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Aberrant Enhanced NLRP3 Inflammasomes and Cell Pyroptosis in the Brains of Prion-Infected Rodent Models Are Largely Associated with the Proliferative Astrocytes

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Abstract

Neuroinflammation is a common pathological feature in a number of neurodegenerative diseases, which is mediated primarily by the activated glial cells. Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome-associated neuroinflammatory response is mostly considered. To investigate the situation of the NLRP3-related inflammation in prion disease, we assessed the levels of the main components of NLRP3 inflammasome and its downstream biomarkers in the scrapie-infected rodent brain tissues. The results showed that the transcriptional and expressional levels of NLRP3, caspase-1, and apoptosis-associated speck-like protein (ASC) in the brains of scrapie-infected rodents were significantly increased at terminal stage. The increased NLPR3 overlapped morphologically well with the proliferated GFAP-positive astrocytes, but little with microglia and neurons. Using the brain samples collected at the different time-points after infection, we found the NLRP3 signals increased in a time-dependent manner, which were coincidental with the increase of GFAP. Two main downstream cytokines, IL-1β and IL-18, were also upregulated in the brains of prion-infected mice. Moreover, the gasdermin D (GSDMD) levels, particularly the levels of GSDMD-NT, in the prion-infected brain tissues were remarkably increased, indicating activation of cell pyroptosis. The GSDMD not only co-localized well with the astrocytes but also with neurons at terminal stage, also showing a time-dependent increase after infection. Those data indicate that NLRP3 inflammasomes were remarkably activated in the infected brains, which is largely mediated by the proliferated astrocytes. Both astrocytes and neurons probably undergo a pyroptosis process, which may help the astrocytes to release inflammatory factors and contribute to neuron death during prion infection.

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References

  1. Ma Y, Shi Q, Xiao K, Wang J, Chen C, Gao LP, Gao C, Dong XP (2019) Stimulations of the culture medium of activated microglia and TNF-alpha on a scrapie-infected cell line decrease the cell viability and induce marked necroptosis that also occurs in the brains from the patients of human prion diseases. ACS Chem Neurosci 10(3):1273–1283. https://doi.org/10.1021/acschemneuro.8b00354

    Article  CAS  PubMed  Google Scholar 

  2. Zhou DH, Wang J, Xiao K, Wu YZ, Maimaitiming A, Hu C, Gao LP, Chen J, Gao C, Chen C, Shi Q, Dong XP (2020) Stilbene compounds inhibit the replications of various strains of prions in the levels of cell culture, PMCA, and RT-QuIC possibly via molecular binding. ACS Chem Neurosci 11(14):2117–2128. https://doi.org/10.1021/acschemneuro.0c00218

    Article  CAS  PubMed  Google Scholar 

  3. Mead S, Khalili-Shirazi A, Potter C, Mok T, Nihat A, Hyare H, Canning S, Schmidt C, Campbell T, Darwent L, Muirhead N, Ebsworth N, Hextall P, Wakeling M, Linehan J, Libri V, Williams B, Jaunmuktane Z, Brandner S, Rudge P, Collinge J (2022) Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt-Jakob disease: evaluation of a first-in-human treatment programme. Lancet Neurol 21(4):342–354. https://doi.org/10.1016/s1474-4422(22)00082-5

    Article  CAS  PubMed  Google Scholar 

  4. Ma Y, Shi Q, Wang J, Xiao K, Sun J, Lv Y, Guo M, Zhou W, Chen C, Gao C, Zhang BY, Dong XP (2017) Reduction of NF-κB (p65) in scrapie-infected cultured cells and in the brains of scrapie-infected rodents. ACS Chem Neurosci 8(11):2535–2548. https://doi.org/10.1021/acschemneuro.7b00273

    Article  CAS  PubMed  Google Scholar 

  5. Heneka MT, McManus RM, Latz E (2018) Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci 19(10):610–621. https://doi.org/10.1038/s41583-018-0055-7

    Article  CAS  PubMed  Google Scholar 

  6. Moonen S, Koper MJ, Van Schoor E, Schaeverbeke JM, Vandenberghe R, von Arnim CAF, Tousseyn T, De Strooper B, Thal DR (2023) Pyroptosis in Alzheimer’’s disease: cell type-specific activation in microglia, astrocytes and neurons. Acta Neuropathol 145(2):175–195. https://doi.org/10.1007/s00401-022-02528-y

