Toll-like Receptors in the Intestinal Epithelium: Receptors of Survival or Death or Both?

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The intestinal epithelium serves as an essential defensive barrier of the mucosal immune system that forms a bipolar interface between the diverse populations of microbes of the lumen and subjacent immune cells present in the lamina propria. Intestinal epithelial cells (IEC) express Toll-like receptors (TLR) as pattern recognition receptors at their apical pole - poised to recognize microbial "pathogen-associated molecular patterns" (PAMPs) as "non-self" and to rapidly initiate innate immune responses. Lumenal PAMPs play a central role in initiation and perpetuation of inflammatory bowel disease (IBD). Recent studies have demonstrated that intestinal epithelial TLR expression is differentially altered in IBD. However, so far, very little is known, about the complex recognition mechanisms and functional immune consequences of TLRs through which the intestinal epithelium constantly interacts with PAMPs. Parallel activation of intestinal epithelial pro- and anti-apoptosis reflects an essential mechanism of mucosal immune defense which appears to be severely imbalanced in IBD. It remains elusive whether PAMP-induced activation of TLRs may mediate apoptosis in IEC. Thus, the aim of this research project is to characterize the potential checkpoint function of TLRs and interacting signaling cascades under physiological and pathophysiological conditions - distinctly triggering either pro- or anti-apoptosis in IEC in response to specific PAMPs in vitro and in vivo. Long-term goal is to comprehend the pathogenetic role of intestinal epithelial TLR dysregulation in IBD and to develop new therapeutic strategies of modulation of immune dysfunction.