Reactive microglia and mitochondrial unfolded protein response following ventriculomegaly and behavior defects in kaolin-induced hydrocephalus

Zhu, Jiebo; Lee, Min Joung; Chang, Hee Jin; Ju, Xianshu; Cui, Jianchen; Lee, Yu Lim; Go, Dahyun; Chung, Woosuk; Oh, Eungseok; Heo, Jun Young

doi:10.5483/bmbrep.2022.55.4.126

Cited by 5 publications

(4 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Microglia activation has been associated with both vasospasm and hydrocephalus and is closely regulated by the IL-6 pathway and NLRP3 in ammasome. [31] We had previously reported bene t of NLRP3 inhibition following SAH. In this paper, we found that IL-6 blockade had signi cant regulation on another armn of the in ammatory spectrum starting on post SAH day 3 and extending to day 5.…”

Section: Discussionmentioning

confidence: 97%

Investigation and Modulation of Interleukin 6 following Subarachnoid Hemorrhage: Targeting Inflammatory Activation for Cerebral Vasospasm

Lucke‐Wold

2023

32nd Annual Meeting North American Skull Base Society

View full text Add to dashboard Cite

Background: Cerebral vasospasm (CV) can contribute signi cant morbidity for subarachnoid hemorrhage (SAH) patients. A key unknown is how CV induction is triggered following SAH. Methods: human aneurysmal blood was collected for evaluation. To con rm mechanism, c57/bl6 wild type and c57/bl6 IL-6 female knockout (KO) mice were utilized with groups: saline injected, SAH, SAH + IL-6 blockade, SAH IL-6 KO, SAH IL-6 KO + IL-6 administration. For SAH, 50mm blood was collected from tail puncture and administered into basal cisterns. IL-6 blockade was given at various time points. Various markers of neuroin ammation were measured with western blot and immunohistochemistry.Cerebral blood ow was also measured. Vasospasm was measured via cardiac injection of indiaink/gelatin. Turning test and Garcia's modi ed SAH score were utilized. P<0.05 was considered signi cant.Results: IL-6 expression peaked 3 days following SAH (p<0.05). Human IL-6 was increased in aneurysmal blood (p<0.05). Receptor upregulation was periventricular and perivascular. A signi cant increase in BBB markers endothelin 1 and occludin were noted following SAH but reduced with IL-6 blockade (p<0.01). CV occurred 5 days post SAH but was absent in IL-6 KO mice and mitigated with IL-6 blockade (p<0.05). IL-6 blockade, and IL-6 KO mitigated effects of SAH on cerebral blood ow (p<0.05). SAH mice had impaired performance on turn test and poor Modi ed Garcia Scores compared to saline and IL-6 blockade. A distinct microglia phenotype was noted day 5 in the SAH group (overlap coe cients r=0.96 and r=0.94) for Arg1 and iNOS, which was altered by IL-6 blockade. Day 7, a signi cant increase in toll-like receptor 4 and Stat3 were noted. This was mitigated by IL-6 blockade and IL-6 KO, which also reduced Caspase 3 (p<0.05). Ventricular dilation and increased tunel positivity were noted day 9 but resolved by IL-6 blockade (p<0.05).Conclusion: correlation between IL-6 and CV has been well documented. We show that a mechanistic connection exists via the in ammatory response, and IL-6 blockade provides bene t in reducing CV and its consequences.

show abstract

Section: Discussionmentioning

confidence: 97%

Investigation and Modulation of Interleukin 6 following Subarachnoid Hemorrhage: Targeting Inflammatory Activation for Cerebral Vasospasm

Lucke‐Wold

2023

32nd Annual Meeting North American Skull Base Society

View full text Add to dashboard Cite

show abstract

“…To accomplish their functions, microglia consume substantial amounts of energy, a heightened demand that is met by an increase in the bioenergetic metabolism of mitochondria [ 22 ]. We previously reported that activated microglia and the UPRmt (reflecting mitochondrial stress) are involved in the pathogenic mechanism underlying hydrocephalus in a kaolin-induced hydrocephalus mouse model [ 16 ]. To further establish the relationship between activated microglia and the UPRmt, we analyzed the microglia-mediated inflammatory response, UPRmt and mitochondrial OXPHOS function in LPS-stimulated BV-2 cells.…”

Section: Discussionmentioning

confidence: 99%

“…LPS also activates the UPRmt in cardiomyocytes, which act to reduce inflammation-mediated myocardial injury [ 15 ]. We previously reported that microglia are activated and the UPRmt is upregulated in a mouse model of kaolin-induced hydrocephalus [ 16 ]. However, the potential link between microglia-induced neuroinflammation and the UPRmt has not been well studied.…”

