The use of microRNAs to modulate redox and immune response to stroke

Abstract

Significance: Cerebral ischemia is a major cause of death and disability throughout the world, yet therapeutic options remain limited. The interplay between the cellular redox state and the immune response plays a critical role in determining the extent of neural cell injury after ischemia and reperfusion. Excessive amounts of reactive oxygen species (ROS) generated by mitochondria and other sources act both as triggers and effectors of inflammation. This review will focus on the interplay between these two mechanisms.

Recent advances: MicroRNAs (miRNAs) are important post-transcriptional regulators that interact with multiple target messenger RNAs coordinately regulating target genes, including those involved in controlling mitochondrial function, redox state, and inflammatory pathways. This review will focus on the regulation of mitochondria, ROS, and inflammation by miRNAs in the chain of deleterious intra- and intercellular events that lead to brain cell death after cerebral ischemia.

Critical issues: Although pretreatment using miRNAs was effective in cerebral ischemia in rodents, testing treatment after the onset of ischemia is an essential next step in the development of acute stroke treatment. In addition, miRNA formulation and delivery into the CNS remain a challenge in the clinical translation of miRNA therapy.

Future directions: Future research should focus on post-treatment and potential clinical use of miRNAs.

FIG. 1.

Reactive oxygen species (ROS) metabolism and regulation by miRNA. Excessive amounts of superoxide anion (O₂^•−) are produced in mitochondria, mainly through complex I and III, during ischemia–reperfusion. Superoxide dismutase (SOD) detoxifies O₂^•− to hydrogen peroxide (H₂O₂), which is converted to water (H₂O) by catalase (CATs) or glutathione peroxidase (GSHPx). Hydroxyl radicals ( ^•OH), produced from H₂O₂ through the Fenton or Haber-Weiss reactions, cause cell injury through oxidized lipid, protein, DNA, and RNA. On the right side, miRNAs reported to target mitochondrial protective proteins and antioxidative enzymes are indicated. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Nuclear factor-kappa B (NF-κB) proinflammatory signaling pathway and regulation by miR-181. NF-κB, a dimer often consisting of p50/p65 subunits, is normally resident in the cytosol and is maintained in an inactive form by its inhibitor IκB. Stroke stimulates mitochondria to release ROS that activate the IκB kinase (IKK) complex. The activated IKK complex phosphorylates IκB and initiates its ubiquitination and degradation, freeing NF-κB to translocate to the nucleus, and binds the promoters of genes expressing proinflammatory cytokines, IκB, and other targets. miR-181 interacts with this pathway at multiple points. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

microRNAs modulate the immune response to stroke. Immediately following stroke, the innate immune system triggers a localized inflammatory response, which then activates the adaptive immune response. The adaptive immune response can promote a proinflammatory state, exacerbating outcome, or can inhibit proinflammatory activation, depending on microglial and T-helper cell subtype differentiation, and local environmental cues. To date, several miRNAs (miR-124, miR-146a, miR-155, and miR-181c) appear to modulate both the innate and adaptive immune responses to stroke and may provide a therapeutic avenue for improving clinical outcome. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

miR-181 influences immune response, mitochondria, and ROS. Stroke leads to increased proneurogenic signals, but also dysfunction of mitochondria, which inhibits neurogenesis and increases ROS. Overproduction of ROS triggers immune response and the release of inflammatory factors, such as tumor necrosis factor alpha (TNF-α) and IL-6 as well as further increasing ROS, causing additional mitochondrial damage. miR-181 antagomir can increase mitochondrial protective proteins (HSP70 family members and BCL2 family members) to reduce ROS production and inhibit inflammation, thereby efficiently regulating multiple ischemic cell death pathways and facilitating neurogenesis. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars