The Salmonella pathogenicity island-2 subverts human NLRP3 and NLRC4 inflammasome responses
The Salmonella pathogenicity island-2 subverts human NLRP3 and NLRC4 inflammasome responses
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DOI：
10.1002/jlb.ma0318-112rr
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发表时间：
2019-02-01
影响因子：
5.5
通讯作者：
Schroder, Kate
中科院分区：
文献类型：
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作者：
Bierschenk, Damien;Monteleone, Mercedes;Schroder, Kate
炎症体是激活炎症半胱氨酸酶以驱动细胞因子成熟和细胞溶解的信号中枢。鼠伤寒沙门氏菌感染或沙门氏菌衍生分子对炎性小体的激活在小鼠髓系细胞中被广泛研究。然而，沙门氏菌诱导的人类先天免疫细胞中的炎症体信号却没有得到很好的描述。在这里，我们证明了沙门氏菌突变使沙门氏菌致病岛-2 III型分泌系统(SPI2 T3SS)失活，增强了鼠伤寒沙门氏菌诱导的原代人巨噬细胞的炎症体反应，导致强烈的IL-1β产生和巨噬细胞死亡。SPI1 T3SS的失活降低了人巨噬细胞对WT和Delta SPI2沙门氏菌的反应。沙门氏菌DeltaSPI2可引起人髓系细胞的混合性炎症体反应，其中NLRC4(NLRC4)和NLRP3(NLRP3)在产生IL-1β和诱导下睑下垂方面具有一定的冗余功能。我们的数据表明，沙门氏菌使用SPI2 T3SS来颠覆SPI1诱导的人原代巨噬细胞的NLRP3和NLRC4炎症体反应，这是一种物种特异性免疫逃避机制。
Inflammasomes are signaling hubs that activate inflammatory caspases to drive cytokine maturation and cell lysis. Inflammasome activation by Salmonella Typhimurium infection or Salmonella-derived molecules is extensively studied in murine myeloid cells. Salmonella-induced inflammasome signaling in human innate immune cells, is however, poorly characterized. Here, we show that Salmonella mutation to inactivate the Salmonella pathogenicity island-2 type III secretion system (SPI2 T3SS) potentiates S. Typhimurium-induced inflammasome responses from primary human macrophages, resulting in strong IL-1 beta production and macrophage death. Inactivation of the SPI1 T3SS diminished human macrophage responses to WT and Delta SPI2 Salmonella. Salmonella Delta SPI2 elicited a mixed inflammasome response from human myeloid cells, in which NLR family CARD-domain containing protein 4 (NLRC4) and NLR family PYRIN-domain containing protein 3 (NLRP3) perform somewhat redundant functions in generating IL-1 beta and inducing pyroptosis. Our data suggest that Salmonella employs the SPI2 T3SS to subvert SPI1-induced NLRP3 and NLRC4 inflammasome responses in human primary macrophages, in a species-specific immune evasion mechanism.