Reactive oxygen species as modulators and effectors of epithelial defense: A role for NOD-like receptors?

在许多真核生物中，杀微生物活性氧（ROS）的产生是先天免疫系统的关键保护成分。NOD（nucleotide oligomerisation domain containing protein，核苷酸寡聚化结构域）样受体（nucleotide oligomerisation domain containing protein，NLR）被认为是细胞内病原体或内源性危险信号的遗传学上古老的传感器。NOD 2识别细菌细胞壁组分胞壁酰二肽（MDP），通过丝氨酸苏氨酸激酶RIP 2通过诱导的邻近信号传导导致NF-κB和MAPK活化。除了随后诱导细胞因子和抗微生物肽外，NOD 2还显示出直接的抗菌作用。有证据表明，NLR作为分子开关参与ROS产生的启动和检测具有决定性作用。虽然氧化猝发被很好地表征为人类中性粒细胞的防御工具，但是关于氧化还原稳态作为上皮防御机制的作用知之甚少。该项目的主要目标是研究细胞氧化还原稳态和NLR信号传导之间的联系，作为一种保守的抗菌效应途径和肠道屏障功能背景下先天免疫信号传导的调节原理。

Generation of microbicidal reactive oxygen species (ROS) is a pivotal protective component of the innate immune system in many eukaryotes. NOD (nucleotide oligomerisation domain containing protein)-like receptors (NLRs) have been implicated as phylogenetically ancient sensors of intracellular pathogens or endogenous danger signals. NOD2 recognizes the bacterial cell wall component muramyldipeptide (MDP) leading to NF-κB and MAPK activation via induced proximity signaling through the serine threonine kinase RIP2. In addition to the subsequent induction of cytokines and antimicrobial peptides, NOD2 has been shown to exert a direct antibacterial effect. Evidence points to a decisive role of NLRs as molecular switches involved both in the initiation and sensing of ROS production. Although the oxidative burst is well characterized as a defense tool of human neutrophils, very little is known about the role of redox homeostasis as an epithelial defense mechanism. The main goals of the project will be to investigate the link between cellular redox homeostasis and NLR signaling as a conserved antibacterial effector pathway and modulating principle of innate immunity signaling in the context of intestinal barrier function.