Abstract
Microglia, the major endogenous immune cells of the central nervous system, mediate critical degenerative and regenerative responses in ischaemic stroke. Microglia become “activated”, proliferating, and undergoing changes in morphology, gene and protein expression over days and weeks post-ischaemia, with deleterious and beneficial effects. Pro-inflammatory microglia (commonly referred to as M1) exacerbate secondary neuronal injury through the release of reactive oxygen species, cytokines and proteases. In contrast, microglia may facilitate neuronal recovery via tissue and vascular remodelling, through the secretion of anti-inflammatory cytokines and growth factors (a profile often termed M2). This M1/M2 nomenclature does not fully account for the microglial heterogeneity in the ischaemic brain, with some simultaneous expression of both M1 and M2 markers at the single-cell level. Understanding and regulating microglial activation status, reducing detrimental and promoting repair behaviours, present the potential for therapeutic intervention, and open a longer window of opportunity than offered by acute neuroprotective strategies. Pharmacological modulation of microglial activation status to promote anti-inflammatory gene expression can increase neurogenesis and improve functional recovery post-stroke, based on promising preclinical data. Cell-based therapies, using preconditioned microglia, are of interest as a method of therapeutic modulation of the post-ischaemic inflammatory response. Currently, there are no clinically-approved pharmacological options targeting post-ischaemic inflammation. A major developmental challenge for clinical translation will be the selective suppression of the deleterious effects of microglial activity after stroke whilst retaining (or enhancing) the neurovascular repair and remodelling responses of microglia.
Highlights
Ischaemic stroke constitutes about 85% of all stroke events [1]
The high degree of overlap between subtypes suggests that microglia exist as a spectrum of phenotypes depending on external stimuli, so we have focused on the M2 phenotype as a whole as a therapeutic target for ischaemic stroke
Peroxisome proliferator-activated receptor–r (PPAR-r) has the ability to inhibit the expression of inflammatory cytokines and direct the differentiation of immune cells towards anti-inflammatory phenotypes. 1,25-D3 pretreatment activated PPAR-r, reduced NF-κB and Tumour necrosis factor (TNF) αexpression, improved neurological functions in the rat after transient middle cerebral artery occlusion (tMCAo) [136]
Summary
Ischaemic stroke constitutes about 85% of all stroke events [1]. The underlying pathophysiology of ischaemic stroke is complex and has not yet been fully elucidated. Pro-inflammatory an endogenous agonist for the P2X7 purinergic receptor, activation of which has been suggested as a mediators, released by M1-activated microglia, can initiate neuronal apoptosis and blood-brain mechanism for microglial proliferation [46,47,48]. Arginase 1; BDNF, brain-derived neurotrophic factor; bFGF, basic fibroblast growth factor; GDNF, glial cell-derived neurotrophic factor; GSH, glutathione; HO-1, heme oxygenase; IGF-1, insulin-like growth factor 1; IL-1β, interleukin-1β; IL-13, interleukin-13; IL-4, interleukin-4; IL-6, interleukin-6; IL-10, interleukin-10; IL-12, interleukin-12; IL-23, interleukin-23; iNOS, inducible nitric oxide synthase; MMP-3, matrix metalloproteinase-3; MMP-9, matrix metalloproteinase-9; NGF, nerve growth factor; NLRC4, neuronal apoptosis inhibitory protein (NAIP)/NOD-like receptor 4; NO, nitric oxide; PS, phosphatidylserine; ROS, reactive oxygen species; TGF-β, transforming growth factor-β, tMCAo, transient middle cerebral artery occlusion.
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