Department of Neuroscience, Genentech Inc, South San Francisco, United States.
Department of OMNI Bioinformatics, Genentech Inc, South San Francisco, United States.
Elife. 2023 Aug 9;12:e83451. doi: 10.7554/eLife.83451.
Tumor progression locus 2 (TPL2) (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNA sequencing analysis indicates that protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS (inducible nitric oxide synthase) induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.
肿瘤进展基因座 2（TPL2）（MAP3K8）是外周免疫细胞炎症反应的核心信号节点。我们发现 TPL2 激酶活性调节小胶质细胞细胞因子的释放，并且是小胶质细胞介导的体外神经元死亡所必需的。在急性体内神经炎症环境中，TPL2 激酶活性调节小胶质细胞的激活状态和大脑细胞因子水平。在慢性神经退行性疾病的 tau 病变模型中，TPL2 激酶活性的丧失减少了神经炎症并挽救了突触丢失、脑容量损失和行为缺陷。单细胞 RNA 测序分析表明，tau 病变模型中的保护与激活的小胶质细胞亚群以及浸润的外周免疫细胞的减少有关。总的来说，我们使用各种模型发现，TPL2 激酶活性可以促进小胶质细胞激活在大脑中的多种有害后果，包括细胞因子释放、iNOS（诱导型一氧化氮合酶）诱导、星形胶质细胞激活和免疫细胞浸润。因此，抑制 TPL2 激酶活性可能代表神经退行性疾病的一种潜在治疗策略。
