The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia

Abstract

Neuroinflammation is a key element in the ischemic cascade after cerebral ischemia that results in cell damage and death in the subacute phase. However, anti-inflammatory drugs do not improve outcome in clinical settings suggesting that the neuroinflammatory response after an ischemic stroke is not entirely detrimental. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. Because of its inhibitory influence on several pathways of the ischemic cascade, hypothermia has been introduced as a promising neuroprotective strategy. This review also discusses the influence of hypothermia on the neuroinflammatory response. We conclude that hypothermia exerts both stimulating and inhibiting effects on different aspects of neuroinflammation and hypothesize that these effects are key to neuroprotection.

Figure 1

Schematic overview of the neuroinflammatory response after ischemic stroke. Microglia become activated after ischemia (grey area) and release pro- and anti-inflammatory mediators. Astrocytes are activated as well and will neglect the maintenance of the neurons, which are most vulnerable to ischemia, and produce neurotoxic and neurotrophic factors. In the ischemic core, neurons die due to necrosis and release necrotic debris into the ischemic tissue, thereby stimulating further activation of glial cells. Astrocytes, together with the attachment of astrocyte endfeet to endothelium and connection with neurons define the neurovascular unit. Neutrophils roll onto the endothelial surface (which is primed by pro-inflammatory cytokines (blue and purple)) until they have slowed down to such a degree that they stick to the endothelium. After binding of selectins to sialyl-Lewis^x and CAMs to integrins, the neutrophils undergo conformational changes and flatten. Subsequently, the neutrophils crawl on the endothelium to find an intercellular junction between the endothelial cells for extravasation to the abluminal side and transmigration to the ischemic tissue under the influence of chemokines (red and yellow). Adapted from [26].