Protective effects of XBP1 against oxygen and glucose deprivation/reoxygenation injury in rat primary hippocampal neurons

Ibuki, Tatsuki; Yamasaki, Yoshio; Mizuguchi, Hiroshi; Sokabe, Masahiro

doi:10.1016/j.neulet.2012.04.053

Cited by 31 publications

(19 citation statements)

References 34 publications

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“…Overexpression of ATF6 in myocardium increased Grp78 induction against ex vivo IR and reduced cell death, while ATF6 KD did the opposite. Similar cytoprotective effects were observed with ER-stressinduced XBP1 in vitro (32)(33)(34). Despite its adaptive nature, prolonged UPR that resulted from unresolved/lethal ER stress could lead to cell death.…”

Section: Discussionsupporting

confidence: 68%

ATF6 Mediates a Pro-Inflammatory Synergy Between ER Stress and TLR Activation in the Pathogenesis of Liver Ischemia-Reperfusion Injury

Rao

Shi

et al. 2014

American Journal of Transplantation

139

114

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Although roles of the metabolic stress in organ ischemia reperfusion injury (IRI) have been well recognized, the question of whether and how these stress responses regulate innate immune activation against IR remains unclear. In a murine liver partial warm ischemia mode, we showed that prolonged ischemia triggered endoplasmic reticulum (ER) stress response, particularly, the ATF6 branch, in liver Kupffer cells and altered their responsiveness against TLR stimulation. Ischemia-primed cells increased pro-, but decreased anti-, inflammatory cytokine productions. Alleviation of ER stress in vivo by small chemical chaperon 4-phenylbutyrate or ATF6 siRNA diminished the pro-inflammatory priming effect of ischemia in KCs, leading to the inhibition of liver immune response against IR and protection of livers from IRI. In vitro, ATF6 siRNA abrogated the ER stress-mediated pro-inflammatory enhancement of macrophage TLR4 response, by restricting NF-kB and restoring Akt activations. Thus, ischemia primes liver innate immune cells by ATF6-mediated ER stress response. The IR-induced metabolic stress and TLR activation function in synergy to activate tissue inflammatory immune response.

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Section: Discussionsupporting

confidence: 68%

ATF6 Mediates a Pro-Inflammatory Synergy Between ER Stress and TLR Activation in the Pathogenesis of Liver Ischemia-Reperfusion Injury

Rao

Shi

et al. 2014

American Journal of Transplantation

139

114

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“…Early stage retinal vasculogenesis and angiogenesis in ischemic muscles were affected in EC-specific XBP1 knockout mice . These findings are consistent with previous reports showing that XBP1 activation can ameliorate cerebral ischemia/reperfusion injury (Urban et al, 2009;Nakka et al, 2010;Ibuki et al, 2012). In addition, transient XBP1activation resulted in an EC cell size increase, but not in an Akt/GSK/b-catenin/E2F2-dependent manner .…”

Section: Ischemiasupporting

confidence: 93%

Involvement of the IRE1α-XBP1 Pathway and XBP1s-Dependent Transcriptional Reprogramming in Metabolic Diseases

Zhang²,

Lu³

et al. 2015

DNA and Cell Biology

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The X-box binding protein 1 (XBP1) is not only an important component of the unfolded protein response (UPR), but also an important nuclear transcription factor. Upon endoplasmic reticulum stress, XBP1 is spliced by inositol-requiring enzyme 1 (IRE1), thereby generating functional spliced XBP1 (XBP1s). XBP1s functions by translocating into the nucleus to initiate transcriptional programs that regulate a subset of UPR-and non-UPR-associated genes involved in the pathophysiological processes of various diseases. Recent reports have implicated XBP1 in metabolic diseases. This review summarizes the effects of XBP1-mediated regulation on lipid metabolism, glucose metabolism, obesity, and atherosclerosis. Additionally, for the first time, we present XBP1s-dependent transcriptional reprogramming in metabolic diseases under different conditions, including pathology and physiology. Understanding the function of XBP1 in metabolic diseases may provide a basic knowledge for the development of novel therapeutic targets for ameliorating these diseases.

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“…10 Manipulations of these ER stress sensors altered cell vulnerability to injury. 11,12 A recent study has shown that pretreatment with ER stressors limits ischemia-induced cardiocyte injury. 13 Therefore, it is very likely that ER stress may protect against ischemia-induced brain damage, although the underlying mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury

Zhang¹,

et al. 2014

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Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2(+/-) mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation.

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Protective effects of XBP1 against oxygen and glucose deprivation/reoxygenation injury in rat primary hippocampal neurons

Cited by 31 publications

References 34 publications

ATF6 Mediates a Pro-Inflammatory Synergy Between ER Stress and TLR Activation in the Pathogenesis of Liver Ischemia-Reperfusion Injury

ATF6 Mediates a Pro-Inflammatory Synergy Between ER Stress and TLR Activation in the Pathogenesis of Liver Ischemia-Reperfusion Injury

Involvement of the IRE1α-XBP1 Pathway and XBP1s-Dependent Transcriptional Reprogramming in Metabolic Diseases

Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury

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