Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection
Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection
复制标题
TLR 和 NOD 信号传导的激活协同作用，赋予宿主先天免疫介导的针对微生物感染的保护
DOI：
10.3389/fimmu.2018.03082
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发表时间：
2019-01-14
影响因子：
7.3
通讯作者：
Wang, Jian
中科院分区：
文献类型：
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作者：
Zhou, Huiting;Coveney, Andrew P.;Wang, Jian
微生物病原体的检测依赖于膜传感器Toll样受体（TLR）和胞质传感器NOD样受体（NLR）对高度保守的微生物结构的识别。一旦检测到，这些传感器就会触发先天免疫反应，以消灭入侵的微生物病原体。然而，目前尚不清楚 TLR 和 NOD 信号传导是否对于先天免疫启动针对微生物感染的炎症和抗菌反应至关重要。在这里，我们报告说，TLR 和 NOD 信号传导的激活导致炎症反应增强，并且 TLR 和 NOD 之间的串扰导致下游 NF-κ B 激活放大，同时 TNF-α 和 IL-6 启动子处 p65 的核反式激活增加。此外，TLR 和 NOD 激动剂共同刺激巨噬细胞可最大限度地提高抗菌活性，并加速吞噬体的成熟。重要的是，给予 TLR 和 NOD 激动剂可以保护小鼠免受多种微生物败血症相关的致死，增加血清炎性细胞因子水平并加速细菌从循环和内脏器官的清除。这些结果表明，TLR 和 NOD 信号传导的激活协同作用，诱导有效的炎症和抗菌反应，从而提供针对微生物感染的保护。
The detection of microbial pathogens relies on the recognition of highly conserved microbial structures by the membrane sensor Toll-like receptors (TLRs) and cytosolic sensor NOD-like receptors (NLRs). Upon detection, these sensors trigger innate immune responses to eradicate the invaded microbial pathogens. However, it is unclear whether TLR and NOD signaling are both critical for innate immunity to initiate inflammatory and antimicrobial responses against microbial infection. Here we report that activation of both TLR and NOD signaling resulted in an augmented inflammatory response and the crosstalk between TLR and NOD led to an amplified downstream NF-kappa B activation with increased nuclear transactivation of p65 at both TNF-alpha and IL-6 promoters. Furthermore, co-stimulation of macrophages with TLR and NOD agonists maximized antimicrobial activity with accelerated phagosome maturation. Importantly, administration of both TLR and NOD agonists protected mice against polymicrobial sepsis-associated lethality with increased serum levels of inflammatory cytokines and accelerated clearance of bacteria from the circulation and visceral organs. These results demonstrate that activation of both TLR and NOD signaling synergizes to induce efficient inflammatory and antimicrobial responses, thus conferring protection against microbial infection.