NOD1 controls tolerogenic DCs

Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an important member of the family of NOD-like receptors, all of which are cytoplasmic pattern recognition receptors. Thus, the main function of NOD1 is to sense bacterial components and to mediate inflammatory processes in order to protect the host against pathogenic bacteria. Although NOD1 plays a key role in host defense against pathogenic microbes, excessive NOD1 activation and genetic polymorphisms associated with the human NOD1 gene have been closely correlated with chronic inflammatory diseases and elevated cancer risk. Therefore, NOD1 might represent a promising target for novel treatments of chronic inflammation. However, very little progress has been made in this area, possibly over concerns that targeting NOD1 activity may be accompanied by deregulated responses against endogenous microflora and pathogenic microorganisms. The only way to resolve the remaining uncertainties is by acquiring a detailed understanding of NOD1 and the cellular and molecular mechanisms that contribute to its activation. Moreover, for the development of future therapeutic strategies, potential additional functions of NOD1, beyond ligand recognition, have to be investigated as well. In the present project, we propose that NOD1 itself, independent of its task as a pattern recognition receptor, plays an important role in regulating the function of dendritic cells (DCs). This would have far-reaching consequences, because the activation state of DCs directly governs the development of specific T-helper cell subsets and thus determines the outcome of T-cell dependent immune responses; therefore, therapeutics targeting NOD1 could have unanticipated negative consequences if NOD1 biology is not fully understood. The present project aims to thoroughly examine the ligand-independent function of NOD1 as a regulator of DC function at both molecular and cellular levels. To elucidate the molecular mechanisms underlying the interaction of NOD1 with the processes that result in DC activation, we will apply various molecular, biochemical and cellular in vitro assays. We will also investigate the consequences of NOD1-dependent DC activation for T-cell mediated immunity in vitro and in vivo. Taken together, our study proposes a novel, ligand-independent role for NOD1 as a regulator of DC functions and DC-mediated immune-responses. Confirmation of this hypothesis by the experiments described here will open up new perspectives in understanding the role of NOD1-driven inflammation and its role in chronic inflammatory diseases. In turn, this new knowledge may lead to the development of safe and effective treatments for chronic inflammatory disorders.

Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an important member of the family of NOD-like receptors, all of which are cytoplasmic pattern recognition receptors. Thus, the main function of NOD1 is to sense bacterial components ("patterns") and to mediate inflammatory processes to prevent the bacteria from multiplying in the host organism (e.g., humans). Although NOD1 plays a key role in host defense against pathogenic microbes, uncontrolled NOD1 expression, or mutations in the NOD1 gene, play an important function in chronic inflammatory diseases and pose an increased risk of cancer. Therefore, NOD1 might represent a promising target for novel treatments of chronic inflammation. However, very little progress has been made in this area, possibly over concerns that targeting NOD1 activity may be accompanied by deregulated responses against endogenous microflora and pathogenic microorganisms. Therefore, our goal was to gain a more detailed understanding of NOD1, and the cellular and molecular mechanisms that contribute to its activation. In the present project, we report that NOD1, even independent of its function as a pattern recognition receptor, can promote inflammation by suppressing anti-inflammatory signaling pathways. This finding supports our hypothesis that inhibition of NOD1 may represent a potential strategy for treating chronic inflammation. To further our understanding of the molecular mechanisms leading to the development of chronic inflammatory diseases, we focused on the human pathogen Helicobacter pylori (H. pylori). This Gram-negative bacterium can cause persistent infection of the gastric mucosa and has been identified as an important risk factor in the development of gastric cancer, one of the most aggressive malignancies, and the fifth leading cause of cancer-related mortality worldwide. In this project, we identified a certain type of primary immune cells termed human CD1c+ dendritic cells, as relevant model to study immune responses to H. pylori. Based on this and other relevant cell models, we were able to elucidate novel molecular mechanisms, leading to chronic inflammatory immune responses induced by H. pylori. Overall, the current project has significantly improved our understanding of tolerogenic dendritic cells in the context of chronic inflammation and further clarified the pro-inflammatory role of NOD1 in addition to its known function as a pattern recognition receptor.