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

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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.