Dissection of the dual role of inflammatory mediators in ischemic stroke for validating novel neurotherapeutics

The immune system affects all phases of the ischemic cascade, from the acute intravascular reaction due to blood flow disruption, to the development of brain tissue damage, repair and regeneration. An early inflammatory signalling is activated in the brain within hours from the ischemic insult, consisting in release of cytokines (e.g., IL-1beta) and chemokines from distinct cells. These soluble mediators promote endothelial expression of adhesion molecules and blood-brain barrier breakdown facilitating extravasation and brain recruitment of blood-borne cells, including macrophages, neutrophils and T lymphocytes. In turn, infiltrating leukocytes participate to the evolution of ischemic brain damage by releasing pro-inflammatory mediators or promoting tissue recovery. This dualism is virtually expressed by all the players of the inflammatory response to stroke injury, also including enzymes and transcription factors. Indeed, matrix metalloproteinases (MMPs) exert an early detrimental effect by cleaving protein components of the extracellular matrix and by processing cell surface and soluble proteins including IL-1beta; whereas, during the late repair phases, MMPs promote release of growth factors that contribute to neurovascular regeneration. The transcription factor STAT3 is subjected to a time- and region-specific phosphorylation during stroke. Its early activation in penumbra astrocytes may promote neuronal survival, whereas its late activation in microglia/macrophages may contribute to detrimental responses by inducing expression of proinflammatory cytokines. A better understanding of the dualistic role played by each component of the inflammatory response in relation to the spatio-temporal evolution of ischemic stroke injury is pivotal for the development of novel neurotherapeutics.