Autophagy regulates inflammation in intracerebral hemorrhage: Enemy or friend?

Kaijing Fu; Weilin Xu; Cameron Lenahan; Yong Mo; Jing Wen; Teng Deng; Qianrong Huang; Fangzhou Guo; Ligen Mo; Jun Yan

doi:10.3389/fncel.2022.1036313

Autophagy regulates inflammation in intracerebral hemorrhage: Enemy or friend?

Front Cell Neurosci. 2023 Jan 16:16:1036313. doi: 10.3389/fncel.2022.1036313. eCollection 2022.

Authors

Kaijing Fu¹, Weilin Xu², Cameron Lenahan³, Yong Mo¹, Jing Wen⁴, Teng Deng¹, Qianrong Huang¹, Fangzhou Guo¹, Ligen Mo¹, Jun Yan¹

Affiliations

¹ Department of Neurosurgery, Guangxi Medical University Cancer Hospital, Nanning, China.
² Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
³ Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM, United States.
⁴ Department of Rheumatism, First Affiliated Hospital of Guangxi Medical University, Nanning, China.

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.

Keywords: NLRP3 inflammasome; autophagy; intracerebral hemorrhage; microglia; mitophagy; neuroinflammatory; secondary brain injury.

Publication types

Review

Grants and funding

This study was supported by grants from National Natural Science Foundation of China (nos. 82060225 and 82260239), Guangxi Natural Science Foundation (no. 2020GXNSFAA297154), and Guangxi Medical University Education and Teaching Reform Project (2020XJGA24) to JY.