Defects in microvillus crosslinking sensitize to colitis and inflammatory bowel disease

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Kenner, Lukas

Abstrakt

Intestinal 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. imageCrosslinking of microvilli in the intestinal brush border mediated by CDHR5 represents an important barrier against invasion of luminal bacteria. A combination of reduced crosslinking with increased mucus layer permeability may sensitize to inflammatory bowel disease.Deletion of CDHR5 leads to microvilli shortening and brush border disorganization in the small and large intestine of mice.CDHR5 protects mice from DSS-induced colitis, but not from hapten-induced T cell-mediated colitis.Microvilli crosslinking prevents entry when the mucus layer becomes permeable and bacteria reach intestinal epithelia.CDHR5 is downregulated in the inflamed epithelium compared to the non-inflamed epithelium of ulcerative colitis patients. Crosslinking of microvilli in the intestinal brush border mediated by CDHR5 represents an important barrier against invasion of luminal bacteria. A combination of reduced crosslinking with increased mucus layer permeability may sensitize to inflammatory bowel disease.image

Dokumententyp

Originalarbeit

Open Access Type

Hybrid

DOI

10.15252/embr.202357084

PubMed ID

MEDLINE:37691494