The SLC15A4/TASL/IRF5 axis role in the immunopathogenesis of IBD and associated cancer

Abstract Background and aims This project aims at unveiling the relevance of the signaling pathway SLC15A4/TASL-IRF5 in the immunopathogenesis of inflammatory bowel diseases (IBD) and one of its most serious complications, colitis-associated cancer (CAC). Previous studies indicate that deficiencies in either the solute transporter SLC15A4 or IRF5, independently, can protect mice from colitis, but their activation cues or mode-of-action have not been revealed. Upon engagement of TLR7-9, the immune adaptor SLC15A4/TASL complex mediates activation of Interferon Regulatory Factor 5 (IRF5), leading to a potent inflammatory response. We hypothesize that the SLC15A4/TASL complex is the pivotal link between microbial TLR sensing and IRF5-mediated pro-inflammatory response, which fosters IBD onset and inflammation-driven CAC. Our preliminary data shows TASL-deficient mice are indeed protected from DSS-colitis, and further research is needed to unveil its relevance in CAC. Moreover, thanks to our latest discovery of an SLC15A4/TASL inhibitor (feeblin), we will assess its IBD therapeutic potential. Methods We will study CAC development in SLC15A4 or TASL deficient mice using the AOM/DSS model, while assessing colitis progression and modulation of the inflammatory response. Next, we will use cell type-specific deletion of SLC15A4 to analyze the immune compartment-specific contribution of SLC15A4 in colitis and CAC. In parallel, we will evaluate IRF5 activation in biopsy samples from IBD patients, and finally, test the SLC15A4/TASL inhibitor feeblin in explants from IBD patients as ex vivo models of disease. Anticipated impact This project will be instrumental in elucidating the relevance of a newly discovered TLR7-9 signaling hub in the pathogenesis of IBD and inflammation-associated colorectal cancer. By uncovering the specific pathway leading to IRF5 activation and downstream inflammatory response in IBD and CAC, this project may identify SLC15A4/TASL as a novel therapeutic target. The proof-of-concept evidence that we will provide could pioneer innovative therapeutic strategies for IBD and CAC.