Group Müller

Our group has a longstanding interest in the complex immunoregulatory mechanisms that are operative in the intestinal mucosa during homeostatic conditions and the potential predispositions or events which can lead to disruption of tissue homeostasis during inflammatory conditions as in the case of inflammatory bowel diseases (Crohn's disease, Ulcerative colitis). In recent years, the importance of the intestinal microflora in shaping the education of the local immune system, but also the reciprocal effects of local immune responses on the composition of the intestinal microflora have become increasingly acknowledged. Thus, we aim to link the molecular and cellular characterization of distinct immune cell subsets in the intestinal mucosa and their phenotypical and functional alterations during intestinal inflammation with concurrent analyses of the intestinal microflora and any associated metabolic changes. Since microbial-driven immune responses can predispose for development of tumors or even cardiovascular diseases, we have recently extended our research to other chronic inflammatory disorders (colorectal tumors and atherosclerosis). While we often use experimental mouse models to test our hypotheses, whenever possible, we validate these experimental findings using state-of-the-art technologies with patient materials, mostly archived tissue samples or biosamples obtained from the SIBDCS biobank (Head: Christoph Mueller).

Specific research interests

The research interests of our research group are currently focused on:

  • The molecular and cellular events that are operative during induction and resolution of chronic intestinal inflammation
  • The functional plasticity of tissue-resident T cell subsets, notably in the intestinal mucosa
  • The contribution of distinct monocyte / macrophage subsets in immunosurveillance of tumors but also in the induction of chronic inflammatory disorders such as inflammatory bowel diseases or atherosclerosis.

Current research projects

Changes in local immune cells during onset vs. remission of colitis

Group Müller Understanding the mechanisms that drive remission induction and maintenance in the intestine is critical for a rational treatment of patients with inflammatory bowel diseases. We have recently established a reversible, relapsing-remitting mouse model of colitis with reproducible onset of colitis and induced remission (Brasseit et al., Mucosal Immunol 2016). In this model we will monitor the composition of the intestinal microbiota during relapsing – remitting colitis and define its consequences on the metabolic profile in the feces and the host. Furthermore, we investigate how these changes influence the host immune response and vice versa. An ultimate goal is to identify strategies to specifically extend the remission period, or even prevent further relapses of the disease.

In the healthy intestine, luminal bacteria are separated by a mucus layer (green) from the intestinal epithelium (blue), containing mucus-secreting goblet cells (green) and the lamina propria, containing numerous immune cells

TREM-1 as an amplifier of inflammation in immunosurveillance and immunopathologies

Group Müller TREM-1 (Triggering Receptor Expressed on Myeloid Cells-1) is an activating innate immune receptor on neutrophils and subsets of monocytes / macrophages. We previously described a critical pathogenic role for TREM-1 in acute inflammation, and also during chronic inflammation such as in inflammatory bowel diseases (Schenk et al., J Immunol 2005, J Clin Invest 2007). We further generated a Trem1-/- mouse (Weber et al. PLoS Pathog 2014) and investigated the consequences of TREM-1-activation on the pathogenesis of atherosclerosis (Zysset et al., Nat Comms 2016) and on the development of colitis-associated colorectal carcinoma (Saurer and Zysset et al., Sci Rep 2017). Current research interests include the involvement of TREM-1 in neurological disorders and in infections with intracellular pathogens.

TREM-1-activation on monocytes leads to an enhanced lipid uptake (red droplets) when cultured in the presence of 5% dyslipidemic serum from ApoE-/- mice, maintained on a high fat/high cholesterol diet

Functional plasticity and retention of tissue-resident TRM cells in the intestinal mucosa

Group Müller Our group has a longstanding interest in the functions of intestinal T cells which comprise a heterogenous population of conventional and unconventional T cells. Some intestinal T cell subsets represent the prototypical example of tissue-resident T cells due to their resident location at a barrier site, their abundance, and their limited capacity to recirculate. Currently, we mainly focus on the regulation of intestinal resident T cells in protective immunity during infectious diseases (e.g. infection with Listeria monocytogenes), but also on their contribution to the development of  chronic inflammatory disorders. In particular, we investigate the molecular mechanisms that regulate their tissue-resident phenotype, notably, their retention in the intestinal mucosa, and assess how functional activities of this T cell subset may contribute to protective immunity versus inflammatory or even immunopathological conditions.

Intestinal tissue resident T cells show a unique molecular signature which is distinct from the core transcriptome in their circulating counterparts