Project Area A (Immune Regulation of Intestinal Barrier Functions)
It is well recognized that innate and adaptive immunity are inappropriately activated in inflammatory bowel diseases (IBD) and promote tissue destruction. Innate mechanisms protecting intestinal epithelial cells have been recently identified but are less well understood. We will dissect the mechanisms leading to IL-22-mediated epithelial protection, granuloma formation and granuloma-mediated epithelial barrier repair program in the context of IBD. These studies may lead us to identify innate immune targets for the treatment of IBD.
(Prof. Dr. Andreas Diefenbach & Dr. Antigoni Triantafyllopoulou)
Despite the fact that interferons (IFNs) act at mucosal surfaces, limited knowledge is available on the molecular mechanism of their mucosal functions. Our unpublished data suggest a major contribution of IFN-induced programmed necrosis to the pathogenesis of intestinal inflammation. Accordingly, IFNs promote non-apoptotic epithelial cell death, upregulation of mixed lineage kinase domain-like protein and loss of immune homeostasis. The central question of this project is if and by which pathways epithelial IFN-regulated necrosis contributes to intestinal inflammation. We aim to discover novel functions of IFNs in immune-epithelial communication that could be targeted for future therapeutic intervention.
(PD Dr. Claudia Günther)
Central mediators of prototypical type 2 responses such as IL-33 are upregulated in the mucosa of patients with IBD, but how type 2 responses may drive pathological features of IBD or vitally contribute to the protective tissue response to damage still remains ill-defined. In this proposal, we aim to comprehensively address, how IL-33 production and signaling controls mutual interactions between the immune, stromal and epithelial cell compartments in vitro and in vivo. These insights together with the analysis of large cohorts of IBD patients and their stratification will be used to predict, whether targeting of type 2 molecules may be a strategy for personalized medicine in IBD.
(Prof. Dr. Christoph Becker & PD Dr. Stefan Wirtz)
Intestinal epithelial cell (IEC) homeostasis during IBD can be facilitated by increased expression of cytokines, such as tumor necrosis factor-α (TNF-α), and by toll-like receptor (TLR) ligands derived from microbiota. However, the mechanisms of immune system-mediated tissue repair in IBD remain elusive. We have previously found that anti-TNF-α therapy induced IEC restitution is mediated by IL 22-driven IEC proliferation. Next, we revealed that antibiotic-induced changes in microbiota distinctly contributed to the restoration of the epithelial barrier via a TLR4-dependent mechanism. Thus, we aim to dissect the significance of the microbiota-TLR4-TNFα axis for IEC layer restoration during IBD.
(Dr. Andrey Kruglov)
Oncostatin M (OSM) is a highly expressed cytokine in IBD and high pretreatment expression is strongly associated with failure of anti-TNF-a therapy. OSM promotes intestinal inflammatory pathology and genetic deletion or pharmacological blockade of OSM significantly attenuates colitis in mice. Our hypothesis is that OSM acts as an inflammatory amplifier and driver of disease chronicity by impacting on both stromal and epithelial cells. We believe that a better understanding of OSM-OSMR pathway in intestinal biology could facilitate the development of novel therapeutic strategies targeting this pathway in IBD.
(Prof. Dr. Ahmed N. Hegazy)
The intestinal vascular system exerts a critical barrier function during inflammatory bowel diseases (IBD). IFN-gamma is an important pathogenesis factor in IBD with potent vascular-directed activities. The principal aim of the project is to elucidate the molecular mechanisms by which the activation of vascular endothelial cells by IFN-gamma impairs vascular barrier functions and disturbs the immune – epithelial cell crosstalk in the course of IBD pathogenesis. On the long term, we aim to identify novel molecular mechanisms of IFN-gamma-induced gut-vascular barrier dysfunction, which may be exploited as new targets of therapy in IBD.
(Prof. Dr. Michael Stürzl & PD Dr. Natalie Britzen-Laurent)
Our project aims on an improved understanding of the regulation of prenylation within intestinal epithelial cells (IECs) and its function in epithelial integrity in the context of inflammatory bowel diseases (IBD). We will investigate molecular mechanisms regulating epithelial prenylation in order to experimentally validate our key hypothesis that the inflammation-dependent alteration of prenylation in IECs is regulated via IEC-intrinsic (prenyltransferase activity and availability of isoprenoids), but also via IEC-extrinsic mechanisms (immune cell- or microbiota-derived mediators). Finally, we intend to translate our findings in innovative biomarker and therapy strategies in IBD.
