The Role of NOD-Mediated Innate Immune Activation in Lung Epithelia

The ability to recognize and remove pathogens that invade the lower airway, while maintaining homeostasis in the lung microenvironment, is an essential function of the innate immune system. An evolving hypothesis in this relatively new area of research is that in addition to maintaining normal host function, the molecular machinery responsible for pathogen recognition and activation of the innate immune response, may also contribute to chronic inflammatory diseases if a break down in normal function occurs [9]. This thesis focuses on the investigation of NOD-like receptor proteins (NLRs) which are involved in intracellular pathogen recognition and activation of the innate immune response. Recent work by others has identified that NOD1 and NOD2, of the NLR family, are critical components in intestinal inflammatory diseases [1]. An association between NOD1 and NOD2 with autoimmune diseases of the lung, primarily asthma and sarcoidosis respectively, has also been described [3,11]. The main goal of this thesis is to investigate the intracellular NLRs present in lung epithelium and their role in directing innate immune activation. The specific hypothesis is that NOD1 and NOD2 activate the innate protein complex called the “signalosome” leading to NF-κB activation in human lung epithelia. Data presented show that NOD1 and NOD2 along with RIP2, a key signaling protein of the NLR pathway, are constitutively present and associate in the lung epithelia. Upon recognition of the PAMP, iE-DAP, NOD1 facilitates physical recruitment of RIP2 activating the “signalosome”. Furthermore exposure to the NOD1 specific agonist, iE-DAP, but not NOD2 specific agonist, MDP, result in increased release of Interleukin 6 and Interleukin 8 mediated through the activation of the transcription factor NF-κB. These findings provide a framework to explain the recognition of gram negative bacterial invasion by lung epithelium and provide a valid model for future studies that will investigate the proximal entry of PAMPs into the lung epithelium thereby activating the “signalosome” upon NOD recognition and signal transduction. In conclusion our findings indicate that, NOD1 activates the “signalosome” machinery resulting in activation of the NF-κB pathway thereby inducing proinflammatory cytokine and chemokine release. This highlights the importance of NOD1 function in bacterial clearance and epithelial homeostasis, as well as, a potential for aberrant immune responses potentiated by dysregualtion in lung pathogenesis and inflammatory diseases.College of Pharmacy Undergraduate Research Scholarshi