Cellular and Molecular Life Sciences

, Volume 69, Issue 24, pp 4215–4228 | Cite as

NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1β and neuronal toxicity

  • Iva Hafner-Bratkovič
  • Mojca Benčina
  • Katherine A. Fitzgerald
  • Douglas Golenbock
  • Roman Jerala
Research article


Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1β has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1β upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K+, and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL-1 signaling pathway as the perspective target for the therapy of prion disease.


Prions Amyloid Inflammasome NLRP3 IL-1β Neuroinflammation 



Apoptosis-associated speck-like protein


NACHT, LRR, and PYD domains-containing protein 3


Prion protein



We would like to thank Darija Oven and Robert Bremšak for excellent technical assistance, Manuel Ritter and Clarissa Prazeres da Costa (TUM) for valuable discussions, Kurt Wüthrich for providing plasmid encoding mouse PrP ORF and Dona M. Chikaraishi for CAD cell line. This work was funded by Slovenian Research Agency (Z7-2059 to I.H.-B., P4-0176, N5-003, L4-2404 and J1-4170 to R.J.) and by NIH grant AI083713 to K.A.F.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

18_2012_1140_MOESM1_ESM.pdf (498 kb)
Supplementary material 1 (PDF 498 kb)


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Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  • Iva Hafner-Bratkovič
    • 1
  • Mojca Benčina
    • 1
    • 2
  • Katherine A. Fitzgerald
    • 3
  • Douglas Golenbock
    • 3
  • Roman Jerala
    • 1
    • 2
    • 4
  1. 1.Department of BiotechnologyNational Institute of ChemistryLjubljanaSlovenia
  2. 2.EN→FIST Centre of ExcellenceLjubljanaSlovenia
  3. 3.Department of Medicine, Division of Infectious Diseases and ImmunologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  4. 4.Faculty of Chemistry and Chemical TechnologyUniversity of LjubljanaLjubljanaSlovenia

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