Gram-positive pathogens, including Staphylococcus aureus, cause necrotizing pneumonia. The central feature of S. aureus pneumonia is toxin-induced necroptosis of immune and resident cells, which impedes host defense. However, the role of the NLRC4 in the lung following S. aureus infection remains elusive. Here, we demonstrate that S. aureus activates the NLRC4 to drive necroptosis and IL-18 production, which impaired IL-17A-dependent neutrophil-mediated host susceptibility. In particular, Nlrc4^-/- mice exhibit reduced necroptosis, enhanced neutrophil influx into the lungs, decreased bacterial burden, and improved host survival. Loss of NLRC4 signaling in both hematopoietic and non-hematopoietic cells contributes to the host protection against S. aureus pneumonia. Secretion of IL-17A by γδ T cells is essential for neutrophil recruitment into the lungs of Nlrc4^-/- mice following infection. Moreover, treatment of wild-type mice with necroptosis inhibitors or genetic ablation of MLKL and IL-18 improves host defense against S. aureus infection, which is associated with increased IL-17A+γδ T cells and neutrophils. Taken together, these novel findings reveal that S. aureus activates the NLRC4 to dampen IL-17A-dependent neutrophil accumulation through induction of necroptosis and IL-18. Thus, modulating the function of the NLRC4 may be an attractive therapeutic approach for treating S. aureus infections.

中文翻译：

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NLRC4 通过在革兰氏阳性肺炎期间上调 IL-18 和诱导坏死性凋亡来抑制 IL-17A 介导的嗜中性粒细胞依赖性宿主防御。

革兰氏阳性病原体，包括金黄色葡萄球菌，可引起坏死性肺炎。金黄色葡萄球菌肺炎的主要特征是毒素诱导的免疫细胞和常驻细胞坏死，这会阻碍宿主防御。然而，金黄色葡萄球菌感染后 NLRC4 在肺中的作用仍然难以捉摸。在这里，我们证明金黄色葡萄球菌激活 NLRC4 以驱动细胞坏死和 IL-18 的产生，这损害了 IL-17A 依赖性中性粒细胞介导的宿主易感性。特别是，Nlrc4 ^-/-小鼠表现出坏死性凋亡减少，中性粒细胞流入肺部增加，细菌负荷减少，宿主存活率提高。造血细胞和非造血细胞中 NLRC4 信号的缺失有助于宿主保护免受金黄色葡萄球菌肺炎。γδ T 细胞分泌 IL-17A 对于中性粒细胞募集到 Nlrc4 的肺部至关重要^-/-感染后的小鼠。此外，用坏死性凋亡抑制剂或 MLKL 和 IL-18 的基因消融治疗野生型小鼠可提高宿主对金黄色葡萄球菌感染的防御能力，这与 IL-17A+γδ T 细胞和中性粒细胞的增加有关。总之，这些新发现表明金黄色葡萄球菌通过诱导坏死性凋亡和 IL-18 激活 NLRC4 以抑制 IL-17A 依赖性中性粒细胞的积累。因此，调节 NLRC4 的功能可能是治疗金黄色葡萄球菌感染的一种有吸引力的治疗方法。