Prion Pathogenesis in the Absence of NLRP3/ASC Inflammasomes

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Feb 12

PMID 25671600

Citations 24

Authors

Mario Nuvolone

Silvia Sorce

Petra Schwarz

Adriano Aguzzi

Affiliations

Soon will be listed here.

Abstract

The accumulation of the scrapie prion protein PrPSc, a misfolded conformer of the cellular prion protein PrPC, is a crucial feature of prion diseases. In the central nervous system, this process is accompanied by conspicuous microglia activation. The NLRP3 inflammasome is a multi-molecular complex which can sense heterogeneous pathogen-associated molecular patterns and culminates in the activation of caspase 1 and release of IL 1β. The NLRP3 inflammasome was reported to be essential for IL 1β release after in vitro exposure to the amyloidogenic peptide PrP106-126 and to recombinant PrP fibrils. We therefore studied the role of the NLRP3 inflammasome in a mouse model of prion infection. Upon intracerebral inoculation with scrapie prions (strain RML), mice lacking NLRP3 (Nlrp3-/-) or the inflammasome adaptor protein ASC (Pycard-/-) succumbed to scrapie with attack rates and incubation times similar to wild-type mice, and developed the classic histologic and biochemical features of prion diseases. Genetic ablation of NLRP3 or ASC did not significantly impact on brain levels of IL 1β at the terminal stage of disease. Our results exclude a significant role for NLRP3 and ASC in prion pathogenesis and invalidate their claimed potential as therapeutic target against prion diseases.

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References

Sharief M, Green A, Dick J, Gawler J, Thompson E . Heightened intrathecal release of proinflammatory cytokines in Creutzfeldt-Jakob disease. Neurology. 1999; 52(6):1289-91. DOI: 10.1212/wnl.52.6.1289. View

Baker C, Lu Z, Zaitsev I, Manuelidis L . Microglial activation varies in different models of Creutzfeldt-Jakob disease. J Virol. 1999; 73(6):5089-97. PMC: 112554. DOI: 10.1128/JVI.73.6.5089-5097.1999. View

Coeshott C, Ohnemus C, Pilyavskaya A, Ross S, Wieczorek M, Kroona H . Converting enzyme-independent release of tumor necrosis factor alpha and IL-1beta from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3. Proc Natl Acad Sci U S A. 1999; 96(11):6261-6. PMC: 26869. DOI: 10.1073/pnas.96.11.6261. View

Kim J, Ju W, Choi J, Choi E, Carp R, Wisniewski H . Expression of cytokine genes and increased nuclear factor-kappa B activity in the brains of scrapie-infected mice. Brain Res Mol Brain Res. 1999; 73(1-2):17-27. DOI: 10.1016/s0169-328x(99)00229-6. View

Walsh D, Betmouni S, Perry V . Absence of detectable IL-1beta production in murine prion disease: a model of chronic neurodegeneration. J Neuropathol Exp Neurol. 2001; 60(2):173-82. DOI: 10.1093/jnen/60.2.173. View

Van Everbroeck B, Dewulf E, Pals P, Lubke U, Martin J, Cras P . The role of cytokines, astrocytes, microglia and apoptosis in Creutzfeldt-Jakob disease. Neurobiol Aging. 2002; 23(1):59-64. DOI: 10.1016/s0197-4580(01)00236-6. View

Wang L, Manji G, Grenier J, Al-Garawi A, Merriam S, Lora J . 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. DOI: 10.1074/jbc.M203915200. View

Baker C, Martin D, Manuelidis L . Microglia from Creutzfeldt-Jakob disease-infected brains are infectious and show specific mRNA activation profiles. J Virol. 2002; 76(21):10905-13. PMC: 136595. DOI: 10.1128/jvi.76.21.10905-10913.2002. View

Grenier J, Wang L, Manji G, Huang W, Al-Garawi A, Kelly R . Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-kappaB and caspase-1. FEBS Lett. 2002; 530(1-3):73-8. DOI: 10.1016/s0014-5793(02)03416-6. View

10.

Baker C, Manuelidis L . Unique inflammatory RNA profiles of microglia in Creutzfeldt-Jakob disease. Proc Natl Acad Sci U S A. 2003; 100(2):675-9. PMC: 141055. DOI: 10.1073/pnas.0237313100. View

11.

Prinz M, Heikenwalder M, Schwarz P, Takeda K, Akira S, Aguzzi A . Prion pathogenesis in the absence of Toll-like receptor signalling. EMBO Rep. 2003; 4(2):195-9. PMC: 1315829. DOI: 10.1038/sj.embor.embor731. View

12.

Brown A, Webb J, Rebus S, Walker R, Williams A, Fazakerley J . Inducible cytokine gene expression in the brain in the ME7/CV mouse model of scrapie is highly restricted, is at a strikingly low level relative to the degree of gliosis and occurs only late in disease. J Gen Virol. 2003; 84(Pt 9):2605-2611. DOI: 10.1099/vir.0.19137-0. View

13.

Bueler H, Fischer M, Lang Y, Bluethmann H, Lipp H, DeArmond S . Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature. 1992; 356(6370):577-82. DOI: 10.1038/356577a0. View

14.

Agostini L, Martinon F, Burns K, McDermott M, Hawkins P, Tschopp J . NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004; 20(3):319-25. DOI: 10.1016/s1074-7613(04)00046-9. View

15.

Schultz J, Schwarz A, Neidhold S, Burwinkel M, Riemer C, Simon D . Role of interleukin-1 in prion disease-associated astrocyte activation. Am J Pathol. 2004; 165(2):671-8. PMC: 1618583. DOI: 10.1016/S0002-9440(10)63331-7. View

16.

Polymenidou M, Heppner F, Pellicioli E, Urich E, Miele G, Braun N . Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection. Proc Natl Acad Sci U S A. 2004; 101 Suppl 2:14670-6. PMC: 521983. DOI: 10.1073/pnas.0404772101. View

17.

Puoti G, Giaccone G, Mangieri M, Limido L, Fociani P, Zerbi P . Sporadic Creutzfeldt-Jakob disease: the extent of microglia activation is dependent on the biochemical type of PrPSc. J Neuropathol Exp Neurol. 2005; 64(10):902-9. DOI: 10.1097/01.jnen.0000183346.19447.55. View

18.

Stoeck K, Bodemer M, Zerr I . Pro- and anti-inflammatory cytokines in the CSF of patients with Creutzfeldt-Jakob disease. J Neuroimmunol. 2005; 172(1-2):175-81. DOI: 10.1016/j.jneuroim.2005.10.008. View

19.

Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J . Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006; 440(7081):237-41. DOI: 10.1038/nature04516. View

20.

Mariathasan S, Weiss D, Newton K, McBride J, ORourke K, Roose-Girma M . Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006; 440(7081):228-32. DOI: 10.1038/nature04515. View