    Article  CAS  PubMed  Google Scholar 

  7. Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D, Griep A, Santarelli F, Brosseron F, Opitz S, Stunden J, Merten M, Kayed R, Golenbock DT, Blum D, Latz E, Buée L, Heneka MT (2019) NLRP3 inflammasome activation drives tau pathology. Nature 575(7784):669–673. https://doi.org/10.1038/s41586-019-1769-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang Y, Huang R, Cheng M, Wang L, Chao J, Li J, Zheng P, Xie P, Zhang Z, Yao H (2019) Gut microbiota from NLRP3-deficient mice ameliorates depressive-like behaviors by regulating astrocyte dysfunction via circHIPK2. Microbiome 7(1):116. https://doi.org/10.1186/s40168-019-0733-3

    Article  PubMed  PubMed Central  Google Scholar 

  9. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’’s disease and contributes to pathology in APP/PS1 mice. Nature 493(7434):674–678. https://doi.org/10.1038/nature11729

    Article  CAS  PubMed  Google Scholar 

  10. Barnett KC, Li S, Liang K, Ting JP (2023) A 360° view of the inflammasome: mMechanisms of activation, cell death, and diseases. Cell 186(11):2288–2312. https://doi.org/10.1016/j.cell.2023.04.025

    Article  CAS  PubMed  Google Scholar 

  11. Nozaki K, Maltez VI, Rayamajhi M, Tubbs AL, Mitchell JE, Lacey CA, Harvest CK, Li L, Nash WT, Larson HN, McGlaughon BD, Moorman NJ, Brown MG, Whitmire JK, Miao EA (2022) Caspase-7 activates ASM to repair gasdermin and perforin pores. Nature 606(7916):960–967. https://doi.org/10.1038/s41586-022-04825-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Knorr M, Hoppe J, Steuhl KP, Dartsch PC (1992) Effect of PDGF-AB heterodimer on a corneal epithelial cell line. Eur J Cell Biol 57(2):202–209

    CAS  PubMed  Google Scholar 

  13. Ma X, Hao J, Wu J, Li Y, Cai X, Zheng Y (2022) Prussian blue nanozyme as a pyroptosis inhibitor alleviates neurodegeneration. Adv Mater 34(15):e2106723. https://doi.org/10.1002/adma.202106723

    Article  CAS  PubMed  Google Scholar 

  14. Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J (2016) Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535(7610):153–158. https://doi.org/10.1038/nature18629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang X, Li X, Liu S, Brickell AN, Zhang J, Wu Z, Zhou S, Ding Z (2020) PCSK9 regulates pyroptosis via mtDNA damage in chronic myocardial ischemia. Basic Res Cardiol 115(6):66. https://doi.org/10.1007/s00395-020-00832-w

    Article  CAS  PubMed  Google Scholar 

  16. Siew JJ, Chen HM, Chen HY, Chen HL, Chen CM, Soong BW, Wu YR, Chang CP, Chan YC, Lin CH, Liu FT, Chern Y (2019) Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’’s disease. Nat Commun 10(1):3473. https://doi.org/10.1038/s41467-019-11441-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu AG, Zhou XG, Qiao G, Yu L, Tang Y, Yan L, Qiu WQ, Pan R, Yu CL, Law BY, Qin DL, Wu JM (2021) Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases. Ageing Res Rev 65:101202. https://doi.org/10.1016/j.arr.2020.101202

    Article  CAS  PubMed  Google Scholar 

  18. Xu F, Wu Y, Yang Q, Cheng Y, Xu J, Zhang Y, Dai H, Wang B, Ma Q, Chen Y, Lin F, Wang C (2022) Engineered extracellular vesicles with SHP2 high expression promote mitophagy for Alzheimer’’s disease treatment. Adv Mater 34(49):e2207107. https://doi.org/10.1002/adma.202207107

    Article  CAS  PubMed  Google Scholar 

  19. Panicker N, Kam TI, Wang H, Neifert S, Chou SC, Kumar M, Brahmachari S, Jhaldiyal A, Hinkle JT, Akkentli F, Mao X, Xu E, Karuppagounder SS, Hsu ET, Kang SU, Pletnikova O, Troncoso J, Dawson VL, Dawson TM (2022) Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’’s disease. Neuron 110(15):2422-2437.e2429. https://doi.org/10.1016/j.neuron.2022.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lawrence G, Holley CL, Schroder K (2022) Parkinson’’s disease: connecting mitochondria to inflammasomes. Trends Immunol 43(11):877–885. https://doi.org/10.1016/j.it.2022.09.010

    Article  CAS  PubMed  Google Scholar 

  21. Xiao K, Zhang BY, Zhang XM, Wang J, Chen C, Chen LN, Lv Y, Shi Q, Dong XP (2016) Re-infection of the prion from the scrapie-infected cell line SMB-S15 in three strains of mice, CD1, C57BL/6 and Balb/c. Int J Mol Med 37(3):716–726. https://doi.org/10.3892/ijmm.2016.2465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim YS, Carp RI, Callahan SM, Wisniewski HM (1987) Incubation periods and survival times for mice injected stereotaxically with three scrapie strains in different brain regions. J Gen Virol 68(Pt 3):695–702. https://doi.org/10.1099/0022-1317-68-3-695

