Hypoxia-Inducible Factor-1α Target Genes Contribute to Retinal Neuroprotection

Cheng, Lin; Yu, Honghua; Yan, Naihong; Lai, Kunbei; Xiang, Mengqing

doi:10.3389/fncel.2017.00020

Cited by 68 publications

(59 citation statements)

References 158 publications

(166 reference statements)

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“…Research has increasingly shown that HIF-1α plays a critical role in regulating gene expression during the pathogenesis of retinal hypoxia/ischemia injury [45][46][47][48], which has been further confirmed in our study. Intravitreally knockdown of HIF-1α significantly alleviated retinal damage and RGCs loss (Fig.…”

Section: Inhibition Of Casp8-mediated Hif-1α Signaling Protects the Rsupporting

confidence: 86%

NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma

Chen

Deng

Gan

et al. 2020

Mol Neurodegeneration

109

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Background: Acute glaucoma, characterized by a sudden elevation in intraocular pressure (IOP) and retinal ganglion cells (RGCs) death, is a major cause of irreversible blindness worldwide that lacks approved effective therapies, validated treatment targets and clear molecular mechanisms. We sought to explore the potential molecular mechanisms underlying the causal link between high IOP and glaucomatous RGCs death.Methods: A murine retinal ischemia/ reperfusion (RIR) model and an in vitro oxygen and glucose deprivation/ reoxygenation (OGDR) model were used to investigate the pathogenic mechanisms of acute glaucoma.Results: Our findings reveal a novel mechanism of microglia-induced pyroptosis-mediated RGCs death associated with glaucomatous vision loss. Genetic deletion of gasdermin D (GSDMD), the effector of pyroptosis, markedly ameliorated the RGCs death and retinal tissue damage in acute glaucoma. Moreover, GSDMD cleavage of microglial cells was dependent on caspase-8 (CASP8)-hypoxia-inducible factor-1α (HIF-1α) signaling. Mechanistically, the newly identified nucleotide-binding leucine-rich repeat-containing receptor (NLR) family pyrin domain-containing 12 (NLRP12) collaborated with NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing protein 4 (NLRC4) downstream of the CASP8-HIF-1α axis, to elicit pyroptotic processes and interleukin-1β (IL-1β) maturation through caspase-1 activation, facilitating pyroptosis and neuroinflammation in acute glaucoma. Interestingly, processing of IL-1β in turn magnified the CASP8-HIF-1α-NLRP12/ NLRP3/NLRC4-pyroptosis circuit to accelerate inflammatory cascades.Conclusions: These data not only indicate that the collaborative effects of NLRP12, NLRP3 and NLRC4 on pyroptosis are responsible for RGCs death, but also shed novel mechanistic insights into microglial pyroptosis, paving novel therapeutic avenues for the treatment of glaucoma-induced irreversible vision loss through simultaneously targeting of pyroptosis.

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Section: Inhibition Of Casp8-mediated Hif-1α Signaling Protects the Rsupporting

confidence: 86%

NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma

Chen

Deng

Gan

et al. 2020

Mol Neurodegeneration

109

View full text Add to dashboard Cite

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“…Further corroborating these findings, purified primary OPCs respond to HIFα signaling stabilizer (DMOG) and blocker (Chetomin) by activating and inactivating VEGFA, respectively. Our results are consistent with previous data showing that VEGFA is a direct transcriptional target of HIFα 40–42 . By leveraging our unique in vivo genetic models of VHL/VEGFA double cKO, we unequivocally prove that VEGFA is an essential downstream molecule that couples oligodendroglial HIFα function and vascular angiogenesis in the CNS, which is different from Yuen et al, 9 who reported that VEGFA was unchanged in the CNS of oligodendroglial HIFα-stabilized mutants.…”

