Abstract
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 language | English (US) |
|---|---|
| Article number | 109720 |
| Journal | Cell reports |
| Volume | 36 |
| Issue number | 12 |
| DOIs | |
| State | Published - Sep 21 2021 |
Funding
We thank Dr. Vishwa Dixit (Genentech) and Dr. Vojo Deretic (UNM) for providing ASC \u2212/\u2212 mice and various reagents, respectively. We thank Drs. Xiaoxia Li and Zizhen Kang (Cleveland Clinic) for providing CD11bCre/MyD88 flox mice. We thank Dr. Amir Yazdi (University of Lausanne) for providing ASC flox mice. We are thankful to Dr. Michael Paffett at the UNM Cancer Center Fluorescence Microscopy facility and CTSC T1 lab for help with confocal imaging and RNA quantification, respectively. We thank Dr. Paulus Mrass for his assistance in processing live image files. We thank Dr. Bryce Chackerian, Ms. Julianne Peabody, Mr. Jeff Thompson, and Ms. Sasha Hobson for assistance with tau immunization experiments and analyzing tau levels in the CSF samples. The graphical abstract was created with https://www.biorender.com . This study was supported by the NIH ( RF1NS083704-05A1 , R01NS083704 , and R21NS077089 ; R21NS093442 to K.B.; and R01NS116051 to J.P.W.), AIM CoBRE Center ( P20GM121176-04 ), the University of New Mexico (UNM) Health Sciences Center Bridge Funding , UNM Department of Molecular Genetics and Microbiology intradepartmental grant funding, Dr. Stephanie Ruby travel award (to N.M. and J.B.), and a T32 training grant (to L.W.). This study was also supported in part by Alzheimer\u2019s Disease Core Center ( P30AG013854 ) from the National Institute on Aging (NIA) to Northwestern University and New Mexico Alzheimer\u2019s Disease Research Center ( P20AG068077-01 ) from NIA to G.A.R. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank Dr. Vishwa Dixit (Genentech) and Dr. Vojo Deretic (UNM) for providing ASC\u2212/\u2212 mice and various reagents, respectively. We thank Drs. Xiaoxia Li and Zizhen Kang (Cleveland Clinic) for providing CD11bCre/MyD88 flox mice. We thank Dr. Amir Yazdi (University of Lausanne) for providing ASC flox mice. We are thankful to Dr. Michael Paffett at the UNM Cancer Center Fluorescence Microscopy facility and CTSC T1 lab for help with confocal imaging and RNA quantification, respectively. We thank Dr. Paulus Mrass for his assistance in processing live image files. We thank Dr. Bryce Chackerian, Ms. Julianne Peabody, Mr. Jeff Thompson, and Ms. Sasha Hobson for assistance with tau immunization experiments and analyzing tau levels in the CSF samples. The graphical abstract was created with https://www.biorender.com. This study was supported by the NIH (RF1NS083704-05A1, R01NS083704, and R21NS077089; R21NS093442 to K.B.; and R01NS116051 to J.P.W.), AIM CoBRE Center (P20GM121176-04), the University of New Mexico (UNM) Health Sciences Center Bridge Funding, UNM Department of Molecular Genetics and Microbiology intradepartmental grant funding, Dr. Stephanie Ruby travel award (to N.M. and J.B.), and a T32 training grant (to L.W.). This study was also supported in part by Alzheimer's Disease Core Center (P30AG013854) from the National Institute on Aging (NIA) to Northwestern University and New Mexico Alzheimer's Disease Research Center (P20AG068077-01) from NIA to G.A.R. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. K.B. and S.J designed experiments. S.J performed majority of the experiments. J.P.W. E.L. and M.T.H. helped with conceptual planning and assisted with manuscript preparation. S.J. C.P. A.Z. and N.M. performed RNA-seq analysis and assisted with interpretations. S.J. L.W. N.M.M. and D.C. generated the mice and performed various biochemical analysis. J.B. performed exosome experiments. W.D. assisted in cell-culture experiments with S.J. and J.B. S.D.J. performed immune electron microscopy. E.B. and C.G. provided human autopsy brain samples. G.A.R. provided CSF. E.B. C.G. and G.A.R. assisted with manuscript preparation. M.A.M. performed NF-\u03BAB in vitro experiments. K.B. wrote the manuscript. The authors declare no competing interests.
Keywords
- ASC
- IL-1β
- MAPT
- MyD88
- NLRP3
- inflammasomes
- microglia
- neuroinflammation
- tau
- tauopathies
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology