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

Rawlinson, C; Jenkins, S; Thei, L; Dallas, ML; Chen, R

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.

Citation

Rawlinson, C., Jenkins, S., Thei, L., Dallas, M., & Chen, R. (2020). Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy. Brain Sciences, 10(3), https://doi.org/10.3390/brainsci10030159

• Journal Article Type: Article
• Acceptance Date: Mar 7, 2020
• Publication Date: Mar 11, 2020
• Journal: Brain Sciences
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 3
• DOI: https://doi.org/10.3390/brainsci10030159
• Keywords: ischaemic stroke; neuroinflammation; microglia; pro-inflammatory; anti-inflammatory; phenotype
• Publisher URL: https://www.mdpi.com/2076-3425/10/3/159