Agr2 regulates host-microbe responses in Crohn's disease

Summary: Crohn's disease (CD) affects millions of people worldwide and there is currently no cure. CD results from an interaction between a dysbiotic microbiota and genetic susceptibility variants that lead to inflammatory disease, but the cellular and microbial mechanisms underlying this are incompletely understood. Despite the emergence of new therapies for CD, most patients that require advanced therapy develop refractory disease requiring sequential therapy and / or surgery. There is therefore an urgent unmet medical need to identify the cellular and molecular mechanisms that can stratify disease and provide insight into new therapeutic strategies. Protein folding is a critical cellular process by which nascent peptides synthesized in the endoplasmic reticulum (ER) are assembled and trafficked within the cell. Disruption of ER homeostasis can lead to an ER stress response and activation of the unfolded protein response (UPR), in which various signaling pathways act to restore organelle function or trigger cell death. Seminal research has revealed a key role for the UPR in regulating proliferative and secretory intestinal epithelial cells in CD. One of the genetic variants associated with CD is the endoplasmic reticulum (ER) protein disulfide isomerase Anterior Gradient 2 (AGR2) and our cells, Crohn's expansion, leads E. IL-23-dependent the that folds, traffics, assembles cysteine-rich transmembrane receptors and intestinal glycoprotein mucins. Published data from group and others revealed that deletion of AGR2 leads to abnormalities in i ntestinal Paneth cells, goblet and stem cell proliferation resulting i n spontaneous granulomatous i ntestinal inflammation characteristic of disease. Our preliminary data reveal that bacterial dysbiosis, characterized by Enterobacteriaceae is associated with AGR2 expression i n Crohn's disease and that AGR2 deficiency in mice similarly to bacterial dysbiosis, characterized by the expansion of the CD associated pathobiont adherent-invasive coli (AIEC). Our data further reveals that AIEC are sufficient to selectively trigger epithelial cell ER stress and ileocolitis in AGR2 deficiency. Based on these preliminary data, we propose three aims to test hypothesis thatAGR2 regulates epithelial cell-specific ER stress responses that shape AIEC-host interactions in mediating ileocolitis in Crohn's disease. This research has the potential to reveal new cellular and molecular mechanisms by which AGR2 restrains ER stress to shape AIEC dysbiosis and IL-23-dependent inflammation in Crohn's disease. If successful, this research has the potential to reveal new diagnostic and therapeutic modalities for refractory Crohn's disease.