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
Affiliations
Won Ho Yang
Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center; La Jolla, CA 92037, USA; Glycosylation Network Research Center and Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; Corresponding author
Peter V. Aziz
Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center; La Jolla, CA 92037, USA
Douglas M. Heithoff
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
Yeolhoe Kim
Glycosylation Network Research Center and Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Jeong Yeon Ko
Glycosylation Network Research Center and Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Jin Won Cho
Glycosylation Network Research Center and Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Michael J. Mahan
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
Markus Sperandio
Walter Brendel Center for Experimental Medicine, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilians University, Munich, Germany
Jamey D. Marth
Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center; La Jolla, CA 92037, USA; Corresponding author
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.
