microglia, leading to the release of pro-inflammatory mediators. Neurotransmitters can counteract the inflammatory response by downregulating microglial cytokine, ROS, and NO production. The loss of immunosuppressive mechanisms, such as CD200 and CX3CL1, promotes microglial activation, contributing to post-ischemic inflammation. Antigen presentation by damaged cells leads to the development of cellular and humoral immunity against the antigens. This adaptive immune response has the potential to induce autoimmunity against the organ where cell death occurred, as seen in conditions like Dressler's syndrome, sympathetic ophthalmia, and diabetes. Adaptive immunity is also well established in multiple sclerosis and autoimmune demyelination. However, the role of adaptive immunity in stroke is not fully understood, as the temporal profile of T-cell involvement in brain damage