Inflammasome activation links enteric Salmonella Typhimurium infection to a rapid, cytokine-dependent increase in intestinal mucin release
Xiao Han,
Joannie M. Allaire,
Shauna M. Crowley,
Jocelyn J. Chan,
Kelly Lau,
Conghao Zhang,
Simon A. Hirota,
Kirk Bergstrom,
Leigh A. Knodler,
Bruce A. Vallance
Affiliations
Xiao Han
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada
Joannie M. Allaire
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada
Shauna M. Crowley
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada
Jocelyn J. Chan
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada
Kelly Lau
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada
Conghao Zhang
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada
Simon A. Hirota
Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
Kirk Bergstrom
Department of Biology, University of British Columbia, Kelowna, British Columbia, Canada
Leigh A. Knodler
Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, VT, USA
Bruce A. Vallance
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada
The host restricts Salmonella enterica serovar Typhimurium infection of the gut via inflammasome-dependent sloughing of infected epithelial cells. Here we determined that concurrent caspase 1/11-dependent release of the goblet cell-derived mucin, Muc2, into the intestinal lumen also controls Salmonella burdens in infected mice. The increased release of mucins from goblet cells in the cecum and nearby proximal colon, and the subsequent thickening of the protective mucus barrier layer in the distal colon, were all dependent on the cytokines interleukin (IL)-18 and IL-22, as deficiencies in either cytokine resulted in reduced mucin secretion. Supplementation of IL-18 into IL-22 deficient mice restored mucin secretion, indicating that IL-22 acted upstream of IL-18 secretion during infection. In contrast, IL-18 and IL-22 independent signaling through Nlrp6 underlies only a modest, infection-induced increase in mucin secretion from goblet cells in the distal colon. These findings reveal that inflammasome signaling orchestrates multiple levels of protection centered on the intestinal epithelium, including pyroptosis and expulsion of infected enterocytes, as well as the release of mucins by goblet cells in the cecum and along the length of the colon. Our studies underscore the pivotal, multi-faceted role of inflammasome signaling in promoting host defense at the intestinal mucosal surface.
