NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1beta and neuronal toxicity
Department of Medicine, Division of Infectious Diseases and Immunology
Prion Diseases; Carrier Proteins; Inflammasomes; Interleukin-1beta
Immunology and Infectious Disease
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-1beta 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-1beta 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.
DOI of Published Version
Cell Mol Life Sci. 2012 Dec;69(24):4215-28. doi: 10.1007/s00018-012-1140-0. Link to article on publisher's site
Cellular and molecular life sciences : CMLS
Hafner-Bratkovic, Iva; Bencina, Mojca; Fitzgerald, Katherine A.; Golenbock, Douglas T.; and Jerala, Roman, "NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1beta and neuronal toxicity" (2012). Infectious Diseases and Immunology Publications and Presentations. 141.