Epigenetic regulation of inflammation in stroke

Abstract

Despite extensive research, treatments for clinical stroke are still limited only to the administration of tissue plasminogen activator and the recent introduction of mechanical thrombectomy, which can be used in only a limited proportion of patients due to time constraints. A plethora of inflammatory events occur during stroke, arising in part due to the body’s immune response to brain injury. Neuroinflammation contributes significantly to neuronal cell death and the development of functional impairment and death in stroke patients. Therefore, elucidating the molecular and cellular mechanisms underlying inflammatory damage following stroke injury will be essential for the development of useful therapies. Research findings increasingly point to the likelihood that epigenetic mechanisms play a role in the pathophysiology of stroke. Epigenetics involves the differential regulation of gene expression, including those involved in brain inflammation and remodelling after stroke. Hence, it is conceivable that epigenetic mechanisms may contribute to differential interindividual vulnerability and injury responses to cerebral ischaemia. In this review, we summarize recent findings on the emerging role of epigenetics in the regulation of neuroinflammation in stroke. We also discuss potential epigenetic targets that may be assessed for the development of stroke therapies.

Epigenetic reprogramming of immune cells in injury, repair, and resolution

“…Stroke is one example of tissue injury for which the impact of epigenetic regulation is already addressed (119). Dynamic global changes in DNA methylation are associated with atherosclerosis progression (120) and stroke outcome (121).…”

“…More specifically, studies have linked stroke incidence or outcome to the regulation of genes involved in platelet conglomeration ( [125][126][127][128]). Yet, contradictory reports concerning DNA methylation's impact in different stroke subtypes indicate a need for more in-depth analysis of different pathological settings, discrimination of epigenetic changes on the gene level, and, more importantly, study of cell type-specific alterations (119). As histone H3 acetylation is greatly reduced upon ischemic stroke, many studies found that inhibition of histone deacetylation was favorable for stroke outcome: it suppressed microglia activation, induced neuroprotective proteins (e.g., IGF-1 or Hsp70), and favored functional recovery (reviewed in ref.…”

“…As histone H3 acetylation is greatly reduced upon ischemic stroke, many studies found that inhibition of histone deacetylation was favorable for stroke outcome: it suppressed microglia activation, induced neuroprotective proteins (e.g., IGF-1 or Hsp70), and favored functional recovery (reviewed in ref. 119). Albeit encouraging, detailed knowledge concerning the influence of the different histone deacetylase (HDAC) inhibitors on different members of the HDAC family and their specific effects in different cell types remains incomplete.…”

“…Similarly, histone methylation status and transcriptome regulation by differential miRNA production have been addressed in the context of stroke. While some altered epigenetic marks were generally described, studies have not yet addressed immune cells in particular, as descriptions remain on the tissue level (119). Recent results from the miRNA field address this issue; e.g., miR-155 and miR-210 induce a proinflammatory signature in microglia (129), and a miR-155 antagomir proved neuroprotective by reducing inflammation and infarct size in a mouse model for ischemic stroke (130).…”

The Emerging Spectrum of Early Life Exposure-Related Inflammation and Epigenetic Therapy

“…An increased body of evidence show that a variety of pro-inflammatory mediators is regulated via epigenetic mechanism, which contributes to pathogenesis of diseases [27–33]. A recent study by Li et al demonstrate that epigenetic regulation of keratinocytes can contribute to chronic skin inflammation [34].…”