Role of inflammation and its mediators in acute ischemic stroke

Abstract

Inflammation plays an important role in the pathogenesis of ischemic stroke and other forms of ischemic brain injury. Increasing evidence suggests that inflammatory response is a double-edged sword, as it not only exacerbates secondary brain injury in the acute stage of stroke but also beneficially contributes to brain recovery after stroke. In this article, we provide an overview on the role of inflammation and its mediators in acute ischemic stroke. We discuss various pro-inflammatory and anti-inflammatory responses in different phases after ischemic stroke and the possible reasons for their failures in clinical trials. Undoubtedly, there is still much to be done in order to translate promising pre-clinical findings into clinical practice. A better understanding of the dynamic balance between pro- and anti-inflammatory responses and identifying the discrepancies between pre-clinical studies and clinical trials may serve as a basis for designing effective therapies.

Figure 1. Postischemic inflammatory response

Stroke induces activation of microglia and astrocytes which react by secreting cytokines, chemokines, ROS and matrix metalloproteases (MMPs). These mediators increase the expression of adhesion molecules on cerebral endothelial cells, which promotes adhesion and infiltration of the blood-derived leukocytes (neutrophils, macrophages and lymphocytes) to ischemic brain. Infiltrating leukocytes further amplify brain inflammatory response by secreting a variety of proinflammatory mediators. Meanwhile, activated microglia/macrophage and infiltrated Treg cells also secrete some neuroprotective factors (e.g. IL-10, TGF-β) that could suppress postischemic inflammation.

Figure 2. TNF-α pathway

The TNF-α signaling is mediated via TNF-R p55 and TNF-R p75. TNF-R p55 seems to lead to TNF-α-induced apoptosis, whereas TNF-R p75 appears to involve in cell survival.

Figure 3. TLRs pathway following ischemic stroke

TLRs pathway could be activated by stroke and induce a serious of pro-inflammatory and anti-inflammatory responses.

Figure 4. MAPK pathways following ischemic stroke

MAPK pathway could be activated by stroke and induce a serious of pro-inflammatory and anti-inflammatory responses.

Figure 5. the roles of pro-inflammatory and anti-inflammatory responses in ischemic stroke

The balance between pro-inflammatory and anti-inflammatory responses acts key roles in injury following ischemic stroke.