EPO regulates neuroprotective Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) family members GRINA and FAIM2 after cerebral ischemia-reperfusion injury

Habib, Pardes; Stamm, Ann-Sophie; Zeyen, Thomas; Noristani, Rozina; Slowik, Alexander; Beyer, Cordian; Wilhelm, Thomas; Huber, Michael; Komnig, Daniel; Schulz, Jörg B.; Reich, Arno

doi:10.1016/j.expneurol.2019.112978

Cited by 17 publications

(35 citation statements)

References 53 publications

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“…We examined the extent of apoptosis after 30 min of tMCAo followed by 6 h or 72 h of reperfusion using TUNEL assay as previously described [33]. While sham-operated mice of both genotypes displayed nearly no apparent TUNEL positive/apoptotic cells, tMCAo significantly increased the number of apoptotic cells (sham vs. WT, 3.33 ± 4.30 vs. 34.7 ± 12.15 per mm 2 ) (Figure 3a).…”

Section: Resultsmentioning

confidence: 98%

“…In addition, gene expression of TMBIM3/GRINA is dysregulated in brains of patients with major depression [34] and in various cancers [35]. GRINA-deficiency is not lethal in fruit flies [29] and does not show a pathological phenotype in mice, consistent with the knockout of other TMBIM family members (FAIM2, TMBIM1 and TMBIM6) [30,33,36,37]. Mostly located at the ER membrane and inhibiting ER calcium release by inositol-1,4,5-trisphosphate receptors, GRINA might have a crucial role in diminishing ER stress.…”

Section: Introductionmentioning

confidence: 94%

“…Furthermore, GRINA does not only seem to be equally expressed in cortex, striatum, cerebellum and hindbrain, but also shows similar expression levels in neurons, astrocytes, microglia and oligodendrocytes on a cellular level. [30,31,32,33]. In addition, gene expression of TMBIM3/GRINA is dysregulated in brains of patients with major depression [34] and in various cancers [35].…”

Section: Introductionmentioning

confidence: 99%

“…We have recently demonstrated that GRINA-deficiency increased infarct volumes after murine cerebral ischemia and enhanced apoptosis rates in neurons after oxygen–glucose deprivation (OGD). In addition, GRINA conferred neuroprotection and was regulated by erythropoietin (EPO) after in vitro and in vivo ischemia [33].…”

Section: Introductionmentioning

confidence: 99%

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EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia

Habib

Stamm

Schulz

et al. 2019

IJMS

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Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis leading to impairment of endoplasmic reticulum (ER) function. The unfolded protein response (UPR) is an ER-located and cytoprotective pathway that aims to resolve ER stress. Transmembrane BAX inhibitor-1 motif-containing (TMBIM) protein family member TMBIM3/GRINA is highly expressed in the brain and mostly located at the ER membrane suppressing ER calcium release by inositol-1,4,5-trisphosphate receptors. GRINA confers neuroprotection and is regulated by erythropoietin (EPO) after murine cerebral ischemia. However, the role of GRINA and the impact of EPO treatment on the post-ischemic UPR have not been elucidated yet. We subjected GRINA-deficient (Grina−/−) and wildtype mice to transient (30 min) middle cerebral artery occlusion (tMCAo) followed by 6 h or 72 h of reperfusion. We administered EPO or saline 0, 24 and 48 h after tMCAo/sham surgery. Oxygen–glucose deprivation (OGD) and pharmacological stimulation of the UPR using Tunicamycin and Thapsigargin were carried out in primary murine cortical mixed cell cultures. Treatment with the PERK-inhibitor GSK-2606414, IRE1a-RNase-inhibitor STF-083010 and EPO was performed 1 h prior to either 1 h, 2 h or 3 h of OGD. We found earlier and larger infarct demarcations in Grina−/− mice compared to wildtype mice, which was accompanied by a worse neurological outcome and an abolishment of EPO-mediated neuroprotection after ischemic stroke. In addition, GRINA-deficiency increased apoptosis and the activation of the corresponding PERK arm of the UPR after stroke. EPO enhanced the post-ischemic activation of pro-survival IRE1a and counteracted the pro-apoptotic PERK branch of the UPR. Both EPO and the PERK-inhibitor GSK-2606414 reduced cell death and regulated Grina mRNA levels after OGD. In conclusion, GRINA plays a crucial role in post-ischemic UPR and the use of both GSK-2606414 and EPO might lead to neuroprotection.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia

