The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after
ischemia, perivascular astrocytes release
cytokines and activate
metalloproteases (
MMPs) that contribute to blood-brain barrier (BBB) disruption and vasogenic oedema; whereas at later stages, they provide extracellular
glutamate uptake, BBB regeneration and
neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic
brain injury via the production of inflammatory
cytokines, including
tumor necrosis factor (TNF) and
interleukin (IL)-1, reactive
oxygen and
nitrogen species and
proteases. Nevertheless, microglia also contributes to the resolution of
inflammation, by releasing
IL-10 and
tumor growth factor (TGF)-β, and to the late reparative processes by phagocytic activity and
growth factors production. Indeed, after
ischemia, microglia/macrophages differentiate toward several phenotypes: the M1 pro-inflammatory phenotype is classically activated via
toll-like receptors or
interferon-γ, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13, or TGF-β. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair. Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including
toll-like receptors and
cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of
ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction.