Neuroinflammation in Ischaemic Stroke: Utilizing the Biphasic Niche of Neuroprotection and Neurotoxicity for Clinic

Abstract

Ischaemic stroke is a devastating disease that results in neurological disorder with maximum disease burden caused by blockade of blood vessels in the brain leading to neuronal cell death and tissue damage. Inflammatory processes have a fundamental role in the pathophysiology of ischaemic stroke, and recent studies indicate that inflammation has a temporally biphasic behaviour and acts as a double-edged sword, not only exacerbating secondary brain injury in the acute stage of stroke, but also thereafter beneficially contributing to brain recovery after the stroke. An initial event of inflammation in ischaemic stroke is activation of microglia, leading to a cascade of delicately balanced orchestration between both pro- and anti-inflammatory mediators, acting through multiple receptor signalling pathways. Understanding how microglia can actuate to both its phenotypes—such as neurotoxic M1 type (‘bad microglia’) vis-a-vis neuroprotective M2 type (‘good microglia’)—may be essential to implement therapeutic strategies of using differential immunomodulatory interventions in ischaemic stroke. We elucidate the role of the bimodality in inflammation in ischaemic stroke, the related signalling pathways, and the resulting immunomodulation and immunosuppression processes. A pathophysiological integration of the findings from cell culture models, animal studies, human investigations and population-based clinical trials, is undertaken. We delineate how one can utilize the manoeuvre the dynamics of inflammation and immunomodulation for enhancing therapeutic interventions on ischaemic stroke.