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.

由白细胞介素 1β (IL-1β) 驱动的 tau (pTau) 病理性过度磷酸化和聚集以及神经炎症是 tau 蛋白病的主要标志。在这里，我们证明 pTau 启动并激活 IL-1β。首先，RNA 序列分析表明，来自人 tau 蛋白病大脑的成对螺旋丝 (PHF) 会启动人原代小胶质细胞中的核因子 κB (NF-κB)、趋化因子和 IL-1β 信号簇。用含有 pTau 的神经元介质、外泌体或 PHF 处理小胶质细胞会导致 IL-1β 激活，这是 NLRP3、ASC 和 caspase-1 依赖性的。抑制 pTau 或 ASC 分别减少 rTg4510 和 hTau 小鼠的 tau 病理学和炎症小体激活。尽管 MyD88 的缺失会阻止 hTau 小鼠 tau 病模型中 IL-1β 的表达和激活，但骨髓细胞中的 ASC 缺陷会减少 pTau 诱导的 IL-1β 激活并改善 hTau 小鼠的认知功能。最后，在人类 tau 病尸检大脑中，pTau 负荷与升高的 IL-1β 和 ASC 共存。总之，我们的结果表明 pTau 通过 MyD88 和 NLRP3-ASC 依赖的骨髓细胞（包括小胶质细胞）途径激活 IL-1β。