| First Author | Jiang S | Year | 2021 |
| Journal | Cell Rep | Volume | 36 |
| Issue | 12 | Pages | 109720 |
| PubMed ID | 34551296 | Mgi Jnum | J:327010 |
| Mgi Id | MGI:6876869 | Doi | 10.1016/j.celrep.2021.109720 |
| Citation | Jiang S, et al. (2021) Proteopathic tau primes and activates interleukin-1beta via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway. Cell Rep 36(12):109720 |
| abstractText | Pathological hyperphosphorylation and aggregation of tau (pTau) and neuroinflammation, driven by interleukin-1beta (IL-1beta), are the major hallmarks of tauopathies. Here, we show that pTau primes and activates IL-1beta. First, RNA-sequence analysis suggests paired-helical filaments (PHFs) from human tauopathy brain primes nuclear factor kappaB (NF-kappaB), chemokine, and IL-1beta signaling clusters in human primary microglia. Treating microglia with pTau-containing neuronal media, exosomes, or PHFs causes IL-1beta 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-1beta expression and activation in the hTau mouse model of tauopathy, ASC deficiency in myeloid cells reduces pTau-induced IL-1beta activation and improves cognitive function in hTau mice. Finally, pTau burden co-exists with elevated IL-1beta and ASC in autopsy brains of human tauopathies. Together, our results suggest pTau activates IL-1beta via MyD88- and NLRP3-ASC-dependent pathways in myeloid cells, including microglia. |
