A Nonpyroptotic IFN-γ-Triggered Cell Death Mechanism in Nonphagocytic Cells Promotes Salmonella Clearance In Vivo.
A Nonpyroptotic IFN-γ-Triggered Cell Death Mechanism in Nonphagocytic Cells Promotes Salmonella Clearance In Vivo.
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DOI：
10.4049/jimmunol.1701386
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发表时间：
2018-05-15
期刊：
影响因子：
--
通讯作者：
Balachandran S
中科院分区：
文献类型：
--
作者：
Ingram JP;Tursi S;Zhang T;Guo W;Yin C;A Wynosky-Dolfi M;van der Heijden J;Cai KQ;Yamamoto M;Finlay BB;Brodsky IE;Grivennikov SI;Tükel Ç;Balachandran S
细胞因子IFN-γ对吞噬细胞中的肠道沙门氏菌具有良好的抗菌特性，但关于IFN-γ对沙门氏菌感染的非吞噬细胞如肠上皮细胞（IEC）和成纤维细胞的作用知之甚少。在这里，我们表明，暴露人类和小鼠IEC和成纤维细胞与沙门氏菌感染后IFN-γ触发一种新形式的细胞死亡，既不是pyroptosis，也不是任何主要的已知形式的程序性细胞死亡。细胞死亡需要通过STAT 1-IRF 1介导的鸟苷酸结合蛋白（GBP）诱导的IFN-γ信号传导和胞质溶胶中活沙门氏菌的存在。在体内，在鼠IEC中选择性地消融IFN-γ信号传导导致结肠内容物中更高的细菌负荷，并增加感染小鼠肠道中的炎症。总之，这些结果表明，IFN-γ信号转导触发沙门氏菌从SCV释放到感染的非吞噬细胞的胞质溶胶中，导致一种防止肠道中细菌传播的非pyroptotic细胞死亡形式。
The cytokine IFN-γ has well-established antibacterial properties against the bacterium Salmonella enterica in phagocytes, but less is known about the effects of IFN-γ on Salmonella-infected non-phagocytic cells, such as intestinal epithelial cells (IECs) and fibroblasts. Here we show that exposing human and murine IECs and fibroblasts to IFN-γ following infection with Salmonella triggers a novel form of cell death that is neither pyroptosis, nor any of the major known forms of programmed cell death. Cell death required IFN-γ-signaling via STAT1-IRF1-mediated induction of Guanylate Binding Proteins (GBPs) and the presence of live Salmonella in the cytosol. In vivo, ablating IFN-γ signaling selectively in murine IECs led to higher bacterial burden in colon contents, and increased inflammation in the intestine of infected mice. Together, these results demonstrate that IFN-γ signaling triggers release of Salmonella from the SCV into the cytosol of infected non-phagocytic cells, resulting in a form of non-pyroptotic cell death that prevents bacterial spread in the gut.
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