Targeting integrated stress response regulates microglial M1/M2 polarization and attenuates neuroinflammation following surgical brain injury in rat

Huang, Tengchao; Luo, Ling; Jiang, Shihai; Chen, Chuan; He, Hongju; Liang, Chaofeng; Li, Wensheng; Wang, Hui; Zhu, Lei; Wang, Kun; Guo, Ying

doi:10.1016/j.cellsig.2021.110048

Cited by 9 publications

(3 citation statements)

References 59 publications

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“…Further, Salubrinal and ISRIB were delivered systemically, and western blot analysis was performed in whole tissue lysate. It is possible that other retinal cells and glia play a role in ER stress responses to injury as several studies have reported both photoreceptor (Gorbatyuk et al, 2020) and glial (McMahon et al, 2012; Chen et al, 2016; Logsdon et al, 2016; Huang et al, 2021; Goodall et al, 2010; Martinon et al, 2010) ER stress responses after injury or disease. To elucidate cell-type specific responses to PERK pathway inhibition, more targeted genetic strategies might also be revealing in this model of TON.…”

Section: Limitationsmentioning

confidence: 99%

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Hetzer,

Bellary,

Torrens

et al. 2024

Preprint

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Traumatic brain injury (TBI) can induce traumatic axonal injury in the optic nerve, which is referred to as traumatic optic neuropathy (TON). TON occurs in up to 5% of TBI cases and leads to irreversible visual deficits. TON-induced phosphorylation of eIF2α, a downstream ER stress activator in the PERK pathway presents a potential point for therapeutic intervention. For eIF2α phosphorylation can lead to apoptosis or adaptation to stress. We hypothesized that dephosphorylation, rather than phosphorylation, of eIF2α would lead to reduced apoptosis and improved visual performance and retinal cell survival. Adult male mice were injected with Salubrinal (increases p-eIF2α) or ISRIB (decreases p-eIF2α) 60 minutes post-injury. Contrary to literature, both drugs hindered control animal visual function with minimal improvements in injured mice. Additionally, differences in eIF2α phosphorylation, antioxidant responses, and protein folding chaperones were different when examining protein expression between the retina and its axons in the optic nerve. These results reveal important compartmentalized ER stress responses to axon injury and suggest that interventions in the PERK pathway may alter necessary homeostatic regulation of the UPR in the retina.

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Section: Limitationsmentioning

confidence: 99%

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Hetzer,

Bellary,

Torrens

et al. 2024

Preprint

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“…Therapy with a small molecule integrated stress response inhibitor improves neuroinflammatory responses and behavioral outcomes in rats by inhibiting lipopolysaccharide (LPS)-stimulated M1 microglia from polarizing into the M2 state. The underlying mechanism may involve the downregulation of intracellular NADPH oxidase 4 (NOX4) under neuroinflammatory conditions (42). M2 microglial activity determines its role in reducing neuroinflammation and improving brain function.…”

Section: Phenotype and Functions Of Microgliamentioning

confidence: 99%

Role of microglia in sepsis-associated encephalopathy pathogenesis: an update

Yu,

Shi,

Zhang

et al. 2023

Shock

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Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis, which is characterized by cognitive dysfunction, a poor prognosis, and high incidences of morbidity and mortality. Substantial levels of systemic inflammatory factors induce neuroinflammatory responses during sepsis, ultimately disrupting the central nervous system's (CNS) homeostasis. This disruption results in brain dysfunction through various underlying mechanisms, contributing further to SAE’s development. Microglia, the most important macrophage in the CNS, can induce neuroinflammatory responses, brain tissue injury, and neuronal dysregulation, resulting in brain dysfunction. They serve an important regulatory role in CNS homeostasis and can be activated through multiple pathways. Consequently, activated microglia are involved in several pathogenic mechanisms related to SAE and play a crucial role in its development. This article discusses the role of microglia in neuroinflammation, dysfunction of neurotransmitters, disruption of the blood-brain barrier (BBB), abnormal control of cerebral blood flow, mitochondrial dysfunction, and reduction in the number of good bacteria in the gut as main pathogenic mechanisms of SAE, and focuses on studies targeting microglia to ameliorate SAE to provide a theoretical basis for targeted microglial therapy for SAE.

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“…Interestingly, this study further showed that both PERK/CHOP and IRE1α/XBP1s are involved in modulating IL-6 secretion in microglia ( 145 ). Furthermore, the eIF2α/ATF4 signaling pathway has been reported to be involved in modulating microglial activation and M1/M2 polarization, which in turn regulates microglia-mediated generation of inflammatory cytokines ( 146 – 149 ). Recently, MAP kinase phosphatase 1 (MKP1), an antiapoptotic protein, has been shown to inhibit microglial activation by modulating ER stress and mitochondrial function ( 150 ).…”

Section: The Role Of Endoplasmic Reticulum Stress In Innate Immune Re...mentioning

confidence: 99%

Endoplasmic Reticulum Stress-Associated Neuronal Death and Innate Immune Response in Neurological Diseases

Shi

Chai²,

Zhang

et al. 2022

Front. Immunol.

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Neuronal death and inflammatory response are two common pathological hallmarks of acute central nervous system injury and chronic degenerative disorders, both of which are closely related to cognitive and motor dysfunction associated with various neurological diseases. Neurological diseases are highly heterogeneous; however, they share a common pathogenesis, that is, the aberrant accumulation of misfolded/unfolded proteins within the endoplasmic reticulum (ER). Fortunately, the cell has intrinsic quality control mechanisms to maintain the proteostasis network, such as chaperone-mediated folding and ER-associated degradation. However, when these control mechanisms fail, misfolded/unfolded proteins accumulate in the ER lumen and contribute to ER stress. ER stress has been implicated in nearly all neurological diseases. ER stress initiates the unfolded protein response to restore proteostasis, and if the damage is irreversible, it elicits intracellular cascades of death and inflammation. With the growing appreciation of a functional association between ER stress and neurological diseases and with the improved understanding of the multiple underlying molecular mechanisms, pharmacological and genetic targeting of ER stress are beginning to emerge as therapeutic approaches for neurological diseases.

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Targeting integrated stress response regulates microglial M1/M2 polarization and attenuates neuroinflammation following surgical brain injury in rat

Cited by 9 publications

References 59 publications

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Role of microglia in sepsis-associated encephalopathy pathogenesis: an update

Endoplasmic Reticulum Stress-Associated Neuronal Death and Innate Immune Response in Neurological Diseases

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