Receptor interacting protein kinase 3 (Ripk3) is a signal relay protein involved in initiation of programmed cell death (necroptosis) and modulation of inflammasome activation. While caspase 1 and 11 are pro-inflammatory caspases responsible for unleashing inflammation and cell death by enzymatic activation of the executioners of inflammation and cell death (pyroptosis). Upon Salmonella infection, the host mounts a pro-inflammatory response which require Ripk3 and Caspase1/11. Here we show that bone marrow derived macrophages with combined deficiency of Ripk3 and Casp1/11 are highly resistant to Salmonella induced cell death, and that these macrophages show an anti-inflammatory cytokine profile. We confirm what was previously known that mice deficient in Casp1/11 have impaired ability to control Salmonella burden, and that the absence of Ripk3 alone does not influence the innate immune responses to Salmonella infection. However, we describe a synergistic role of Ripk3 and Casp1/11 in regulating Salmonella in vivo burden and that Ripk3-dependent host protection in the absence of Casp1/11 is evident during infection by sifA-expressing Salmonella. In summary, we show that the Ripk3 protection to Salmonella infection is obscured by presence of Caspase 1/11 and that the Ripk3-dependent protection requires a phagosome-bound Salmonella.

中文翻译：

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Ripk3许可在不存在Caspase1-11炎性小体的情况下针对微生物感染提供保护。

受体相互作用蛋白激酶3（Ripk3）是一种信号中继蛋白，参与程序性细胞死亡（坏死病）的启动和炎症小体活化的调控。半胱天冬酶1和11是促炎性胱天蛋白酶，其通过酶促激活炎症和细胞死亡（促脓性）的执行者来释放炎症和细胞死亡。沙门氏菌感染后，宿主发炎，需要Ripk3和Caspase1 / 11促炎症反应。在这里，我们显示具有Ripk3和Casp1 / 11联合缺乏的骨髓来源的巨噬细胞对沙门氏菌诱导的细胞死亡具有高度抗性，并且这些巨噬细胞显示出抗炎性细胞因子谱。我们证实了先前已知的缺陷，即缺乏Casp1 / 11的小鼠控制沙门氏菌负担的能力受损，单独使用Ripk3并不影响沙门氏菌感染的先天免疫反应。但是，我们描述了Ripk3和Casp1 / 11在调节沙门氏菌体内负担中的协同作用，并且在不表达Casp1 / 11的情况下，Ripk3依赖性宿主保护在表达sifA的沙门氏菌感染期间很明显。总而言之，我们显示Caspase 1/11的存在掩盖了对沙门氏菌感染的Ripk3保护，并且依赖Ripk3的保护需要结合吞噬体的沙门氏菌。