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

Gao, Yuan; Zhang, Mingyang; Wang, Tao; Fan, Yanyan; Yu, Linsheng; Ye, Guanghua; Wang, Zufeng; Gao, Cheng; Wang, Hao‐Chen; Luo, Chengliang; Tao, Luyang

doi:10.3389/fncel.2018.00095

Cited by 51 publications

(42 citation statements)

References 58 publications

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“…In this study, we demonstrated an unreported role of IL‐33 in counteracting DCM by inhibiting ER stress‐related cardiomyocyte apoptosis. In fact, IL‐33 has been reported to modulate ER stress in other cells (Gao et al, 2018; Hasnain et al, 2014), suggesting that IL‐33 is an important regulator of ER stress. However, the precise mechanism by which IL‐33 modulates ER stress is not described in these studies.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin‐33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin‐like growth factor‐binding protein 3

Wang

Xie

et al. 2020

Journal Cellular Physiology

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Prolonged endoplasmic reticulum (ER) stress is the key driving force behind diabetic cardiomyopathy (DCM). Autophagy is extensively implicated in adaptive mechanisms for cell survival. Interleukin-33 (IL-33) is known to be a potent cardiac protector, but its roles in DCM, ER stress, and autophagy are currently unknown. We aimed to explore the effects of IL-33 on DCM and characterize the roles that ER stress and autophagy play in DCM. The effects of IL-33 on DCM, ER stress, and autophagy were characterized both in db/db mice and in palmitic acid (PA)-treated cardiomyocytes. The manipulators of ER stress and autophagy were used to clarify their roles in DCM remittance conferred by IL-33. Gene expression analysis was used to identify IL-33-dependent regulators of ER stress and autophagy. Both db/db mice and PA-treated cells presented with enhanced levels of ER stress, apoptosis, and lipid deposition, as well as impaired autophagy, all of which could be reversed by IL-33. Treatment with IL-33 improved the cardiac diastolic function of diabetic mice. Nonselective autophagy inhibitors, such as 3-methyladenine (3-MA) or wortmannin, abolished the protective effects of IL-33, resulting in an increase in both ER stress and apoptosis. Strikingly, insulin-like growth factor-binding protein 3 (IGFBP3) was identified as the gene most significantly differentially expressed between IL-33 and control groups. Knockdown of IGFBP3 expression, similar to the effect of nonselective autophagy inhibitors, resulted in high levels of ER stress, impaired autophagy, and apoptosis that were not rescued upon treatment with IL-33. IL-33 abates DCM by alleviating ER stress and promoting autophagy. IGFBP3 is essential for IL-33-induced ER stress resolution and autophagic enhancement during DCM.

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Section: Discussionmentioning

confidence: 99%

“…Our previous study demonstrated that it inhibited the FFA uptake receptor, CD36, in macrophages (Zhang et al, 2017). In the fields out of the cardiovascular system, IL‐33 is found to be implicated in the regulation of autophagy and ER stress (Dickinson et al, 2016; Gao et al, 2017, 2018; Wu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Interleukin‐33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin‐like growth factor‐binding protein 3

Wang

Xie

et al. 2020

Journal Cellular Physiology

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“…Serum sST2 levels are also elevated in TBI patients, and the increased concentrations are positively related to inflammation, severity and prognosis (55), which indicates that sST2 is a potential prognostic biomarker for TBI. In mice, IL-33 is released immediately from damaged oligodendrocytes and astrocytes in injured CNS tissue during TBI induced by controlled cortical impact (CCI) and experimental SCI (4,11,13,56).…”

Section: Il-33 In Traumamentioning

confidence: 99%

Therapeutic Opportunities of Interleukin-33 in the Central Nervous System

et al. 2021

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Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is involved in various diseases. IL-33 exerts its effects via its heterodimeric receptor complex, which comprises suppression of tumorigenicity 2 (ST2) and the IL-1 receptor accessory protein (IL-1RAP). Increasing evidence has demonstrated that IL-33/ST2 signaling plays diverse but crucial roles in the homeostasis of the central nervous system (CNS) and the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infection, trauma, and ischemic stroke. In the current review, we focus on the functional roles and cellular signaling mechanisms of IL-33 in the CNS and evaluate the potential for diagnostic and therapeutic applications.

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“…IL-33 is released from apoptotic and necrotic cells as a vigilant signaling molecule ( Palmer et al, 2009 ), and its synthesis, localization, and secretion are closely related to its dual functional properties. Indeed, IL-33 plays a double-edged sword in a variety of diseases, such as intracerebral hemorrhage (ICH) ( Gao et al, 2017b ), traumatic brain injury (TBI) ( Gao et al, 2018 ) and central multiple sclerosis (MS) ( Jafarzadeh et al, 2016 ). On the one hand, exogenous IL-33 can inhibit autophagic cell death and inflammatory responses, thereby protecting neurons from damage ( Gao et al, 2017b ).…”

Section: Introductionmentioning

confidence: 99%

IL-33 Alleviated Brain Damage via Anti-apoptosis, Endoplasmic Reticulum Stress, and Inflammation After Epilepsy

et al. 2020

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Interleukin (IL)-33 belongs to a novel chromatin-associated cytokine newly recognized by the IL-1 family, and its specific receptor is the orphan IL-1 receptor (ST2). Cumulative evidence suggests that IL-33 plays a crucial effect on the pathological changes and pathogenesis of central nervous system (CNS) diseases and injuries, such as recurrent neonatal seizures (RNS). However, the specific roles of IL-33 and its related molecular mechanisms in RNS remain confused. In the present study, we investigated the protein expression changes and co-localized cell types of IL-33 or ST2, as well as the effect of IL-33 on RNS-induced neurobehavioral defects, weight loss, and apoptosis. Moreover, an inhibitor of IL-33, anti-IL-33 was performed to further exploited underlying mechanisms. We found that administration of IL-33 up-regulated the expression levels of IL-33 and ST2, and increased the number of its co-localization with Olig-2-positive oligodendrocytes and NeuN-positive neurons at 72 h post-RNS. Noteworthily, RNS-induced neurobehavioral deficits, bodyweight loss, and spatial learning and memory impairment, as well as cell apoptosis, were reversed by IL-33 pretreatment. Additionally, the increase in IL-1β and TNF-α levels, up-regulation of ER stress, as well as a decrease in anti-apoptotic protein Bcl-2 and an increase in pro-apoptotic protein CC-3 induced by RNS are prevented by administration of IL-33. Moreover, IL-33 in combination with Anti-IL-33 significantly inverted the effects of IL-33 or Anti-IL-33 alone on apoptosis, ER stress, and inflammation. Collectively, these data suggest that IL-33 attenuates RNS-induced neurobehavioral disorders, bodyweight loss, and spatial learning and memory deficits, at least in part through mechanisms involved in inhibition of apoptosis, ER stress, and neuro-inflammation.

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

Cited by 51 publications

References 58 publications

Interleukin‐33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin‐like growth factor‐binding protein 3

Interleukin‐33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin‐like growth factor‐binding protein 3

Therapeutic Opportunities of Interleukin-33 in the Central Nervous System

IL-33 Alleviated Brain Damage via Anti-apoptosis, Endoplasmic Reticulum Stress, and Inflammation After Epilepsy

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