    Article  PubMed  Google Scholar 

  23. Shi Q, Zhang BY, Gao C, Zhang J, Jiang HY, Chen C, Han J, Dong XP (2012) Mouse-adapted scrapie strains 139A and ME7 overcome species barrier to induce experimental scrapie in hamsters and changed their pathogenic features. Virol J 9:63. https://doi.org/10.1186/1743-422x-9-63

    Article  PubMed  PubMed Central  Google Scholar 

  24. Chou WC, Jha S, Linhoff MW, Ting JP (2023) The NLR gene family: from discovery to present day. Nat Rev Immunol 23(10):635–654. https://doi.org/10.1038/s41577-023-00849-x

    Article  CAS  PubMed  Google Scholar 

  25. Kibby EM, Conte AN, Burroughs AM, Nagy TA, Vargas JA, Whalen LA, Aravind L, Whiteley AT (2023) Bacterial NLR-related proteins protect against phage. Cell 186(11):2410-2424.e2418. https://doi.org/10.1016/j.cell.2023.04.015

    Article  CAS  PubMed  Google Scholar 

  26. Singh J, Habean ML, Panicker N (2023) Inflammasome assembly in neurodegenerative diseases. Trends Neurosci 46(10):814–831. https://doi.org/10.1016/j.tins.2023.07.009

    Article  CAS  PubMed  Google Scholar 

  27. Shao S, Chen C, Shi G, Zhou Y, Wei Y, Fan N, Yang Y, Wu L, Zhang T (2021) Therapeutic potential of the target on NLRP3 inflammasome in multiple sclerosis. Pharmacol Ther 227:107880. https://doi.org/10.1016/j.pharmthera.2021.107880

    Article  CAS  PubMed  Google Scholar 

  28. Osso LA, Chan JR (2015) Astrocytes underlie neuroinflammatory memory impairment. Cell 163(7):1574–1576. https://doi.org/10.1016/j.cell.2015.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhu J, Hu Z, Han X, Wang D, Jiang Q, Ding J, Xiao M, Wang C, Lu M, Hu G (2018) Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3. Cell Death Differ 25(11):2037–2049. https://doi.org/10.1038/s41418-018-0127-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Giordano AMS, Luciani M, Gatto F, Abou Alezz M, Beghè C, Della Volpe L, Migliara A, Valsoni S, Genua M, Dzieciatkowska M, Frati G, Tahraoui-Bories J, Giliani SC, Orcesi S, Fazzi E, Ostuni R, D’Alessandro A, Di Micco R, Merelli I, Lombardo A, Reijns MAM, Gromak N, Gritti A, Kajaste-Rudnitski A (2022) DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes. J Exp Med 219(4):e20211121. https://doi.org/10.1084/jem.20211121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shi F, Yang L, Kouadir M, Yang Y, Wang J, Zhou X, Yin X, Zhao D (2012) The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. J Neuroinflammation 9:73. https://doi.org/10.1186/1742-2094-9-73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lai M, Yao H, Shah SZA, Wu W, Wang D, Zhao Y, Wang L, Zhou X, Zhao D, Yang L (2018) The NLRP3-caspase 1 inflammasome negatively regulates autophagy via TLR4-TRIF in prion peptide-infected microglia. Front Aging Neurosci 10:116. https://doi.org/10.3389/fnagi.2018.00116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li S, Fang Y, Zhang Y, Song M, Zhang X, Ding X, Yao H, Chen M, Sun Y, Ding J, Wang Q, Lu M, Wu G, Hu G (2022) Microglial NLRP3 inflammasome activates neurotoxic astrocytes in depression-like mice. Cell Rep 41(4):111532. https://doi.org/10.1016/j.celrep.2022.111532

    Article  CAS  PubMed  Google Scholar 

  34. Niu T, De Rosny C, Chautard S, Rey A, Patoli D, Groslambert M, Cosson C, Lagrange B, Zhang Z, Visvikis O, Hacot S, Hologne M, Walker O, Wong J, Wang P, Ricci R, Henry T, Boyer L, Petrilli V, Py BF (2021) NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly. Nat Commun 12(1):5862. https://doi.org/10.1038/s41467-021-26142-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hochheiser IV, Pilsl M, Hagelueken G, Moecking J, Marleaux M, Brinkschulte R, Latz E, Engel C, Geyer M (2022) Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3. Nature 604(7904):184–189. https://doi.org/10.1038/s41586-022-04467-w

