The driving hypothesis of our research center is that a dysregulated signal exchange between the intestinal epithelium and local immune cells contribute to the pathogenesis of inflammatory bowel disease (IBD). We are confident that our specialized and multi-modal approaches to investigate these processes will give rise to unique and innovative strategies to counter IBD.
Our recent research discovered unexpected mechanisms by which immune cells and cytokines regulate epithelial cell functions, such as cell survival and cell death programs (e.g. Günther et al., Nature 2011; Nenci et al., Nature 2007; Becker et al., Immunity 2006), epithelial cell differentiation from progenitor cells (e.g. Mahapatro et al., Cell Rep 2016) and antimicrobial defence (e.g. Hernandez et al., Nature Immunol 2015; Vonarbourg et al., Immunity 2010; Pickert et al., J Exp Med 2009). Likewise, our research led to the discovery of mechanisms by which epithelial cell functions or dysfunctions regulate immune cell functions, such as recruitment to the gut (e.g. Fischer et al., Gut 2015), activation and effector functions (e.g. Herrtwich et al., Cell 2016; Bacher et al., Cell 2016) and inflammation (e.g. Lopez-Posadas et al., J Clin Invest 2016; Takahashi et al., Nature 2014; Krug et al., Mol Biol Cell 2009).
In conclusion, it is becoming increasingly clear that the intestinal epithelium is much more than a physical barrier, but rather habors innate immune functions and even educates the mucosal immune system, orchestrates and adapts efficient immune responses and directs the recruitment of immune cells via chemokine and cytokine release. Vice versa intestinal epithelial cells (IEC) express numerous receptors for cytokines or other immune molecules which render them responsive to immune cell signals, which thereby regulate epithelial cell homeostasis as well as anti-microbial defense at the gut barrier. Thus there is a constant signal exchange between the IECs and the underlying immune system. Studies from our consortium moreover demonstrate that tissue cells such as endothelial cells, cells of the enteric nervous system and mesenteric fat are tightly integrated into these pathways and regulate inflammation and intestinal barrier function.
These recent discoveries have led to novel pathophysiological concepts highlighting the significance of immune-epithelial crosstalk in IBD development. However, substantial efforts will have to be made in order to gain a more comprehensive understanding of immune-epithelial interactions in IBD. We conclude that an integrating research approach is necessary to advance our current understanding of IBD development. We hypothesize that the nature as well as the temporal and spatial regulation of immune-epithelial communication determine the pathogenesis of IBD.
To further consolidate our hypothesis and the concept of immune-epithelial crosstalk in IBD, we have identified a number of currently unmet research needs:
1) to identify and characterize key mechanisms of immune-epithelial interaction in IBD
2) to better define the temporal and spatial regulation of these pathways in IBD
3) to understand their integration with IBD-relevant tissue cells
4) to evaluate their functional impact on IBD and their therapeutic potential
Given these unmet research needs, the unifying aim of TRR241 is to better understand the basis of bidirectional signal exchange between the intestinal epithelium and the underlying immune system and to evaluate its significance in IBD.