Thrombo-Inflammation and Immunological Response in Ischemic Stroke: Focusing on Platelet-Tregs Interaction

Abstract

Strokes are mainly caused by thromboembolic obstruction of a major cerebral artery. Major clinical manifestations include paralysis hemiplegia, aphasia, memory, and learning disorders. In the case of ischemic stroke (IS), hyperactive platelets contribute to advancing an acute thrombotic event progression. Therefore, the principal goal of treatment is to recanalize the occluded vessel and restore cerebral blood flow by thrombolysis or mechanical thrombectomy. However, antiplatelets or thrombolytic therapy may increase the risk of bleeding. Beyond the involvement in thrombosis, platelets also contribute to the inflammatory process induced by cerebral ischemia. Platelet-mediated thrombosis and inflammation in IS lie primarily in the interaction of platelet receptors with endothelial cells and immune cells, including T-cells, monocytes/macrophages, and neutrophils. Following revascularization, intervention with conventional antiplatelet medicines such as aspirin or clopidogrel does not substantially diminish infarct development, most likely due to the limited effects on the thrombo-inflammation process. Emerging evidence has shown that T cells, especially regulatory T cells (Tregs), maintain immune homeostasis and suppress immune responses, playing a critical immunomodulatory role in ischemia-reperfusion injury. Hence, considering the deleterious effects of inflammatory and immune responses, there is an urgent need for more targeted agents to limit the thrombotic-inflammatory activity of platelets and minimize the risk of a cerebral hemorrhage. This review highlights the involvement of platelets in neuroinflammation and the evolving role of Tregs and platelets in IS. In response to all issues, preclinical and clinical strategies should generate more viable therapeutics for preventing and managing IS with immunotherapy targeting platelets and Tregs.

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“…The Global Burden of Disease Study indicates that during the past 10 years, the number of fatalities from stroke has dramatically raised and has maintained the second-leading cause of mortality globally [91]. Stroke is a diverse disease with pathogenic types such as ischemic stroke (IS), intracerebral hemorrhage (ICH), and sudden localized damage to the central nervous system (CNS) mediated by vascular sources [92].…”

The intersection of coagulation activation and inflammation after injury: What you need to know

“…42 In addition, in other diseases that are also characterized by ischemia-reperfusion injury, it has been identified that platelets carry a signaling role in the regulatory T cell suppression. 45 Finally, platelets and endothelial cells are symbiotic in their joint regulation of hemostatic functions and inflammatory pathophysiology. 46,47…”

“…It is likely that the known alterations to platelet function after injury have downstream effects on the regulation of endothelial and immune functions and contribute to the microvascular thrombotic complications seen in injured patients who develop venous thromboembolism and multiple organ failure 42 . In addition, in other diseases that are also characterized by ischemia-reperfusion injury, it has been identified that platelets carry a signaling role in the regulatory T cell suppression 45 . Finally, platelets and endothelial cells are symbiotic in their joint regulation of hemostatic functions and inflammatory pathophysiology 46,47 …”

Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis

“…The first cells to be activated following Ischemic brain damage are those of microglia. Subsequently, the monocytes/macrophages and the neutrophils also reach the ischemic area passing the blood–brain barrier (BBB) interacting with the adhesion molecules [ 26 , 27 ]. During reperfusion, glial cells and neurons secrete chemo-attractant protein-1 monocyte (MCP-1/CCL2), which causes the migration of neutrophils into the infarcted area [ 28 ].…”