Journal Article

IL-33/ST2L Signaling Provides Neuroprotection Through Inhibiting Autophagy, Endoplasmic Reticulum Stress, and Apoptosis in a Mouse Model of Traumatic Brain Injury

Gao, Yuan, Wang, Zu-feng, Zhang, Ming-yang, Wang, Hao-chen, Ye, Guang-hua, Luo, Cheng-liang, Tao, Lu-yang, Wang, Tao, Gao, Cheng, Yu, Lin-sheng, Fan, Yan-yan

2018

Overview

Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) cytokine family and an extracellular ligand for the orphan IL-1 receptor ST2. Accumulated evidence shows that the IL-33/ST2 axis plays a crucial role in the pathogenesis of central nervous system (CNS) diseases and injury, including traumatic brain injury (TBI). However, the roles and molecular mechanisms of the IL-33/ST2 axis after TBI remain poorly understood. In this study, we investigated the role of IL-33/ST2 signaling in mouse TBI-induced brain edema and neurobehavioral deficits, and further exploited underlying mechanisms, using salubrinal (SAL), the endoplasmic reticulum (ER) stress inhibitor and anti-ST2L. The increase in IL-33 level and the decrease in ST2L level at injured cortex were first observed at 24 h post-TBI. By immunofluorescent double-labeled staining, IL-33 co-localized in GFAP-positive astrocytes, and Olig-2-positive oligodendrocytes, and predominantly presented in their nucleus. Additionally, TBI-induced brain water content, motor function outcome, and spatial learning and memory deficits were alleviated by IL-33 treatment. Moreover, IL-33 and SAL alone, or their combination prevented TBI-induced the increase of IL-1β and TNF-α levels, suppressed the up-regulation of ER stress, apoptosis and autophagy after TBI. However, anti-ST2L treatment could significantly invert the above effects of IL-33. Together, these data demonstrate that IL-33/ST2 signaling mitigates TBI-induced brain edema, motor function outcome, spatial learning and memory deficits, at least in part, by a mechanism involving suppressing autophagy, ER stress, apoptosis and neuroinflammation.

• Publisher: Frontiers Research Foundation,Frontiers Media S.A
• Subject: Apoptosis / Astrocytes / Autophagy / Central nervous system / Cytokines / Disease / Edema / Endoplasmic reticulum / endoplasmic reticulum (ER) stress / Forensic sciences / Glial fibrillary acidic protein / IL-1β / IL-33-ST2L signaling / Inflammation / Interleukin 1 / Interleukin 1 receptors / Laboratory animals / Molecular modelling / Motor skill learning / Nervous system / neurobehavioral deficits / Neuroprotection / Neuroscience / Oligodendrocytes / Phagocytosis / Roles / Spatial discrimination learning / Spatial memory / Traumatic brain injury / Tumor necrosis factor-α / Water content