Autophagy and inflammation in ischemic stroke

Abstract

Appropriate autophagy has protective effects on ischemic nerve tissue, while excessive autophagy may cause cell death. The inflammatory response plays an important role in the survival of nerve cells and the recovery of neural tissue after ischemia. Many studies have found an interaction between autophagy and inflammation in the pathogenesis of ischemic stroke. This study outlines recent advances regarding the role of autophagy in the post-stroke inflammatory response as follows. (1) Autophagy inhibits inflammatory responses caused by ischemic stimulation through mTOR, the AMPK pathway, and inhibition of inflammasome activation. (2) Activation of inflammation triggers the formation of autophagosomes, and the upregulation of autophagy levels is marked by a significant increase in the autophagy-forming markers LC3-II and Beclin-1. Lipopolysaccharide stimulates microglia and inhibits ULK1 activity by direct phosphorylation of p38 MAPK, reducing the flux and autophagy level, thereby inducing inflammatory activity. (3) By blocking the activation of autophagy, the activation of inflammasomes can alleviate cerebral ischemic injury. Autophagy can also regulate the phenotypic alternation of microglia through the nuclear factor-κB pathway, which is beneficial to the recovery of neural tissue after ischemia. Studies have shown that some drugs such as resveratrol can exert neuroprotective effects by regulating the autophagy-inflammatory pathway. These studies suggest that the autophagy-inflammatory pathway may provide a new direction for the treatment of ischemic stroke.

Keywords: autophagy; cerebral ischemia; function; inflammasome; inflammation; ischemia/refusion; ischemic stroke; macroautophagy; neuroinflammation; oxygen glucose deprivation.

Figure 1

Induction of autophagy. Various stress conditions stimulate ULK1 complex phosphorylation of the VPS34-Beclin-1 complex, which recruits the cellular PI3P effector proteins WIPI2 and DFCP1, promoting the formation of an isolated membrane. ATG7 activates ATG12 and is conjugated to ATG5 via E2-like ATG10, and activated ATG12-ATG5 interacts with ATG16L to form an ATG12-ATG5-ATG16 complex, which promotes phagophore extension. LC3 is processed by ATG4 to expose glycine residues. The resulting LC3-I is activated by the E1-like enzyme ATG7 and binds to PE on the phagophore by activation of ATG3 and is esterified to form LC3-II. After the formation of autophagosomes, the lysosomal fusion and degradation of the contained contents produces amino acids, lipids, nucleosides, and other substances that are reused by the cells. DFCP1: Protein 1 containing zinc finger FYVE domain; LC3: Light chain 3; PE: phosphatidylethanolamine; PI3P: phosphatidylinositol-3-phosphate; ULK1: Unc-51-like kinase 1; VPS34: Vacuolar protein sorting 34; WIPI2: WD-repeat domain phosphoinositide interaction protein.

Figure 2

A mechanism of the cellular inflammatory response after cerebral ischemia. BBB: Blood-brain barrier; DAMPs: damage-associated molecular patterns; ROS: reactive oxygen species.

Figure 3

The TLR-mediated NF-κB pathway has a negative effect on autophagy regulation. Mitochondrial dysfunction with increased ROS activates autophagy and the inflammasome. Upregulation of autophagy prevents an excessive inflammatory response by resisting the inflammasome. MAPK: Mitogen-activated protein kinase; NF-κB: nuclear factor-κB; ROS: reactive oxygen species; TLRs: membrane-associated toll-like receptors.