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Glia. 2019 Oct 9. doi: 10.1002/glia.23728. [Epub ahead of print]

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins.

Author information

1
School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia.
2
University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia.
3
Institute for Molecular Bioscience, and Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, Queensland, Australia.
4
School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia.
5
Illawarra Health and Medical Institute, University of Wollongong, Wollongong, New South Wales, Australia.
6
Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Centre for MND Research, Macquarie University, New South Wales, Australia.
7
School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia.

Abstract

Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as β-amyloid and α-synuclein trigger microglial NLRP3 activation, leading to caspase-1 activation and IL-1β secretion. Both caspase-1 and IL-1β contribute to disease progression in the mouse SOD1G93A model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1G93A mice microglia do not express NLRP3, and SOD1G93A protein generated IL-1β in microglia independent to NLRP3. Here, we demonstrate using Nlrp3-GFP gene knock-in mice that microglia express NLRP3 in SOD1G93A mice. We show that both aggregated and soluble SOD1G93A activates inflammasome in primary mouse microglia leading caspase-1 and IL-1β cleavage, ASC speck formation, and the secretion of IL-1β in a dose- and time-dependent manner. Importantly, SOD1G93A was unable to induce IL-1β secretion from microglia deficient for Nlrp3, or pretreated with the specific NLRP3 inhibitor MCC950, confirming NLRP3 as the key inflammasome complex mediating SOD1-induced microglial IL-1β secretion. Microglial NLRP3 upregulation was also observed in the TDP-43Q331K ALS mouse model, and TDP-43 wild-type and mutant proteins could also activate microglial inflammasomes in a NLRP3-dependent manner. Mechanistically, we identified the generation of reactive oxygen species and ATP as key events required for SOD1G93A -mediated NLRP3 activation. Taken together, our data demonstrate that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NLRP3 inflammasome. NLRP3 inhibition may therefore be a potential therapeutic approach to arrest microglial neuroinflammation and ALS disease progression.

KEYWORDS:

IL-1β; glia; innate immunity; motor neuron disease

PMID:
31596526
DOI:
10.1002/glia.23728

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