Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy

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.

Autocrine Activation of Cerebral Microglia by Allograft Inflammatory Factor-1

“…Activated microglia/macrophages have been reported to be strongly immunoreactive for anti-Iba-1 Ab [6]. Consistently, with UCCAO, intense immunoreactivity was observed in the corpus callosum, where activated microglia accumulated (Fig.…”

“…Although the expression level is low in resting microglia, it is strongly enhanced in cases of brain infarction [5]. Moreover, enhanced expression is accompanied by morphological changes in the microglia, a hallmark of microglia activation [6]. Based on these observations, Iba-1 has been used as a marker for activated microglia.…”

Structural and Functional Remodeling of the Brain Vasculature Following Stroke

“…Following ischemic or hemorrhagic stroke, microglia dynamically transition into a reactive state (Eldahshan et al, 2019;Rawlinson et al, 2020). The initial leakage of blood serum components such as fibrinogen induces local activation of microglia.…”

Inhibited CSF1R Alleviates Ischemia Injury via Inhibition of Microglia M1 Polarization and NLRP3 Pathway

“…Numerous works indicated that activating microglia M1 phenotype response has a negative effect on the process of cerebral ischemia [23]. Inhibiting microglia M1 phenotype and activating M2 phenotype have a broad prospect in treating stroke [24]. In ischemic brain injury, the inflammatory response can prompt the massive release of microglia M1 factors such as TNF-α and iNOS [25].…”