Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2020

01-12-2020 | Glaucoma | Research article

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

Authors: Hui Chen, Yang Deng, Xiaoliang Gan, Yonghao Li, Wenyong Huang, Lin Lu, Lai Wei, Lishi Su, Jiawen Luo, Bin Zou, Yanhua Hong, Yihai Cao, Yizhi Liu, Wei Chi

Published in: Molecular Neurodegeneration | Issue 1/2020

Login to get access

Abstract

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.
Appendix
Available only for authorised users
Literature
1.
Tanner L, Gazzard G, Nolan WP, Foster PJ. Has the EAGLE landed for the use of clear lens extraction in angle-closure glaucoma? And how should primary angle-closure suspects be treated? Eye (London, England). 2020;34(1):40–50.CrossRef
2.
Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121(11):2081–90.PubMedCrossRef
3.
Zhu X, Zeng W, Wu S, Chen X, Zheng T, Ke M. Measurement of retinal changes in primary acute angle closure Glaucoma under different durations of symptoms. J Ophthalmol. 2019;2019:5409837.PubMedPubMedCentral
4.
Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A. The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res. 2012;31(2):152–81.PubMedCrossRef
5.
6.
7.
Chi W, Li F, Chen H, Wang Y, Zhu Y, Yang X, et al. Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1beta production in acute glaucoma. Proc Natl Acad Sci U S A. 2014;111(30):11181–6.PubMedPubMedCentralCrossRef
8.
Cueva Vargas JL, Belforte N, Di Polo A. The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase a signaling. Neurobiol Dis. 2016;93:156–71.PubMedCrossRef
9.
Silverman SM, Kim BJ, Howell GR, Miller J, John SW, Wordinger RJ, et al. C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury. Mol Neurodegener. 2016;11:24.PubMedPubMedCentralCrossRef
10.
Gong Y, Cao X, Gong L, Li W. Sulforaphane alleviates retinal ganglion cell death and inflammation by suppressing NLRP3 inflammasome activation in a rat model of retinal ischemia/reperfusion injury. Int J Immunopathol Pharmacol. 2019;33:2058738419861777.PubMedPubMedCentralCrossRef
11.
Coucha M, Shanab AY, Sayed M, Vazdarjanova A, El-Remessy AB. Modulating Expression of Thioredoxin Interacting Protein (TXNIP) Prevents Secondary Damage and Preserves Visual Function in a Mouse Model of Ischemia/Reperfusion. Int J Mol Sci. 2019;20(16).
12.
Qi Y, Zhao M, Bai Y, Huang L, Yu W, Bian Z, et al. Retinal ischemia/reperfusion injury is mediated by toll-like receptor 4 activation of NLRP3 inflammasomes. Invest Ophthalmol Vis Sci. 2014;55(9):5466–75.PubMedCrossRef
13.
Dvoriantchikova G, Barakat DJ, Hernandez E, Shestopalov VI, Ivanov D. Toll-like receptor 4 contributes to retinal ischemia/reperfusion injury. Mol Vis. 2010;16:1907–12.PubMedPubMedCentral
14.
de Gassart A, Martinon F. Pyroptosis: Caspase-11 unlocks the gates of death. Immunity. 2015;43(5):835–7.PubMedCrossRef
15.
Aglietti RA, Dueber EC. Recent insights into the molecular mechanisms underlying Pyroptosis and Gasdermin family functions. Trends Immunol. 2017;38(4):261–71.PubMedCrossRef
16.
17.
18.
Maltez VI, Tubbs AL, Cook KD, Aachoui Y, Falcone EL, Holland SM, et al. Inflammasomes coordinate Pyroptosis and natural killer cell cytotoxicity to clear infection by a ubiquitous environmental bacterium. Immunity. 2015;43(5):987–97.PubMedPubMedCentralCrossRef
19.
Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535(7610):153–8.PubMedPubMedCentralCrossRef
20.
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526(7575):660–5.PubMedCrossRef
