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
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.
