Innate mechanism of mucosal barrier erosion in the pathogenesis of acquired colitis

Won Ho Yang, Peter V. Aziz, Douglas M. Heithoff, Yeolhoe Kim, Jeong Yeon Ko, Jin Won Cho, Michael J. Mahan, Markus Sperandio, Jamey D. Marth

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Article number107883
JournaliScience
Volume26
Issue number10
DOIs
Publication statusPublished - 2023 Oct 20

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© 2023 The Authors

All Science Journal Classification (ASJC) codes

  • General

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