The good and bad of microglia/macrophages: new hope in stroke therapeutics

Abstract

Ischemic stroke contributes up to 80% of total stroke incidence and is one of the leading causes of death and disability worldwide1,2. Noteworthily, the inflammatory responses triggered after ischemic stroke often amplify and exacerbate the ischemic lesion2. Insufficient blood supply to brain cells initiates the pathophysiology of ischemic stroke and results in a densely ischemic core surrounded by a poorly perfused region termed ischemic penumbra. Cells within the ischemic area become deprived of oxygen, glucose, and other nutrients. Since oxygen and glucose are critical fuels for brain cell survival, lack of these factors leads to dysfunction of neurons, glial cells, endothelial cells, and pericytes. Neuronal microenvironments are no longer tightly maintained and disruption of the blood brain barrier (BBB) occurs. Blood borne immune cells start to infiltrate through the disrupted vessel walls into the ischemic area and release inflammatory mediators, which exaggerate brain edema and promote cell death in the penumbra to result in secondary infarct lesion1,3. Accordingly, ischemic stoke patients who arrived to the hospital within a short time window (3–4.5 h1,2,4) after stroke incidence are commonly treated with the thrombolytic agent, recombinant tissue plasminogen activator (tPA, commonly called “clot buster”), in an attempt to restore perfusion and minimize brain damage1,2. For patients who have missed the short time frame, there is no safe and efficacious treatment that is currently available3. This is because the thrombus in the occluded artery has become too firm for tPA to dissolve. Moreover, the BBB disruption is likely to occur at this point, which would allow tPA to gain excess into the extravascular compartment. tPA residing in the extravascular compartment is associated with higher risk of intracranial hemorrhage and neurotoxicity5. Therefore, the beneficial effect of tPA is greatly compromised in patients with prolonged and untreated ischemic stroke. To develop effective treatments for these patients, it is essential to understand the complex and incompletely defined post ischemic inflammatory response mechanisms. This article highlights a recent work reported by Hu and colleagues6, which sheds new light into the future management of post-ischemic stroke inflammation.