Innate mechanism of mucosal barrier erosion in the pathogenesis of acquired colitis.
iScience
; 26(10): 107883, 2023 Oct 20.
Article
in En
| MEDLINE
| ID: mdl-37752945
ABSTRACT
The colonic mucosal barrier protects against infection, inflammation, and tissue ulceration. Composed primarily of Mucin-2, proteolytic erosion of this barrier is an invariant feature of colitis; however, the molecular mechanisms are not well understood. We have applied a recurrent food poisoning model of acquired inflammatory bowel disease using Salmonella enterica Typhimurium to investigate mucosal barrier erosion. Our findings reveal an innate Toll-like receptor 4-dependent mechanism activated by previous infection that induces Neu3 neuraminidase among colonic epithelial cells concurrent with increased Cathepsin-G protease secretion by Paneth cells. These anatomically separated host responses merge with the desialylation of nascent colonic Mucin-2 by Neu3 rendering the mucosal barrier susceptible to increased proteolytic breakdown by Cathepsin-G. Depletion of Cathepsin-G or Neu3 function using pharmacological inhibitors or genetic-null alleles protected against Mucin-2 proteolysis and barrier erosion and reduced the frequency and severity of colitis, revealing approaches to preserve and potentially restore the mucosal barrier.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Etiology_studies
/
Prognostic_studies
Language:
En
Journal:
IScience
Year:
2023
Document type:
Article
Affiliation country:
United States