Projekte

In previous work, we uncovered that mucosal barrier dysfunction caused by regulated necrosis was strongly linked to microbial dysbiosis and chronic intestinal inflammation both in preclinical mouse models and human inflammatory bowel disease (IBD) patients. In the current funding period, we not only identified Interferon (IFN) signaling as a strong inducer of regulated necrosis in the gut, but in collaboration with several TRR241 projects further demonstrated that in the context of Crohn´s disease (CD), TNFα, and IFNs act synergistically to trigger Paneth cell death and barrier dysfunction by Mixed lineage kinase domain-like protein (MLKL)-dependent regulated necrosis (necroptosis). Based on these collaborative results, we proposed a novel model in which regulated necrosis, in genetically predisposed individuals, plays a central role during the onset of inflammation and in general results in the perpetuation of inflammation. Furthermore, we could show that genetic susceptibility alone is sufficient to drive mild inflammation but that environmental factors such as a disease-relevant microbial flora, determine the extent and localization of inflammation in the gut. Our observation that a distinct, not yet identified, population in the mucosal microbiota is able to transcriptionally influence cell death mechanisms in the intestinal epithelium, confirmed the current understanding of IBD, that not only host-dependent mechanisms, but also the microenvironment, are critical factors that can promote immune-mediated inflammation. Preliminary data of the ongoing funding period, further indicate that IFN-induced MLKL-mediated Paneth cell death is controlled by microbiota-dependent and -independent Bile Acid (BA) signaling. Accordingly, we observed an increased BA signaling in the context of small intestinal inflammation (Casp8^ΔIEC mouse model and CD patient cohort) particularly in the terminal ileum, the main location of inflammation in this prototype of IBD. Of note, by taking advantage of a preclinical mouse model for CD (Casp8^ΔIEC model), we uncovered that this effect was strongly dependent on environmental factors, since enhanced BA signaling was absent under germ-free conditions. Supported by this TRR, we further uncovered that primary BAs (1°BAs) trigger epithelial cell, while secondary BAs (2°BAs) negatively regulate Mlkl gene expression and thus might directly inhibit necroptosis. As we found that BA further influence T cell function and elasticity, BA might also indirectly affect inflammatory epithelial cell death.  By taking advantage of the IBDome cohort, we further demonstrated that key signaling molecules of BA homeostasis are differentially expressed between IBD prototypes. These data implicate a mechanistic link between enhanced IFN signaling, microbial dysbiosis and Paneth cell death that is regulated by BA signaling. In the second funding period, we will therefore take advantage of the unique expertise within the TRR 241 to investigate the impact of BA signaling on IFN-mediated cell death and its implication for immune-epithelial communication and inflammation. The long-term vision of this project is to identify how environmental factors shape inflammatory epithelial cell death and barrier dysfunction directly or indirectly via immune cells. We are confident that these studies uncover novel mechanisms that can be targeted for therapeutic approaches.

Further information: https://www.transregio241.de/

Summary: Intestinal inflammation and dysbiosis have been linked to autoimmune diseases such as rheumatoid arthritis (RA), however, the underlying mechanisms remain incompletely understood. During the first funding period, we have shown that dysregulated intestinal epithelial cell death by altered CASP8 or HIF2α protein function affects the gut microbiota and subsequently immune cell functions locally in the gut and in the periphery. On a functional level, we could further uncover that HIF proteins influence tight junction biology and epithelial cell death upstream of caspase-8 with opposing functions in experimental arthritis. Interestingly, we further identified that epithelial necroptosis influences tryptophan metabolism and that supplementation of SCFAs ameliorates intestinal inflammation in CASP8 deficient mice. These data indicate that targeting intestinal epithelial cell death might represent a novel promising therapeutic option particularly during the early phase of arthritis. During the second funding period, we therefore propose to better delineate the link between epithelial hypoxia induced necroptosis, SCFAs and arthritis.

Further information: https://www.pandora.for2886.forschung.fau.de/

This is a collaborative project with the Department of Rheumatology (Prof. Dr. rer. nat. Aline Bozec)

Immune-based therapies and diagnostics have proven their enormous potential in the treatment of immune-mediated inflammatory diseases (IMIDs) such as inflammatory bowel disease (IBD), autoimmune hepatitis (AIH), rheumatoid arthritis (RA), multiple sclerosis (MS) and are currently revolutionizing medical practice across numerous disciplines, allowing for highly individualized therapy approaches. Insights into the underlying molecular disease mechanisms thus become increasingly important for researchers and clinicians alike. Common denominators of such diseases are progressive inflammation-driven tissue damage and consecutive dysfunction of the affected organs. My group has been focusing on how tissue injury and the associated response mechanisms are modulated by the microenvironment with a particular interest on IMIDs of the liver and the gut (Wittkopf & Günther et al., Gastroenterology 2013; Günther et al., Gut 2013; Günther et al., JCI 2016; Bittel et al., Cell Death Dis. 2019). A major strength in this endeavour is represented by our interdisciplinary and translational research approach, spanning the spectrum from basic cellular and molecular methods to pre-clinical models and the validation of our findings in a clinical setting using human material. This strategy has successfully resulted in several major observations with a strong clinical relevance for immune-based therapies and diagnostics.

Further information: https://www.izkf.med.fau.de/nachwuchs/jochen-kalden-foerderprogramm/n5-organ-crosstalks-in-imids-guenther/

Failure of gut homeostasis as a typical feature of inflammatory bowel disease (IBD) is an important factor in the pathogenesis and progression of systemic inflammation, which can culminate in multiple organ involvement and damage. Up to 30% of IBD patients show biochemical signs for liver injury and hepatobiliary diseases such as primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are relatively common in IBD. Enteric dysbiosis and translocation of bacteria across the gut epithelial barrier have been widely recognized as major factors in the progression of chronic liver disease by promoting hepatocellular injury and inflammation. However, the sequence of events and the underlying molecular mechanisms are poorly defined. Recent studies by our group have revealed important functions for programmed necrosis in the pathogenesis of gastrointestinal and hepatic inflammation and implicated that programmed necrosis could be implicated in the pathogenesis of many human inflammatory diseases. The proposed project aims at a multidisciplinary approach to characterize the association between programmed necrosis in the gut and the initiation/progression of hepatic inflammation. This comprehensive project will advance our understanding of mechanisms linking failure of gut homeostasis to hepatic inflammation by replacing the organ centered point of view by an interdisciplinary approach that includes analysis in both affected organs (liver and gut). This will provide the basis for the development of a more efficient and safer therapy for IBD patients with clinical/biochemical indications for hepatobiliary involvement.