21.
Liu Y, Zhang T, Zhou Y, Li J, Liang X, Zhou N, et al. Visualization of perforin/gasdermin/complement-formed pores in real cell membranes using atomic force microscopy. Cell Mol Immunol. 2019;16(6):611–20.PubMedCrossRef
22.
Broderick L, De Nardo D, Franklin BS, Hoffman HM, Latz E. The inflammasomes and autoinflammatory syndromes. Annu Rev Pathol. 2015;10:395–424.PubMedCrossRef
23.
Sagoo P, Garcia Z, Breart B, Lemaitre F, Michonneau D, Albert ML, et al. In vivo imaging of inflammasome activation reveals a subcapsular macrophage burst response that mobilizes innate and adaptive immunity. Nat Med. 2016;22(1):64–71.PubMedCrossRef
24.
Place DE, Kanneganti TD. Recent advances in inflammasome biology. Curr Opin Immunol. 2018;50:32–8.PubMedCrossRef
25.
26.
Lukens JR, Gurung P, Shaw PJ, Barr MJ, Zaki MH, Brown SA, et al. The NLRP12 sensor negatively regulates autoinflammatory disease by modulating Interleukin-4 production in T cells. Immunity. 2015;42(4):654–64.PubMedPubMedCentralCrossRef
27.
Chen L, Wilson JE, Koenigsknecht MJ, Chou WC, Montgomery SA, Truax AD, et al. NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nat Immunol. 2017;18(5):541–51.PubMedPubMedCentralCrossRef
28.
Platnich JM, Chung H, Lau A, Sandall CF, Bondzi-Simpson A, Chen HM, et al. Shiga Toxin/Lipopolysaccharide Activates Caspase-4 and Gasdermin D to Trigger Mitochondrial Reactive Oxygen Species Upstream of the NLRP3 Inflammasome. Cell Rep. 2018;25(6):1525–36 e7.PubMedCrossRef
29.
Kang R, Zeng L, Zhu S, Xie Y, Liu J, Wen Q, et al. Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis. Cell Host Microbe. 2018;24(1):97–108 e4.PubMedPubMedCentralCrossRef
30.
Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 2008;8(9):705–13.PubMedCrossRef
31.
32.
Montagner M, Enzo E, Forcato M, Zanconato F, Parenti A, Rampazzo E, et al. SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature. 2012;487(7407):380–4.PubMedCrossRef
33.
Cai Z, Luo W, Zhan H, Semenza GL. Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart. Proc Natl Acad Sci U S A. 2013;110(43):17462–7.PubMedPubMedCentralCrossRef
34.
35.
Wen H, Ting JP. Agitation by suffocation: how hypoxia activates innate immunity via the Warburg effect. Cell Metab. 2013;17(6):814–5.PubMedCrossRef
36.
Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496(7444):238–42.PubMedPubMedCentral
37.
Stockslager MA, Samuels BC, Allingham RR, Klesmith ZA, Schwaner SA, Forest CR, et al. System for rapid, precise modulation of intraocular pressure, toward minimally-invasive in vivo measurement of intracranial pressure. PLoS One. 2016;11(1):e0147020.PubMedPubMedCentralCrossRef
38.
Shi J, Gao W, Shao F. Pyroptosis: Gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci. 2017;42(4):245–54.PubMedCrossRef
39.
40.
Wree A, Eguchi A, McGeough MD, Pena CA, Johnson CD, Canbay A, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology. 2014;59(3):898–910.PubMedCrossRef
41.
Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, et al. Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron. 2014;81(5):1009–23.PubMedPubMedCentralCrossRef
42.
Baruch K, Kertser A, Porat Z, Schwartz M. Cerebral nitric oxide represses choroid plexus NFkappaB-dependent gateway activity for leukocyte trafficking. EMBO J. 2015;34(13):1816–28.PubMedPubMedCentralCrossRef
43.
Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature. 2011;471(7338):368–72.PubMedPubMedCentralCrossRef
44.
Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity. 1998;9(2):267–76.PubMedCrossRef
