Group Müller

Our group has a longstanding interest in the complex immunoregulatory mechanisms that are operative in the intestinal mucosa during homeostasis, and in the potential events leading to disruption of these mutualistic interactions between host and microbiome during inflammatory conditions as typically seen  in inflammatory bowel diseases (Crohn's disease, ulcerative colitis). The importance of the intestinal microflora in shaping the differentiation of the local immune system, but also on 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 the associated metabolic changes. While we often use experimental mouse models to test our hypotheses, we also validate these experimental findings using state-of-the-art technologies with patient materials obtained from the SIBDCS biobank.

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

Functional changes in local T cells during onset vs. remission vs. relapse of colitis

Group Müller Understanding the mechanisms that drive remission and relapsing of intestinal inflammation is a prerequisite for treating patients with inflammatory bowel diseases. We have recently established a reversible, relapsing-remitting mouse model of colitis with reproducible onset of intestinal inflammation, induction of remission and repeated flares of inflammation (Brasseit et al., Mucosal Immunol 2016). In this model we 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 a further relapse of disease.

In the healthy intestine, luminal bacteria are separated by a mucus layer (green) from the 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 monocytes/macrophages. We previously described a critical pathogenic role for TREM-1 not only in acute, but also in chronic inflammation, notably, in inflammatory bowel diseases (Schenk et al., J Immunol 2005, J Clin Invest 2007). We generated a Trem1-/- mouse (Weber et al. PLoS Pathog 2014) to determine the Trem1 mediated effects in 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, such as stroke (Liu et al., Nat Immunol 2019), neurodegenerative disorders, and in infections with intracellular pathogens such as Listeria monocytogenes.

TREM-1-activation on monocytes leads to an enhanced lipid uptake (red droplets) when cultured in the presence of 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 Understanding the functions and the regulation of intestinal T cell subsets is one of our long-standing research objectives. Some of these T cells in the intestine represent the prototypical example of tissue-resident T cells due to their resident location at a barrier site, and their limited capacity to recirculate. Currently, we investigate the regulation of intestinal resident T cells in the protective immunity against pathogens (e.g. infection with Listeria monocytogenes), but also their contribution to the development of chronic inflammatory disorders. In particular, we investigate the molecular mechanisms that regulate their tissue-resident phenotype, and assess how distinct functional activities of this T cell subset may either result in protective immunity, or inflammatory pathologies.

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

News

Dr. Lutz Zwillenberg-Preis 2017

At the 183rd Dies Academicus of the University of Bern the Dr. Lutz Zwillenberg Prize for an outstanding publication or PhD thesis in Biological Sciences was awarded to Daniel Zysset, PhD, for his work “TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis”.

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