Medizin 1

Prof. Dr. med. Markus F. Neurath

Nachwuchs - Arbeitsgruppe: MUCOSAL INFECTION BIOLOGY


MLKL-mediated necrosis in the pathogenesis of hepatitis

Although the liver is an organ of remarkable regenerative capacity, cell death related compensatory tissue injury responses commonly culminate in fibrosis and eventually cirrhosis, a major cause of morbidity worldwide. With regard of this vital contribution of hepatocellular death to virtually all hepatic diseases, precise mechanistic knowledge of cell death regulation is essential to understand the pathophysiology of liver diseases. The aim of this project is to investigate the impact of regulated necrosis and in particular the role of mixed lineage kinase domain-like protein (MLKL)-mediated necrosis on the pathogenesis of inflammation-dependent hepatitis.

Impact of the intestinal microbiota and microbiota mediated immune responses on the host cell death machinery in the intestinal epithelium

In healthy individuals, intestinal homeostasis mainly depends on the diverse functions of intestinal epithelial cells, which form a physical barrier to separate the commensal and pathogenic microorganisms from the underlying immune system. In addition, specialized intestinal epithelial cells, such as Paneth cells and Goblet cells provide innate immune functions by secreting mucus and antimicrobial peptides, which hamper access and survival of bacteria directly adjacent to the intestinal epithelium. Given these fundamental and diverse functions of intestinal epithelial cells, it is obvious that proliferation, differentiation and cell death of these cells need to be tightly controlled in order to maintain intestinal homeostasis. The association between increased bacterial translocation and the risk of developing inflammatory bowel diseases (IBD) suggests a central role of intestinal epithelial barrier dysfunction. Previous studies have demonstrated that intestinal barrier dysfunction is strongly associated with a dysregulation of intestinal epithelial cell death. Our own studies already identified a critical role of necroptosis (a novel form of programmed necrotic cell death) in the regulation of intestinal homeostasis. Although our previous studies demonstrated that necroptosis strongly contributes to intestinal inflammation and barrier dysfunction, little is known about the impact of the intestinal microbiota on this particular form of cell death and the effect of epithelial necroptosis on the gut microbiota. The aim of the proposed project is to define the bi-directional cross-talk between the intestinal microbiota and the host cell death machinery under physiological and pathophysiological conditions. The research project addresses the following issues: (1) Contribution of the microbial environment on intestinal inflammation in a mouse model for Crohn´s disease like ileitis and colitis (Casp8∆IEC mice). (2) Impact of the intestinal microbiota on the host cell death machinery. (3) Impact of bacterial driven Stat1-signaling on (a) Paneth cell death, (b) small intestinal inflammation and (c) gastrointestinal infection. (4) Role of microbiota induced immune responses on Paneth cell homeostasis. A better understanding of the host-microbial interaction in the context of establishing and maintaining intestinal barrier function is essential for the development of novel strategies for the management of intestinal inflammatory disorders.

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