Autophagy regulates inflammation in intracerebral hemorrhage: Enemy or friend?

Abstract

Intracerebral hemorrhage (ICH) is the second-largest stroke subtype and has a high mortality and disability rate. Secondary brain injury (SBI) is delayed after ICH. The main contributors to SBI are inflammation, oxidative stress, and excitotoxicity. Harmful substances from blood and hemolysis, such as hemoglobin, thrombin, and iron, induce SBI. When cells suffer stress, a critical protective mechanism called “autophagy” help to maintain the homeostasis of damaged cells, remove harmful substances or damaged organelles, and recycle them. Autophagy plays a critical role in the pathology of ICH, and its function remains controversial. Several lines of evidence demonstrate a pro-survival role for autophagy in ICH by facilitating the removal of damaged proteins and organelles. However, many studies have found that heme and iron can aggravate SBI by enhancing autophagy. Autophagy and inflammation are essential culprits in the progression of brain injury. It is a fascinating hypothesis that autophagy regulates inflammation in ICH-induced SBI. Autophagy could degrade and clear pro-IL-1β and apoptosis-associated speck-like protein containing a CARD (ASC) to antagonize NLRP3-mediated inflammation. In addition, mitophagy can remove endogenous activators of inflammasomes, such as reactive oxygen species (ROS), inflammatory components, and cytokines, in damaged mitochondria. However, many studies support the idea that autophagy activates microglia and aggravates microglial inflammation via the toll-like receptor 4 (TLR4) pathway. In addition, autophagy can promote ICH-induced SBI through inflammasome-dependent NLRP6-mediated inflammation. Moreover, some resident cells in the brain are involved in autophagy in regulating inflammation after ICH. Some compounds or therapeutic targets that regulate inflammation by autophagy may represent promising candidates for the treatment of ICH-induced SBI. In conclusion, the mutual regulation of autophagy and inflammation in ICH is worth exploring. The control of inflammation by autophagy will hopefully prove to be an essential treatment target for ICH.

Trem2 deficiency attenuates microglial phagocytosis and autophagic‐lysosomal activation in white matter hypoperfusion

“…Therefore, we speculate that after Trem2 knockout, the degradation efficiency of microglia is improved. Further, studies have found that in a two‐point injection of the LPC demyelination model, the overactivation of microglial autophagy lysosomes can lead to the accumulation of lipid droplets, causing microglial dysfunction and transformation to a pro‐inflammatory phenotype (Fu et al., 2022; Zhou et al., 2023). In the aging brain, lipid droplets accumulated in microglia can also cause microglial dysfunction and strong inflammatory responses (Qin et al., 2023).…”

Integrative transcriptomic and network pharmacology analysis reveals the neuroprotective role of BYHWD through enhancing autophagy by inhibiting Ctsb in intracerebral hemorrhage mice

“…Autophagy plays a vital role in degrading intracellular materials and maintaining cellular homeostasis by utilising lysosomal enzymes [ 48 ]. The production and transportation of autophagosomes primarily occur in axons, and proper axonal transport is crucial for clearing damaged mitochondria [ 19 ]. Ctsb is closely associated with autophagy and negatively regulates neurite outgrowth by modulating lysosomal trafficking in neurons [ 49 ].…”

Recent advances in potential therapeutic targets of ferroptosis‑associated pathways for the treatment of stroke (Review)

“…Following a stroke, various forms of cell death occur in the body, the main ones of which are apoptosis ( 139 ), necrosis ( 140 ) and autophagy ( 141 ). It has been shown that the use of different inhibitors to inhibit apoptosis, necrosis and autophagy is more effective than the use of any of these inhibitors in isolation, as in the case of cerebral hemorrhage, where caspase inhibitors have been shown to be unsuccessful in terms of inhibiting hemoglobin-induced neuronal death ( 142 ).…”