45.
Zhu Y, Zhang L, Gidday JM. Role of hypoxia-inducible factor-1alpha in preconditioning-induced protection of retinal ganglion cells in glaucoma. Mol Vis. 2013;19:2360–72.PubMedPubMedCentral
46.
Zhou J, Chen F, Yan A, Xia X. Role of mammalian target of rapamycin in regulating HIF-1alpha and vascular endothelial growth factor signals in glaucoma. Arch Physiol Biochem. 2019:1–7.
47.
Ji YS, Park JW, Heo H, Park JS, Park SW. The neuroprotective effect of carnosine (beta-alanyl-L-histidine) on retinal ganglion cell following ischemia-reperfusion injury. Curr Eye Res. 2014;39(6):634–41.PubMedCrossRef
48.
Cheng L, Yu H, Yan N, Lai K, Xiang M. Hypoxia-inducible factor-1alpha target genes contribute to retinal Neuroprotection. Front Cell Neurosci. 2017;11:20.PubMedPubMedCentral
49.
Seong H, Ryu J, Yoo WS, Kim SJ, Han YS, Park JM, et al. Resveratrol ameliorates retinal ischemia/reperfusion injury in C57BL/6J mice via Downregulation of Caspase-3. Curr Eye Res. 2017:1–9.
50.
Sarhan J, Liu BC, Muendlein HI, Li P, Nilson R, Tang AY, et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc Natl Acad Sci U S A. 2018;115(46):E10888–E97.PubMedPubMedCentralCrossRef
51.
Orning P, Weng D, Starheim K, Ratner D, Best Z, Lee B, et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science. 2018;362(6418):1064–9.PubMedPubMedCentralCrossRef
52.
Della Santina L, Inman DM, Lupien CB, Horner PJ, Wong RO. Differential progression of structural and functional alterations in distinct retinal ganglion cell types in a mouse model of glaucoma. J Neurosci. 2013;33(44):17444–57.PubMedPubMedCentralCrossRef
53.
See JLS, Aquino MCD, Aduan J, Chew PTK. Management of angle closure glaucoma. Indian J Ophthalmol. 2011;59 Suppl (Suppl1):S82-SS7.
54.
Wang K, Peng B, Lin B. Fractalkine receptor regulates microglial neurotoxicity in an experimental mouse glaucoma model. Glia. 2014;62(12):1943–54.PubMedCrossRef
55.
Liu X, Huang P, Wang J, Yang Z, Huang S, Luo X, et al. The effect of A2A receptor antagonist on microglial activation in experimental Glaucoma. Invest Ophthalmol Vis Sci. 2016;57(3):776–86.PubMedCrossRef
56.
Dubois H, Sorgeloos F, Sarvestani ST, Martens L, Saeys Y, Mackenzie JM, et al. Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection. PLoS Pathog. 2019;15(4):e1007709.PubMedPubMedCentralCrossRef
57.
Udden SN, Kwak YT, Godfrey V, Khan MAW, Khan S, Loof N, et al. NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte. eLife. 2019;8.
58.
Zaki MH, Vogel P, Malireddi RK, Body-Malapel M, Anand PK, Bertin J, et al. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell. 2011;20(5):649–60.PubMedPubMedCentralCrossRef
59.
Tuncer S, Fiorillo MT, Sorrentino R. The multifaceted nature of NLRP12. J Leukoc Biol. 2014;96(6):991–1000.PubMedCrossRef
60.
Shi F, Yang Y, Kouadir M, Xu W, Hu S, Wang T. Inflammasome-independent role of NLRP12 in suppressing colonic inflammation regulated by Blimp-1. Oncotarget. 2016;7(21):30575–84.PubMedPubMedCentral
61.
Allen IC, Wilson JE, Schneider M, Lich JD, Roberts RA, Arthur JC, et al. NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signaling. Immunity. 2012;36(5):742–54.PubMedPubMedCentralCrossRef
62.
Truax AD, Chen L, Tam JW, Cheng N, Guo H, Koblansky AA, et al. The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis. Cell Host Microbe. 2018;24(3):364–78 e6.PubMedPubMedCentralCrossRef
63.
Wang L, Manji GA, Grenier JM, Al-Garawi A, Merriam S, Lora JM, et al. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. J Biol Chem. 2002;277(33):29874–80.PubMedCrossRef
