Mechanisms of TL1A-driven Paneth Cell dysfunction in IBD

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PROJECT SUMMARY ABSTRACT Inflammatory bowel diseases (IBD) are chronic relapsing diseases of the gastrointestinal tract believed to be the result of complex interactions between genetic susceptibility and severity genes, the microbial environment, and a dysregulated innate and adaptive immune response against commensal micro-organisms. Paneth cells (PC) are specialized small bowel (SB) epithelial cells that constitutively produce anti-microbial proteins and are important in intestinal homeostasis. Abnormal PC morphology is observed in patients with Crohn’s disease (CD) and in mice with gene deletions in autophagy and unfolded protein response (UPR) pathways. Mice with PC-specific deletions in UPR and autophagy pathways develop early and severe SB inflammation. PC morphologic abnormalities precede onset of ileitis, implicating altered PC biology as central to the pathogenesis and severity of SB CD; yet the cell-extrinsic signals driving these abnormalities are undefined. TNFSF15/(TL1A) is an IBD susceptibility and severity locus and we have previously reported the relationship of a TNFSF15 risk genotype and increased expression of TL1A in peripheral monocytes and in non- inflamed SB CD. In translational studies, we also reported the association between this risk genotype and severe forms of SB CD including fibrostenosis that was phenocopied in mice overexpressing TL1A. We have found a significant association between TL1A and abnormal PC morphology. Commensal microbiota are required in TL1A-overexpressing mice to induce ileal inflammation and in wild type mice to induce normal PC maturation and expansion. We developed a novel stem cell micro-engineered chip model of functional human PC, we showed TL1A directly alters the PC phenotype by inducing diffused and disordered lysozyme granule morphology recapitulating the abnormal PC phenotypes in SB CD with high mucosal expression of TL1A. Evidence that serum levels of IBD-associated anti-bacterial antibodies are elevated in unaffected family members of patients with IBD and also in members of the military prior to clinical evidence of disease suggests defects in the host-bacterial interface precedes onset of IBD. Loss of response to biologics and disease recurrence may represent elimination of a disease driving cytokine but not the underlying process. If pre- inflammatory PC abnormality can be mitigated/prevented by manipulation of TL1A, which, addresses the microbial-host interface, potentially PC function will reset and IBD may be pre-empted in genetically susceptible individuals, and the combination may also prevent loss of response to existing therapeutics or disease recurrence. The foregoing provides a strong rationale for studying the mechanisms of TL1A-driven changes in PC morphology, maturation, and function in promoting SB inflammation, using our novel murine in vivo and human stem cell in vitro systems that allow for parallel investigations to parse out cellular and molecular interactions simultaneously. Our investigations will reveal additional downstream pathways and molecules and potentially targets for combination therapy.