Inflammatory Disequilibrium in Stroke

Abstract

Over the past several decades, there have been substantial advances in our knowledge of the pathophysiology of stroke. Understanding the benefits of timely reperfusion has led to the development of thrombolytic therapy as the cornerstone of current management of ischemic stroke, but there remains much to be learned about mechanisms of neuronal ischemic and reperfusion injury and associated inflammation. For ischemic stroke, novel therapeutic targets have continued to remain elusive. When considering modern molecular biologic techniques, advanced translational stroke models, and clinical studies, a consistent pattern emerges, implicating perturbation of the immune equilibrium by stroke in both central nervous system injury and repair responses. Stroke triggers activation of the neuroimmune axis, comprised of multiple cellular constituents of the immune system resident within the parenchyma of the brain, leptomeninges, and vascular beds, as well as through secretion of biological response modifiers and recruitment of immune effector cells. This neuroimmune activation can directly impact the initiation, propagation, and resolution phases of ischemic brain injury. In order to leverage a potential opportunity to modulate local and systemic immune responses to favorably affect the stroke disease curve, it is necessary to expand our mechanistic understanding of the neuroimmune axis in ischemic stroke. This review explores the frontiers of current knowledge of innate and adaptive immune responses in the brain and how these responses together shape the course of ischemic stroke.

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

“…Loss of BBB integrity after ischemia permits penetration of intravascular proteins, fluid, and immune cells into the extracellular space, resulting in vasoactive edema and expansion of tissue damage. 197 Severity of BBB damage predicts neurological outcome after stroke. 198 While it is well accepted that BBB disruption occurs early after ischemia, the exact temporal profile remains vague.…”

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

“…A variety of danger signals together with pro-inflammatory cytokines and chemokines drive the initial response. Endothelial cells are activated with loss of tight junctions and integrity of the BBB, which is further weakened by MMPs (released by neutrophils, pericytes, pro-inflammatory M1 resident/infiltrating myeloid cells, and endothelial cells), as well as by reactive oxygen species, and oxidative stress (Jin et al, 2017; Petrovic-Djergovic et al, 2016; Rayasam et al, 2017; Takata et al, 2011). This creates a route for entry of immune cells into the brain parenchyma along with solutes and water that result in interstitial inflammation and edema that further damages neuronal tissue.…”

“…As expected, adaptive immunity is engaged during the propagation phase following an initial innate immune response. A detailed description of the temporal pattern of inflammation following an ischemic stroke can be found elsewhere (Petrovic-Djergovic et al, 2016; Rayasam et al, 2017). In theory, any of the 3 phases could be targeted clinically; however, limiting the extent of inflammation or its duration during the propagation phase is more practical.…”

The choroid plexus as a site of damage in hemorrhagic and ischemic stroke and its role in responding to injury

“…Thus, an early influx of leukocytes (particularly neutrophils) into the brain from the blood may exacerbate ischemic and hemorrhagic brain injury [125, 126], but a later inflammation may be beneficial in brain repair [127–129]. In the case of cerebral hemorrhage, infiltrating macrophages/resident microglia have an important role in hematoma resolution via phagocytosis [130, 131].…”