Section: Introductionmentioning

confidence: 99%

ATF5 Attenuates the Secretion of Pro-Inflammatory Cytokines in Activated Microglia

Zhu

Lee

et al. 2023

IJMS

Self Cite

View full text Add to dashboard Cite

The highly dynamic changes in microglia necessary to achieve a rapid neuroinflammatory response require a supply of energy from mitochondrial respiration, which leads to the accumulation of unfolded mitochondrial proteins. We previously reported that microglial activation is correlated with the mitochondrial unfolded protein response (UPRmt) in a kaolin-induced hydrocephalus model, but we still do not know the extent to which these changes in microglia are involved in cytokine release. Here, we investigated the activation of BV-2 cells and found that treatment with lipopolysaccharide (LPS) for 48 h increased the secretion of pro-inflammatory cytokines. This increase was accompanied by a concurrent decrease in oxygen consumption rate (OCR) and mitochondrial membrane potential (MMP), in association with the up-regulation of the UPRmt. Inhibition of the UPRmt by knockdown of ATF5, a key upstream regulator of the UPRmt, using small-interfering RNA against ATF5 (siATF5) not only increased production of the pro-inflammatory cytokines, interleukin-6 (IL-6), IL-1β and tumor necrosis factor-α (TNF-α), but also decreased MMP. Our results suggest that ATF5-dependent induction of the UPRmt in microglia acts as a protective mechanism during neuroinflammation and may be a potential therapeutic target for reducing neuroinflammation.

show abstract

“…Mitochondrial stress has been employed as a strategy to mitigate excessive damage resulting from neuroinflammation. A study by Zhu et al demonstrated the activation of microglia and the UPR mt (reflecting mitochondrial stress) are involved in the pathogenic mechanism underlying hydrocephalus in a kaolin-induced hydrocephalus mouse model in C57BL/6J mice [ 96 ]. Subsequent research by the same group suggested a link between pro-inflammatory microglial polarization and UPR mt [ 97 ].…”

Section: Cross-talk Between Mitochondrial Stress and Neuroinflammatio...mentioning

confidence: 99%

Mitochondrial stress: a key role of neuroinflammation in stroke

Gao,

Peng,

Wang

et al. 2024

J Neuroinflammation

View full text Add to dashboard Cite

Stroke is a clinical syndrome characterized by an acute, focal neurological deficit, primarily caused by the occlusion or rupture of cerebral blood vessels. In stroke, neuroinflammation emerges as a pivotal event contributing to neuronal cell death. The occurrence and progression of neuroinflammation entail intricate processes, prominently featuring mitochondrial dysfunction and adaptive responses. Mitochondria, a double membrane-bound organelle are recognized as the “energy workshop” of the body. Brain is particularly vulnerable to mitochondrial disturbances due to its high energy demands from mitochondria-related energy production. The interplay between mitochondria and neuroinflammation plays a significant role in the pathogenesis of stroke. The biological and pathological consequences resulting from mitochondrial stress have substantial implications for cerebral function. Mitochondrial stress serves as an adaptive mechanism aimed at mitigating the stress induced by the import of misfolded proteins, which occurs in response to stroke. This adaptive response involves a reduction in misfolded protein accumulation and overall protein synthesis. The influence of mitochondrial stress on the pathological state of stroke is underscored by its capacity to interact with neuroinflammation. The impact of mitochondrial stress on neuroinflammation varies according to its severity. Moderate mitochondrial stress can bolster cellular adaptive defenses, enabling cells to better withstand detrimental stressors. In contrast, sustained and excessive mitochondrial stress detrimentally affects cellular and tissue integrity. The relationship between neuroinflammation and mitochondrial stress depends on the degree of mitochondrial stress present. Understanding its role in stroke pathogenesis is instrumental in excavating the novel treatment of stroke. This review aims to provide the evaluation of the cross-talk between mitochondrial stress and neuroinflammation within the context of stroke. We aim to reveal how mitochondrial stress affects neuroinflammation environment in stroke.

show abstract

Reactive microglia and mitochondrial unfolded protein response following ventriculomegaly and behavior defects in kaolin-induced hydrocephalus

Cited by 5 publications

References 52 publications

Investigation and Modulation of Interleukin 6 following Subarachnoid Hemorrhage: Targeting Inflammatory Activation for Cerebral Vasospasm

Investigation and Modulation of Interleukin 6 following Subarachnoid Hemorrhage: Targeting Inflammatory Activation for Cerebral Vasospasm

ATF5 Attenuates the Secretion of Pro-Inflammatory Cytokines in Activated Microglia

Mitochondrial stress: a key role of neuroinflammation in stroke

Contact Info

Product

Resources

About