(Dr. Imke Atreya & Dr. Rocío López-Posadas)
Induced intra-epithelial lymphocytes (iIELs) are widely distributed within the intestinal epithelial cell (IEC) layer. However, differentiation and function of iIELs in healthy individuals and their role within the pathogenesis of inflammatory bowel diseases (IBD) await to be fully elucidated. We found that selected deficiencies within the conventional DC (cDC1) compartment result in distinct iIEL pool alterations. Hence, employing cDC1-targeted mice as iIEL deficiency model systems we seek to study the molecular mechanisms and functional consequences of the iIEL-IEC crosstalk during intestinal homeostasis and inflammation.
(Prof. Dr. Kai Hildner & PD Dr. Clemens Neufert)
Project Area B (Epithelium as Modifier of Mucosal Immunity and Inflammation)
Creeping fat represents a disease characterizing finding in Crohn’s disease but its impact on intestinal inflammation and epithelial barrier function is unknown. The present project aims to define how intestinal barrier defects shape the homeostasis of mesenteric fat, how these alterations confer to an alternative intestinal barrier and how creeping fat modulates epithelial resistance as well as intestinal immune cell composition and immunity. A fat-depleting mouse model will serve to answer these questions and the data will subsequently be correlated to results obtained from a Crohn’s disease patient cohort.
(Dr. Carl Weidinger & Prof. Dr. Britta Siegmund)
Innate lymphoid cells (ILCs) are major regulator of intestinal epithelial cell (IEC) homeostasis and play a dual role in intestinal inflammation. However the mechanisms underlying this phenomenon remain unclear. We postulate that distinct IEC signals can shape ILC effector functions, thereby differentially impacting on epithelium responses and intestinal inflammation. Central focus of this project will be the characterization of signals governing the ILC-IEC crosstalk during homeostasis and inflammation. Identification and manipulation of such pathways will be used to promote IEC regeneration and protective functions, while dampening pathogenic circuits involved in inflammatory bowel disease.
(Prof. Dr. Chiara Romagnani)
The intestinal microbiota can determine functional differentiation of mucosal T helper (Th) cells, licensing them to promote or protect from intestinal inflammation. The central aim of this project is to determine the molecular crosstalk between distinct pro- and anti-inflammatory bacteria of the microbiota and the mucosal Th cells, and the role the intestinal epithelial cells (IEC) play in this. We will identify the bacteria licensing T-bet-deficient Th cells to induce colitis and determine how these bacteria affect the IEC barrier. Furthermore, we will determine how bacteria of the genus Anaeroplasma pass or affect the IEC barrier, induce TGF-β in mucosal Th cells and potentially ameliorate colitis.
(Dr. Hyun-Dong Chang & Prof. Dr. Andreas Radbruch)
Neutrophil extracellular traps (NETs) instigate plasmatic coagulation and form emergency barriers on mucosal wounds with antimicrobial, yet also strong cytotoxic properties. We now identified that NETs take part in guiding mucosal healing responses. Restituting epithelia protect themselves from NET-borne cytotoxic mediators. We will focus on these protective mechanisms used by specialized epithelial cells and envision future therapies directed at NET-epithelial imbalances to support mucosal healing in patients suffering from IBD.
(Prof. Dr. Martin Herrmann & Dr. Moritz Leppkes)
Recent data suggests an emerging role for peptidergic neurons in the pathogenesis of intestinal inflammation. Neuropeptide release is controlled by transient receptor potential (TRP) channels. Own data suggest a previously unknown role of extra-neuronal TRP channel expression in intestinal immune and epithelial cells as well, indicating a complex neuro-immune-epithelial signaling network in the gut. The central topic of this project is to understand how enteric neurons via secretion of neuropeptides orchestrate intestinal homeostasis and how TRP activation regulates intestinal mucosal immunity and epithelial cell function in addition.
(PD Dr. Matthias Engel)
Impairment of the tight junction (TJ) is linked to enhanced luminal antigen uptake supporting inflammatory processes in IBD. We hypothesize that especially the tricellular tight junction (tTJ) is crucially involved in this and in immune cell activation. Thus, we will analyze effects and interactions between the (t)TJ and the immune cells beyond during development of intestinal inflammation. Elucidation of regulatory pathways beyond will identify possible targets of intervention, which then will be used for strategies stabilizing the (t)TJ barrier preventing antigen entry and perpetuation of inflammation in order to protect against development of IBD.