64.
Mascarenhas DPA, Cerqueira DM, Pereira MSF, Castanheira FVS, Fernandes TD, Manin GZ, et al. Inhibition of caspase-1 or gasdermin-D enable caspase-8 activation in the Naip5/NLRC4/ASC inflammasome. PLoS Pathog. 2017;13(8):e1006502.PubMedPubMedCentralCrossRef
65.
Schneider KS, Gross CJ, Dreier RF, Saller BS, Mishra R, Gorka O, et al. The Inflammasome drives GSDMD-independent secondary Pyroptosis and IL-1 release in the absence of Caspase-1 protease activity. Cell Rep. 2017;21(13):3846–59.PubMedPubMedCentralCrossRef
66.
Xie Y, Jiang D, Xiao J, Fu C, Zhang Z, Ye Z, et al. Ischemic preconditioning attenuates ischemia/reperfusion-induced kidney injury by activating autophagy via the SGK1 signaling pathway. Cell Death Dis. 2018;9(3):338.PubMedPubMedCentralCrossRef
67.
Guo Y, Feng L, Zhou Y, Sheng J, Long D, Li S, et al. Systematic review with meta-analysis: HIF-1alpha attenuates liver ischemia-reperfusion injury. Transplant Rev (Orlando). 2015;29(3):127–34.CrossRef
68.
Davis CK, Jain SA, Bae ON, Majid A, Rajanikant GK. Hypoxia mimetic agents for ischemic stroke. Front Cell Dev Biol. 2018;6:175.PubMedCrossRef
69.
70.
Martinez-Garcia JJ, Martinez-Banaclocha H, Angosto-Bazarra D, de Torre-Minguela C, Baroja-Mazo A, Alarcon-Vila C, et al. P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis. Nat Commun. 2019;10(1):2711.PubMedPubMedCentralCrossRef
71.
Gupta N, Sahu A, Prabhakar A, Chatterjee T, Tyagi T, Kumari B, et al. Activation of NLRP3 inflammasome complex potentiates venous thrombosis in response to hypoxia. Proc Natl Acad Sci U S A. 2017;114(18):4763–8.PubMedPubMedCentralCrossRef
72.
Talreja J, Talwar H, Bauerfeld C, Grossman LI, Zhang K, Tranchida P, et al. HIF-1alpha regulates IL-1beta and IL-17 in sarcoidosis. eLife. 2019;8.
73.
Antonopoulos C, Russo HM, El Sanadi C, Martin BN, Li X, Kaiser WJ, et al. Caspase-8 as an effector and regulator of NLRP3 Inflammasome signaling. J Biol Chem. 2015;290(33):20167–84.PubMedPubMedCentralCrossRef
74.
Yamasaki Y, Matsuura N, Shozuhara H, Onodera H, Itoyama Y, Kogure K. Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats. Stroke. 1995;26(4):676–80 discussion 81.PubMedCrossRef
75.
Evavold CL, Ruan J, Tan Y, Xia S, Wu H, Kagan JC. The pore-forming protein Gasdermin D regulates Interleukin-1 secretion from living macrophages. Immunity. 2017.
76.
He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res. 2015;25(12):1285–98.PubMedPubMedCentralCrossRef
Metadata
Title
NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma
Authors
Hui Chen
Yang Deng
Xiaoliang Gan
Yonghao Li
Wenyong Huang
Lin Lu
Lai Wei
Lishi Su
Jiawen Luo
Bin Zou
Yanhua Hong
Yihai Cao
Yizhi Liu
Wei Chi
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Glaucoma
Published in
Molecular Neurodegeneration / Issue 1/2020
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-020-00372-w

Other articles of this Issue 1/2020

Molecular Neurodegeneration 1/2020 Go to the issue

Review

PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease

Research article

Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration

Methodology

Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer’s disease

Correction

Correction to: Divergence, Convergence, and Therapeutic Implications: A Cell Biology Perspective of C9ORF72-ALS/FTD

Review

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Research article

Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice