Abstract:
Leukotriene B4 (LTB4) is critical for initiating the inflammatory cascade in response to infection. However, Yersinia pestis colonizes the host by inhibiting the timely synthesis of LTB4 and inflammation. Here, we show that the bacterial type 3 secretion system (T3SS) is the primary pathogen associated molecular pattern (PAMP) responsible for LTB4 production by leukocytes in response to Yersinia and Salmonella, but synthesis is inhibited by the Yop effectors during Yersinia interactions. Moreover, we unexpectedly discovered that T3SS-mediated LTB4 synthesis by neutrophils and macrophages require two distinct host signaling pathways. We show that the SKAP2/PLC signaling pathway is essential for LTB4 production by neutrophils but not macrophages. Instead, phagocytosis and the NLRP3/CASP1 inflammasome are needed for LTB4 synthesis by macrophages. Finally, while recognition of the T3SS is required for LTB4 production, we also discovered a second unrelated PAMP-mediated signal independently activates the MAP kinase pathway needed for LTB4 synthesis. Together, these data demonstrate significant differences in the signaling pathways required by macrophages and neutrophils to quickly respond to bacterial infections.
摘要:
白三烯B4(LTB4)对于响应感染而启动炎症级联反应至关重要。然而,鼠疫耶尔森氏菌通过抑制LTB4的及时合成和炎症而定植宿主。这里,我们表明,细菌3型分泌系统(T3SS)是主要的病原体相关分子模式(PAMP),负责白细胞响应耶尔森氏菌和沙门氏菌产生LTB4,但是在耶尔森氏菌相互作用期间,Yop效应子抑制了合成。此外,我们意外地发现,T3SS介导的嗜中性粒细胞和巨噬细胞的LTB4合成需要两种不同的宿主信号通路.我们表明,SKAP2/PLC信号通路对于中性粒细胞而不是巨噬细胞产生LTB4至关重要。相反,巨噬细胞合成LTB4需要吞噬作用和NLRP3/CASP1炎性体。最后,虽然LTB4生产需要识别T3SS,我们还发现第二个无关的PAMP介导的信号独立激活LTB4合成所需的MAP激酶途径。一起,这些数据表明巨噬细胞和中性粒细胞对细菌感染快速反应所需的信号通路存在显著差异.
■宿主产生炎性脂质介质对于响应细菌病原体入侵的及时炎症至关重要。因此,确定免疫细胞如何识别病原体并快速产生这些脂质对于我们了解免疫系统如何有效控制感染至关重要。在这项研究中,我们发现白细胞三烯B4(LTB4)合成所需的宿主信号通路在中性粒细胞和巨噬细胞之间不同,强调免疫细胞对感染反应的重要差异。一起,这些数据表明,我们对中性粒细胞和巨噬细胞如何迅速与细菌发生反应的认识有了显著提高,并为鼠疫耶尔森氏菌如何操纵白细胞逃避免疫识别而导致疾病提供了新的见解.