(PD Dr. Susanne M. Krug & Prof. Dr. Jörg-Dieter Schulzke)
Foxp3+ regulatory T cells (Tregs) are key players for the maintenance of tolerance against self and harmless exogenous antigens, such as the intestinal microbiota. Microbiota-specific Tregs therefore represent powerful targets for novel and specific therapies in inflammatory bowel disease (IBD). We have developed technologies to identify and characterize human microbiota-specific Tregs. We will screen for important Treg targets, isolate and expand Tregs with relevant specificities and analyze their functional characteristics as a basis for development of tailor-made Treg for IBD therapy.
(Prof. Dr. Alexander Scheffold)
Project Area C (Diagnostics and Therapeutic Intervention)
Advanced label-free optical technologies such as multiphoton microscopy and Raman spectroscopy hold great potential for a characterization of mucosal inflammation in vivo. Using these approaches, we will evaluate optical properties of epithelial barrier function and dysfunction as well as consequences of epithelial barrier defects including immune cell infiltration and bacterial translocation in preclinical colitis models ex vivo and in vivo. Based on these studies, project C01 will further develop advanced optical technologies for the in vivo evaluation of mucosal inflammation in human IBD.
(Prof. Dr. Maximilian Waldner & Dr. Sebastian Schürmann)
We will test clinically approved antibodies targeting cytokine signaling or integrin-based homing of immune cells in the gut for their potential to allow endoscopic molecular in vivo imaging in ulcerative colitis patients. The GMP conform fluorescent antibodies will be applied to the inflamed mucosa of ulcerative colitis patients during endoscopic confocal laser endomicroscopy to decipher the molecular signature driving mucosal inflammation in individual patients. Such in vivo mapping of relevant inflammatory signaling pathways may allow the selection of the ideally suited neutralizing antibody for subsequent therapy and will thus open new avenues for personalized medicine in ulcerative colitis.
(Prof. Dr. Raja Atreya & PD Dr. Christan Bojarski)
A clinical phase-III-study was designed to test tDCS (transcranial direct current stimulation) on its analgesic effects in IBD-patients with chronic abdominal pain. fMRI scans will be performed in these patients in order to investigate changes in the central nervous system. Based on preliminary data we propose a brain – gut interaction. This will be evaluated by analyzing the effects of tDCS on the intestinal epithelial barrier. To reveal the mechanisms involved, we included a murine model of intestinal inflammation-associated pain where the effects of tDCS on the enteric nervous system, intestinal barrier, neurotransmitters as well as perineural immune cells will be investigated.
(Dr. Magdalena Prüß Dr. Michael Schumann & Prof. Dr. Raja Atreya)
Adoptive transfer of regulatory T cells (Treg) has successfully been used for blockade of experimental colitis in vivo, but their usage for treatment of patients with ulcerative colitis (UC) remains poorly studied. Gut homing and effects on the gut epithelium of these Treg are detrimental to suppress gut-specific inflammation. In this project, we will further define the molecular mechanisms of mucosal trafficking and retention of Treg in UC. We will combine the clinical assessment of our current GMP-approved Treg in a phase II clinical trial with in depth studies on their gut-homing potential. These studies will result in further refinement of the current GMP-approved Treg product in future studies.
(Dr. Caroline Bosch-Voskens & Prof. Dr. Markus F. Neurath)
Project Area Z (Administration and Management)
The IBDome project will develop a web-accessible database that integrates large-scale omic-datasets from IBD patients with corresponding clinical disease status. The database will include two types of data: 1) data from deep profiling using cutting-edge technologies on a specified exemplary patient cohort including controls provided by four preselected projects of the consortium, and 2) data from broad profiling of a large number of samples from the existing tissue banks in Erlangen and Berlin.
(Prof. Dr. Raja Atreya & Prof. Dr. Zlatko Trajanoski & PD Dr. Anja A. Kühl)
The structured educational program provided by the iRTG will qualify the PhD researchers of the TRR 241 for a future scientific career at the interface between clinical and biological research.
(Dr. Imke Atreya & Prof. Dr. Chiara Romagnani)
The Project will cover all administrative tasks of the TRR241.
(Prof. Dr. Christoph Becker & Prof. Dr. Britta Siegmund)