Habib

Stamm

Schulz

et al. 2019

IJMS

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“…Its sensitivity toward Epo treatment in insects and its high conservation throughout metazoans suggests CRLF3 as a potential mammalian neuroprotective Epo-receptor. The neuroprotective function of Epo has been well-investigated in vertebrates and Epo is even used in clinical trials as a treatment after ischemic stroke (Ehrenreich et al, 2009; Subiras et al, 2012; Habib et al, 2019; Simon et al, 2019). However, Epo treatment leads to various adverse side effects (e.g., thromboembolism, cardiovascular events) that mainly arise from its erythropoietic function in vertebrates (Jelkmann et al, 2008; Noguchi et al, 2008; Ehrenreich et al, 2009; Souvenir et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

The Orphan Cytokine Receptor CRLF3 Emerged With the Origin of the Nervous System and Is a Neuroprotective Erythropoietin Receptor in Locusts

Hahn

Büschgens

Schwedhelm-Domeyer

et al. 2019

Front. Mol. Neurosci.

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The orphan cytokine receptor-like factor 3 (CRLF3) was identified as a neuroprotective erythropoietin receptor in locust neurons and emerged with the evolution of the eumetazoan nervous system. Human CRLF3 belongs to class I helical cytokine receptors that mediate pleiotropic cellular reactions to injury and diverse physiological challenges. It is expressed in various tissues including the central nervous system but its ligand remains unidentified. A CRLF3 ortholog in the holometabolous beetle Tribolium castaneum was recently shown to induce anti-apoptotic mechanisms upon stimulation with human recombinant erythropoietin. To test the hypothesis that CRLF3 represents an ancient cell-protective receptor for erythropoietin-like cytokines, we investigated its presence across metazoan species. Furthermore, we examined CRLF3 expression and function in the hemimetabolous insect Locusta migratoria. Phylogenetic analysis of CRLF3 sequences indicated that CRLF3 is absent in Porifera, Placozoa and Ctenophora, all lacking the traditional nervous system. However, it is present in all major eumetazoan groups ranging from cnidarians over protostomians to mammals. The CRLF3 sequence is highly conserved and abundant amongst vertebrates. In contrast, relatively few invertebrates express CRLF3 and these sequences show greater variability, suggesting frequent loss due to low functional importance. In L. migratoria, we identified the transcript Lm-crlf3 by RACE-PCR and detected its expression in locust brain, skeletal muscle and hemocytes. These findings correspond to the ubiquitous expression of crlf3 in mammalian tissues. We demonstrate that the sole addition of double-stranded RNA to the culture medium (called soaking RNA interference) specifically interferes with protein expression in locust primary brain cell cultures. This technique was used to knock down Lm-crlf3 expression and to abolish its physiological function. We confirmed that recombinant human erythropoietin rescues locust brain neurons from hypoxia-induced apoptosis and showed that this neuroprotective effect is absent after knocking down Lm-crlf3. Our results affirm the erythropoietin-induced neuroprotective function of CRLF3 in a second insect species from a different taxonomic group. They suggest that the phylogenetically conserved CRLF3 receptor may function as a cell protective receptor for erythropoietin or a structurally related cytokine also in other animals including vertebrate and mammalian species.

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Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

Tuo

Zhang

Lei

2021

Medicinal Research Reviews

326

185

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Ischemic stroke caused by arterial occlusion is the most common type of stroke, which is among the most frequent causes of disability and death worldwide. Current treatment approaches involve achieving rapid reperfusion either pharmacologically or surgically, both of which are time-sensitive; moreover, blood flow recanalization often causes ischemia/reperfusion injury. However, even though neuroprotective intervention is urgently needed in the event of stroke, the exact mechanisms of neuronal death during ischemic stroke are still unclear, and consequently, the capacity for drug development has remained limited. Multiple cell death pathways are implicated in the pathogenesis of ischemic stroke. Here, we have reviewed these potential neuronal death pathways, including intrinsic and extrinsic apoptosis, necroptosis, autophagy, ferroptosis, parthanatos, phagoptosis, and pyroptosis. We have also reviewed the latest results of pharmacological studies on ischemic stroke and summarized emerging drug targets with a focus on clinical trials. These observations may help to further understand the pathological events in ischemic stroke and bridge the gap between basic and translational research to reveal novel neuroprotective interventions.

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EPO regulates neuroprotective Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) family members GRINA and FAIM2 after cerebral ischemia-reperfusion injury

Cited by 17 publications

References 53 publications

EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia

EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia

The Orphan Cytokine Receptor CRLF3 Emerged With the Origin of the Nervous System and Is a Neuroprotective Erythropoietin Receptor in Locusts

Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

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