Postischemic Inflammation in Acute Stroke

Abstract

Cerebral ischemia is caused by arterial occlusion due to a thrombus or an embolus. Such occlusion induces multiple and concomitant pathophysiological processes that involve bioenergetic failure, acidosis, loss of cell homeostasis, excitotoxicity, and disruption of the blood-brain barrier. All of these mechanisms contribute to neuronal death, mainly via apoptosis or necrosis. The immune system is involved in this process in the early phases after brain injury, which contributes to potential enlargement of the infarct size and involves the penumbra area. Whereas inflammation and the immune system both exert deleterious effects, they also contribute to brain protection by stimulating a preconditioning status and to the concomitant repair of the injured parenchyma. This review describes the main phases of the inflammatory process occurring after arterial cerebral occlusion, with an emphasis on the role of single mediators.

Keywords: immune response; inflammation; ischemic stroke.

Fig. 1. Postischemic inflammation. Necrotic neurons release damage-associated molecular patterns (DAMPs), and these molecules activate macrophages via pattern-recognition receptors and inflammasomes. The activated macrophages contribute to enhance the inflammatory process via the release of proinflammatory cytokines and recruiting T-cells that contribute to maintain inflammation by interleukin (IL)-17. At several days after the acute injury, the cellular elements of the innate immune system change to an anti-inflammatory phenotype, contributing to inhibit the inflammation (dashed lines). In particular, anti-inflammatory cytokines (e.g., IL-10) are released. During this phase, the postischemic inflammation is resolved by the clearance of debris as well as angiogenesis supported by the release of growth factors. IGF: insulin-like growth factor, TGF, transforming growth factor, TNF: tumor necrosis factor, VEGF: vascular endothelial growth factor.

Fig. 2. Cerebral ischemic cascade. AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, BAD: Bcl-2-associated death promoter, BBB: blood-brain barrier, COX: cyclo-oxigenase, IL: interleukin, NMDA: N-methyl-D-aspartate, TNF: tumor necrosis factor.

Fig. 3. DAMP receptors and signaling pathways. Cells detect DAMPs via DAMP receptors in two ways: (1) activation of a type of pattern-recognition receptor [Toll-like receptor (TLR)] and (2) activation of inflammasomes. The first mechanism involves proinflammatory factors being released by the nuclear gene expression mediated by transcriptional mediators activated by TLR. The second mechanism involves the activation of caspase-1 leading to the clivation of the proinflammatory cytokines IL-1 and IL-18, converting them into their activated forms. DAMP: damage-associated molecular pattern, IL: interleukin, NLRP: nod-like receptor pyrin.