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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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.

Original languageEnglish (US)
Article number109720
JournalCell reports
Issue number12
StatePublished - Sep 21 2021


  • ASC
  • IL-1β
  • MAPT
  • MyD88
  • NLRP3
  • inflammasomes
  • microglia
  • neuroinflammation
  • tau
  • tauopathies

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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