Defects in microvillus crosslinking sensitize to colitis and inflammatory bowel disease

Author:

Mödl Bernadette1,Awad Monira1,Zwolanek Daniela1ORCID,Scharf Irene1,Schwertner Katharina1ORCID,Milovanovic Danijela2,Moser Doris3,Schmidt Katy4,Pjevac Petra56,Hausmann Bela57,Krauß Dana1ORCID,Mohr Thomas189,Svinka Jasmin1,Kenner Lukas210ORCID,Casanova Emilio11ORCID,Timelthaler Gerald1ORCID,Sibilia Maria1ORCID,Krieger Sigurd2,Eferl Robert1ORCID

Affiliation:

1. Center for Cancer Research Medical University of Vienna & Comprehensive Cancer Center (CCC) Vienna Austria

2. Department of Experimental and Translational Pathology, Institute of Clinical Pathology Medical University of Vienna Vienna Austria

3. Department of Cranio‐Maxillofacial and Oral Surgery Medical University of Vienna Vienna Austria

4. Cell Imaging & Ultrastructure Research University of Vienna Vienna Austria

5. Joint Microbiome Facility of the Medical University of Vienna and the University of Vienna Vienna Austria

6. Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Centre for Microbiology and Environmental Systems Science University of Vienna Vienna Austria

7. Department of Laboratory Medicine Medical University of Vienna Vienna Austria

8. Department of Analytical Chemistry University of Vienna Vienna Austria

9. Joint Metabolome Facility University of Vienna and Medical University Vienna Vienna Austria

10. Department of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

11. Center of Physiology and Pharmacology, Institute of Pharmacology Medical University of Vienna & Comprehensive Cancer Center (CCC) Vienna Austria

Abstract

AbstractIntestinal epithelial cells are covered by the brush border, which consists of densely packed microvilli. The Intermicrovillar Adhesion Complex (IMAC) links the microvilli and is required for proper brush border organization. Whether microvillus crosslinking is involved in the intestinal barrier function or colitis is currently unknown. We investigate the role of microvillus crosslinking in colitis in mice with deletion of the IMAC component CDHR5. Electron microscopy shows pronounced brush border defects in CDHR5‐deficient mice. The defects result in severe mucosal damage after exposure to the colitis‐inducing agent DSS. DSS increases the permeability of the mucus layer and brings bacteria in direct contact with the disorganized brush border of CDHR5‐deficient mice. This correlates with bacterial invasion into the epithelial cell layer which precedes epithelial apoptosis and inflammation. Single‐cell RNA sequencing data of patients with ulcerative colitis reveals downregulation of CDHR5 in enterocytes of diseased areas. Our results provide experimental evidence that a combination of microvillus crosslinking defects with increased permeability of the mucus layer sensitizes to inflammatory bowel disease.

Funder

Austrian Science Fund

European Research Council

Horizon 2020 Framework Programme

Publisher

Springer Science and Business Media LLC

Subject

Genetics,Molecular Biology,Biochemistry

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