Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan;
Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.
J Immunol. 2019 Aug 15;203(4):783-788. doi: 10.4049/jimmunol.1900202. Epub 2019 Jun 26.
TGF-β-activated kinase 1 (TAK1) is known to play vital roles for innate and adaptive immunity; however, little is known about its potential role in limiting biological responses such as inflammation. In this study, we report that macrophage TAK1 participates in negatively regulating inflammation by restraining proinflammatory cell death. Macrophages from TAK1-deficient mice underwent cell death in response to LPS and poly(I:C), which took place in a manner dependent on TLR/TRIF-induced active Caspase8-mediated cleavage of gasdermin D, known as an executioner of pyroptosis. Likewise, TNF-α induced Caspase8-dependent gasdermin D processing following cell death in TAK1-deficient macrophages. Importantly, we demonstrated that this type of proinflammatory macrophage death is linked to susceptibility to septic shock in mice lacking TAK1 in macrophages in a TNF-α-independent fashion. Taken together, our data revealed that TAK1 acts as a signaling checkpoint to protect macrophages from unique proinflammatory cell death, ensuring the maintenance of innate immune homeostasis.
转化生长因子-β激活激酶 1（TAK1）已知在先天和适应性免疫中发挥重要作用；然而，其在限制炎症等生物学反应方面的潜在作用知之甚少。在这项研究中，我们报告巨噬细胞 TAK1 通过抑制促炎细胞死亡来参与负调控炎症。TAK1 缺陷型小鼠的巨噬细胞在 LPS 和 poly(I:C)的刺激下发生细胞死亡，这种细胞死亡方式依赖于 TLR/TRIF 诱导的活性 Caspase8 介导的 gasdermin D 的切割，gasdermin D 被称为细胞焦亡的执行者。同样，TNF-α 诱导 TAK1 缺陷型巨噬细胞发生细胞死亡后 Caspase8 依赖性的 gasdermin D 加工。重要的是，我们证明了这种促炎型巨噬细胞死亡与缺乏 TAK1 的巨噬细胞在 TNF-α 非依赖性方式下易发生败血性休克有关。总之，我们的数据揭示了 TAK1 作为一种信号检查点，可防止巨噬细胞发生独特的促炎细胞死亡，从而确保先天免疫稳态的维持。
