Center for Molecular Medicine Cologne

Manolis Pasparakis - B 07

Role of FADD and caspase-8 in the regulation of intestinal epithelial cell death and inflammation

Introduction

Inflammatory bowel diseases (IBD) are chronic relapsing inflammatory disorders of the gastrointestinal tract with increasing incidence over the past 50 years. Despite a wide variety of possible triggers, inappropriate immune responses to the commensal microbiota are generally considered a central underlying theme in IBD. The intestinal epithelium forms a structural barrier between the commensal bacteria residing in the intestinal lumen and the mucosal immune cells and plays a critical role for the maintenance of gut immune homeostasis.

We showed previously that mice lacking FADD in intestinal epithelial cells (FADDIEC-KO) develop chronic ileitis and colitis due to RIPK3-mediated death of IECs. Moreover, mice with IEC-specific knockout of caspase-8 (Casp8IEC‑KO) were reported to develop ileitis but not colitis, suggesting that FADD and caspase-8 may have different functions in the regulation of intestinal epithelial homeostasis and inflammation.

Here we aim to dissect the mechanisms by which FADD and caspase-8 regulate intestinal inflammation using genetic mouse models. The recent discovery that human patients with caspase-8 mutations develop severe intestinal inflammation suggests that the FADD/Casp8-dependent pathways regulating intestinal homeostasis and inflammation are conserved between humans and mice.

Therefore, our project is relevant for the pathogenesis of intestinal inflammation in humans and may lead to the identification of new therapeutic targets for patients with IBD.

Our Aims

  1. Dissect the upstream pathways that regulate the development of colitis and ileitis in FADDIEC-KO and CASP8IEC-KO  mice

  2. Unravel the mechanisms by which FADD or Caspase-8 act in intestinal epithelial cells to regulate immune homeostasis and prevent mucosal inflammation

  3. Study the interplay of FADD/Casp8 with other pathways that are important for the pathogenesis of inflammatory bowel diseases

Previous Work

Impaired epithelial barrier function was reported in IBD patients and their healthy first-degree relatives, identifying epithelial permeability defects as possible causal factors in IBD. Our previous studies in mouse models provided evidence that death of intestinal epithelial cells (IECs) triggers severe chronic intestinal inflammation by disrupting the epithelial barrier.

We showed that mice lacking nuclear factor κB (NF-κB) essential modulator (NEMO, also named IKKγ) specifically in intestinal epithelial cells (IECs) develop chronic inflammatory colitis and ileitis that is induced by FADD/RIPK3-dependent death of IECs and depends on the presence of the intestinal microbiota (Nenci et al., 2007; Vlantis et al., 2016). In addition, we showed previously that mice with IEC-specific FADD deficiency developed severe chronic inflammatory colitis that depended on the presence of the intestinal microbiota and TNF (Welz et al., 2011).

Moreover, FADDIEC-KO mice also developed ileitis with loss of Paneth cells, secretory cells that reside in the intestinal crypt and are believed to have important functions in the regulation of the stem cell niche and the crypt microbiota. Interestingly, when FADDIEC-KO mice were raised under germ-free conditions they did not develop colitis but developed ileitis, suggesting that different mechanisms regulate the inflammatory response in the large and small intestine. Furthermore, TNF deficiency inhibited colitis but did not prevent ileitis also pointing towards a fundamentally different mechanism triggering the disease in the colon and the ileum.

However, RIPK3 deficiency prevented both ileitis and colitis, suggesting that FADD prevents inflammation in both the small and large intestine by preventing epithelial cell necroptosis (Welz et al., 2011).

Project Related Publications

  1. Nenci, A., Becker, C., Wullaert, A., Gareus, R., van Loo, G., Danese, S., Huth, M., Nikolaev, A., Neufert, C., Madison, B., Gumucio, D., Neurath, M.F., and Pasparakis, M. (2007). Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557-561.
  2. Vlantis, K., Wullaert, A., Polykratis, A., Kondylis, V., Dannappel, M., Schwarzer, R., Welz, P., Corona, T., Walczak, H., Weih, F., Klein, U., Kelliher, M., and Pasparakis, M. (2016). NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-kappaB-Dependent and -Independent Functions. Immunity 44, 553-567.
  3. Welz, P.S., Wullaert, A., Vlantis, K., Kondylis, V., Fernandez-Majada, V., Ermolaeva, M., Kirsch, P., Sterner-Kock, A., van Loo, G., and Pasparakis, M. (2011). FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330-334.
Prof. Dr. Manolis Pasparakis CMMC Cologne
Prof. Dr. Manolis Pasparakis

Institute for Genetics / RG location - CECAD Building

Principal Investigator - B 07

+49 221 478 84351

+49 221 478 6360

Institute for Genetics / RG location - CECAD Building

Joseph-Stelzmann-Str. 26

50931 Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications - Manolis Pasparakis

Link to PubMed

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