Section: Discussionsupporting

confidence: 94%

Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways

Zhang

Zhu

Gui

et al. 2020

Preprint

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AbstractThe mechanisms by which oligodendroglia modulate CNS angiogenesis remain elusive. Previous in vitro data suggest that oligodendroglia regulate CNS endothelial cell proliferation and blood vessel formation through hypoxia inducible factor alpha (HIFα)-activated Wnt (but not VEGF) signaling. Using in vivo genetic models, we show that HIFα in oligodendroglia is necessary and sufficient for angiogenesis independent of CNS regions. At the molecular level, HIFα stabilization in oligodendroglia does not perturb Wnt signaling but remarkably activates VEGF. At the functional level, genetically blocking oligodendroglia-derived VEGF but not Wnt significantly decreases oligodendroglial HIFα-regulated CNS angiogenesis. Interestingly, blocking astroglia-derived Wnt signaling reduces astroglial HIFα-regulated CNS angiogenesis. Together, our in vivo data clearly demonstrate that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling. Our findings represent an alternative mechanistic understanding of CNS angiogenesis by postnatal glial cells and unveil a glial cell type-dependent HIFα-Wnt axis in regulating CNS vessel formation.

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“…While multiple genes, proteins, and transcription factors have been identified that are associated with axon death [e.g. BAX (BCL2-associated X protein), TRX (thioredoxin), HIF-1a (hypoxia-inducible factor-1a), SNCG (g-synuclein), ATF4 (activating transcription factor 4), DDIT3 (DNA damage inducible transcript 3), and BCAT1 (branched chain amino acid transaminase 1) (Libby et al, 2005a;Soto et al, 2008;Munemasa and Kitaoka, 2013;Yasuda et al, 2014;Cheng et al, 2017), the causative genes and variants remain unknown for the majority of glaucoma cases. Identification of additional sequence variants, and associated molecular and cellular processes that modulate glaucoma endophenotypes in animals and humans can definitely provide critical insights, as well as new targets for therapeutic intervention (Chintalapudi et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Systems Genetics of Optic Nerve Axon Necrosis During Glaucoma

et al. 2020

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In this study, we identify genomic regions that modulate the number of necrotic axons in optic nerves of a family of mice, some of which have severe glaucoma, and define a set of high priority positional candidate genes that modulate retinal ganglion cell (RGC) axonal degeneration. A large cohort of the BXD family were aged to greater than 13 months of age. Optic nerves from 74 strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of necrotic axons per optic nerve crosssection were counted from 1 to 10 replicates per genotype. Strain means and standard errors were uploaded into GeneNetwork 2 for mapping and systems genetics analyses (Trait 18614). The number of necrotic axons per nerve ranged from only a few hundred to more than 4,000. Using conventional interval mapping as well as linear mixed model mapping, we identified a single locus on chromosome 12 between 109 and 112.5 Mb with a likelihood ratio statistic (LRS) of~18.5 (p genome-wide~0.1). Axon necrosis is not linked to locations of major known glaucoma genes in this family, including Gpnmb, Tyrp1, Cdh11, Pou6f2, and Cacna2d1. This indicates that although these genes contribute to pigmentary dispersion or elevated IOP, none directly modulates axon necrosis. Of 156 positional candidates, eight genes-CDC42 binding protein kinase beta (Cdc42bpb); eukaryotic translation initiation factor 5 (Eif5); BCL2-associated athanogene 5 (Bag5); apoptogenic 1, mitochondrial (Apopt1); kinesin light chain 1 (Klc1); X-ray repair cross complementing 3 (Xrcc3); protein phosphatase 1, regulatory subunit 13B (Ppp1r13b); and transmembrane protein 179 (Tmem179)-passed stringent criteria and are high priority candidates. Several candidates are linked to mitochondria and/or axons, strengthening their plausible role as modulators of ON necrosis. Additional studies are required to validate and/or eliminate plausible candidates. Surprisingly, IOP and ON necrosis are inversely correlated across the BXD family in mice >13 months of age and these two traits share few genes among their top ocular and retinal correlates. These data suggest that the two traits are independently modulated or that a more complex and multifaceted approach is required to reveal their association.

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Hypoxia-Inducible Factor-1α Target Genes Contribute to Retinal Neuroprotection

Cited by 68 publications

References 158 publications

NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma

NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma

Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways

Systems Genetics of Optic Nerve Axon Necrosis During Glaucoma

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