Cell-Extrinsic TNF Collaborates with TRIF Signaling To Promote Yersinia-Induced Apoptosis.
Cell-Extrinsic TNF Collaborates with TRIF Signaling To Promote Yersinia-Induced Apoptosis.
复制标题
DOI：
10.4049/jimmunol.1601294
复制
发表时间：
2016-11-15
期刊：
影响因子：
--
通讯作者：
Brodsky IE
中科院分区：
文献类型：
--
作者：
Peterson LW;Philip NH;Dillon CP;Bertin J;Gough PJ;Green DR;Brodsky IE
对于控制感染至关重要的先天免疫反应通常是微生物病原体的目标。通过耶尔森氏菌毒力因子YopJ阻断NF-κB和MAPK信号传导抑制先天免疫细胞产生细胞因子，但也引发细胞死亡。这种细胞死亡需要RIPK 1激酶活性和半胱天冬酶-8，它们由TLR 4和衔接蛋白TRIF参与。然而，TLR 4和TRIF缺陷细胞仍然发生显著的细胞凋亡，暗示TLR 4/TRIF非依赖性途径在耶尔森氏菌感染细胞的死亡中。在这里，我们报告了一个以前未描述的作用，TNF受体信号在耶尔森氏菌诱导的小鼠巨噬细胞的细胞死亡，这发生在尽管NF-κB和MAPK信号的封锁，由耶尔森氏菌感染的细胞。有趣的是，对YopJ注射液的直接分析揭示了注射高和注射低细胞的异质群体，并证明TNF表达来自注射低群体。此外，TNF生产的这个亚群是必要的最大的细胞凋亡的人口高度注射的细胞。这些数据证明了TNF和模式识别受体信号之间的合作在细菌感染期间促进最大细胞凋亡中的重要作用，并证明了毒力因子注射和细胞应答的异质性在促进抗耶尔森氏菌免疫防御中起重要作用。
Innate immune responses that are crucial for control of infection are often targeted by microbial pathogens. Blockade of NF-κB and MAPK signaling by the Yersinia virulence factor YopJ inhibits cytokine production by innate immune cells but also triggers cell death. This cell death requires RIPK1 kinase activity and caspase-8, which are engaged by TLR4 and the adaptor protein TRIF. Nevertheless, TLR4- and TRIF-deficient cells still undergo significant apoptosis, implicating TLR4/TRIF-independent pathways in the death of Yersinia-infected cells. Here we report a previously undescribed role for TNF receptor signaling in Yersinia-induced cell death of murine macrophages, which occurs despite the blockade of NF-κB and MAPK signaling imposed by Yersinia on infected cells. Intriguingly, direct analysis of YopJ injection revealed a heterogeneous population of injection-high and injection-low cells, and demonstrated that TNF expression came from the injection-low population. Moreover, TNF production by this sub-population was necessary for maximal apoptosis in the population of highly injected cells. These data demonstrate an important role for collaboration between TNF and Pattern Recognition Receptor signals in promoting maximal apoptosis during bacterial infection, and demonstrate that heterogeneity in virulence factor injection and cellular responses play an important role in promoting anti-Yersinia immune defense.