Diseases of the respiratory tract are among the leading causes of death in the world population. Increasing evidence points to a key role of the innate immune system with its pattern recognition receptors (PRRs) in both infectious and noninfectious lung diseases, which include pneumonia, chronic obstructive pulmonary disease, acute lung injury, pneumoconioses, and asthma. PRRs are capable of sensing different microbes as well as endogenous molecules that are released after cell damage. This PRR engagement is the prerequisite for the initiation of immune responses to infections and tissue injuries which can be beneficial or detrimental to the host. PRRs include the Toll-like receptors, NOD-like receptors, RIG-I-like receptors, and cytosolic DNA sensors. The PRRs and their signaling pathways represent promising targets for prophylactic and therapeutic interventions in various lung diseases.

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Nucleotide-binding oligomerization domain (Nod) proteins serve as intracellular pattern recognition molecules recognizing peptidoglycans. To further examine intracellular immune recognition, we used Listeria monocytogenes as an organism particularly amenable for studying innate immunity to intracellular pathogens. In contrast to wild-type L. monocytogenes, the nonpathogenic Listeria innocua, or L. monocytogenes mutants lacking internalin B or listeriolysin O, poorly invaded host cells and escaped into host cell cytoplasm, respectively, and were therefore used as controls. In this study, we show that only the invasive wild-type L. monocytogenes, but not the listeriolysin O- or internalin B-negative L. monocytogenes mutants or L. innocua, substantially induced IL-8 production in HUVEC. RNA interference and Nod1-overexpression experiments demonstrated that Nod1 is critically involved in chemokine secretion and NF-κB activation initiated by L. monocytogenes in human endothelial cells. Moreover, we show for the first time that Nod1 mediated activation of p38 MAPK signaling induced by L. monocytogenes. Finally, L. monocytogenes- and Nod1-induced IL-8 production was blocked by a specific p38 inhibitor. In conclusion, L. monocytogenes induced a Nod1-dependent activation of p38 MAPK signaling and NF-κB which resulted in IL-8 production in endothelial cells. Thus, Nod1 is an important component of a cytoplasmic surveillance pathway.