iScience (Oct 2023)

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

Journal volume & issue
Vol. 26, no. 10
p. 107883

Abstract

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Summary: 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.

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