Proteopathic tau primes and activates interleukin-1β via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway

Shanya Jiang; Nicole M. Maphis; Jessica Binder; Devon Chisholm; Lea Weston; Walter Duran; Crina Peterson; Amber Zimmerman; Michael A. Mandell; Stephen D. Jett; Eileen Bigio; Changiz Geula; Nikolaos Mellios; Jason P. Weick; Gary A. Rosenberg; Eicke Latz; Michael T. Heneka; Kiran Bhaskar

Cell Reports (Sep 2021)

Proteopathic tau primes and activates interleukin-1β via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway

Shanya Jiang,
Nicole M. Maphis,
Jessica Binder,
Devon Chisholm,
Lea Weston,
Walter Duran,
Crina Peterson,
Amber Zimmerman,
Michael A. Mandell,
Stephen D. Jett,
Eileen Bigio,
Changiz Geula,
Nikolaos Mellios,
Jason P. Weick,
Gary A. Rosenberg,
Eicke Latz,
Michael T. Heneka,
Kiran Bhaskar

Affiliations

Shanya Jiang: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Nicole M. Maphis: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Jessica Binder: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Devon Chisholm: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Lea Weston: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Walter Duran: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Crina Peterson: Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
Amber Zimmerman: Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
Michael A. Mandell: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Stephen D. Jett: Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
Eileen Bigio: Cognitive Neurology and Alzheimer’s Disease Center (CNADC), Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
Changiz Geula: Cognitive Neurology and Alzheimer’s Disease Center (CNADC), Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
Nikolaos Mellios: Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
Jason P. Weick: Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
Gary A. Rosenberg: Center for Memory and Aging, University of New Mexico, Albuquerque, NM 87131, USA
Eicke Latz: Institute of Innate Immunity, University of Bonn, Bonn 53127, Germany; Department of Medicine, University of Massachusetts, Worcester, MA 01605, USA
Michael T. Heneka: Institute of Innate Immunity, University of Bonn, Bonn 53127, Germany; Department of Medicine, University of Massachusetts, Worcester, MA 01605, USA; Department of Neurodegenerative Disease and Gerontopsychiatry, University of Bonn, Bonn 53127, Germany
Kiran Bhaskar: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA; Department of Neurology, University of New Mexico, Albuquerque, NM 87131, USA; Corresponding author

Journal volume & issue: Vol. 36, no. 12
p. 109720

Abstract

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Summary: Pathological hyperphosphorylation and aggregation of tau (pTau) and neuroinflammation, driven by interleukin-1β (IL-1β), are the major hallmarks of tauopathies. Here, we show that pTau primes and activates IL-1β. First, RNA-sequence analysis suggests paired-helical filaments (PHFs) from human tauopathy brain primes nuclear factor κB (NF-κB), chemokine, and IL-1β signaling clusters in human primary microglia. Treating microglia with pTau-containing neuronal media, exosomes, or PHFs causes IL-1β activation, which is NLRP3, ASC, and caspase-1 dependent. Suppression of pTau or ASC reduces tau pathology and inflammasome activation in rTg4510 and hTau mice, respectively. Although the deletion of MyD88 prevents both IL-1β expression and activation in the hTau mouse model of tauopathy, ASC deficiency in myeloid cells reduces pTau-induced IL-1β activation and improves cognitive function in hTau mice. Finally, pTau burden co-exists with elevated IL-1β and ASC in autopsy brains of human tauopathies. Together, our results suggest pTau activates IL-1β via MyD88- and NLRP3-ASC-dependent pathways in myeloid cells, including microglia.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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