    Article  CAS  PubMed  Google Scholar 

  36. Wang C, Yang T, Xiao J, Xu C, Alippe Y, Sun K, Kanneganti TD, Monahan JB, Abu-Amer Y, Lieberman J, Mbalaviele G (2021) NLRP3 inflammasome activation triggers gasdermin D-independent inflammation. Sci Immunol 6(64):eabj3859. https://doi.org/10.1126/sciimmunol.abj3859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang J, Zhang BY, Zhang J, Xiao K, Chen LN, Wang H, Sun J, Shi Q, Dong XP (2016) Treatment of SMB-S15 cells with resveratrol efficiently removes the PrP(Sc) accumulation in vitro and prion infectivity in vivo. Mol Neurobiol 53(8):5367–5376. https://doi.org/10.1007/s12035-015-9464-z

    Article  CAS  PubMed  Google Scholar 

  38. Sigurdson CJ, Bartz JC, Glatzel M (2019) Cellular and molecular mechanisms of prion disease. Annu Rev Pathol 14:497–516. https://doi.org/10.1146/annurev-pathmechdis-012418-013109

    Article  CAS  PubMed  Google Scholar 

  39. Xu Y, Tian C, Wang SB, Xie WL, Guo Y, Zhang J, Shi Q, Chen C, Dong XP (2012) Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases. Autophagy 8(11):1604–1620. https://doi.org/10.4161/auto.21482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Trudler D, Nazor KL, Eisele YS, Grabauskas T, Dolatabadi N, Parker J, Sultan A, Zhong Z, Goodwin MS, Levites Y, Golde TE, Kelly JW, Sierks MR, Schork NJ, Karin M, Ambasudhan R, Lipton SA (2021) Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proc Natl Acad Sci U S A 118(15):e2025847118. https://doi.org/10.1073/pnas.2025847118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yang T, Zhang L, Shang Y, Zhu Z, Jin S, Guo Z, Wang X (2022) Concurrent suppression of Aβ aggregation and NLRP3 inflammasome activation for treating Alzheimer’’s disease. Chem Sci 13(10):2971–2980. https://doi.org/10.1039/d1sc06071f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Su L, Zhang J, Gomez H, Kellum JA, Peng Z (2023) Mitochondria ROS and mitophagy in acute kidney injury. Autophagy 19(2):401–414. https://doi.org/10.1080/15548627.2022.2084862

    Article  CAS  PubMed  Google Scholar 

  43. Zhu M, Du L, Zhao R, Wang HY, Zhao Y, Nie G, Wang RF (2020) Cell-penetrating nanoparticles activate the inflammasome to enhance antibody production by targeting microtubule-associated protein 1-light chain 3 for degradation. ACS Nano 14(3):3703–3717. https://doi.org/10.1021/acsnano.0c00962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Harrison D, Billinton A, Bock MG, Doedens JR, Gabel CA, Holloway MK, Porter RA, Reader V, Scanlon J, Schooley K, Watt AP (2023) Discovery of clinical candidate NT-0796, a brain-penetrant and highly potent NLRP3 inflammasome inhibitor for neuroinflammatory disorders. J Med Chem. https://doi.org/10.1021/acs.jmedchem.3c01398

    Article  PubMed  PubMed Central  Google Scholar 

  45. . Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, Cooper MA, O’Neill LA (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases Nat Med 21 (3):248-255 https://doi.org/10.1038/nm.3806

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Funding

This work was supported by the grant (2021SKLID101, 2019SKLID501, 2019SKLID603) from the State Key Laboratory for Infectious Disease Prevention and Control, China CDC.

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Authors and Affiliations

  1. National Key-Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, Chinese Center for Disease Control and Prevention, National Institute for Viral Disease Control and Prevention, Beijing, China

    Dong-Hua Zhou, Xiao-Xi Jia, Yue-Zhang Wu, Wei-Wei Zhang, Yuan Wang, Dong-Lin Liang, Li-Ping Gao, Kang Xiao, Cao Chen, Xiao-Ping Dong & Qi Shi

  2. Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China

    Xiao-Ping Dong

  3. China Academy of Chinese Medical Sciences, Beijing, China

    Xiao-Ping Dong & Qi Shi

  4. Shanghai Institute of Infectious Disease and Biosafety, Shanghai, China

    Xiao-Ping Dong

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Contributions

Dong-Hua Zhou, Qi Shi, and Xiao-Ping Dong wrote the main manuscript text. Xiao-Xi Jia, Yue-Zhang Wu, Wei-Wei Zhang, Yuan Wang, Dong-Lin Liang, Li-Ping Gao, King Xiao, and Can Chen participated in analyzing the results. All authors reviewed the manuscript.

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Zhou, DH., Jia, XX., Wu, YZ. et al. Aberrant Enhanced NLRP3 Inflammasomes and Cell Pyroptosis in the Brains of Prion-Infected Rodent Models Are Largely Associated with the Proliferative Astrocytes. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04169-6

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