title: NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion.
abstract: Mucus production by goblet cells of the large intestine serves as a crucial antimicrobial protective mechanism at the interface between the eukaryotic and prokaryotic cells of the mammalian intestinal ecosystem. However, the regulatory pathways involved in goblet cell-induced mucus secretion remain largely unknown. Here, we demonstrate that the NLRP6 inflammasome, a recently described regulator of colonic microbiota composition and biogeographical distribution, is a critical orchestrator of goblet cell mucin granule exocytosis. NLRP6 deficiency leads to defective autophagy in goblet cells and abrogated mucus secretion into the large intestinal lumen. Consequently, NLRP6 inflammasome-deficient mice are unable to clear enteric pathogens from the mucosal surface, rendering them highly susceptible to persistent infection. This study identifies an innate immune regulatory pathway governing goblet cell mucus secretion, linking nonhematopoietic inflammasome signaling to autophagy and highlighting the goblet cell as a critical innate immune player in the control of intestinal host-microbial mutualism. PAPERCLIP:
authors.affiliation: Michael Smith Laboratories, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Marta
authors.initials: M
authors.lastname: Wlodarska
authors.affiliation: Immunology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Thaiss
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Roni
authors.initials: R
authors.lastname: Nowarski
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Henao-Mejia
authors.affiliation: Center on Endocrinology and Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zhang
authors.affiliation: Michael Smith Laboratories, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Brown
authors.affiliation: MRC Center for Molecular Bacteriology and Infection, Department of Life Sciences, Flowers Building, Imperial College, London SW7 2AZ, UK.
authors.forename: Gad
authors.initials: G
authors.lastname: Frankel
authors.affiliation: Immunology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Maayan
authors.initials: M
authors.lastname: Levy
authors.affiliation: Immunology Department, Weizmann Institute of Science, Rehovot 76100, Israel; Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 64239, Israel.
authors.forename: Meirav N
authors.initials: MN
authors.lastname: Katz
authors.affiliation: Center on Endocrinology and Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Philbrick
authors.affiliation: Immunology Department, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: eran.elinav@weizmann.ac.il.
authors.forename: Eran
authors.initials: E
authors.lastname: Elinav
authors.affiliation: Michael Smith Laboratories, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. Electronic address: bfinlay@interchange.ubc.ca.
authors.forename: B Brett
authors.initials: BB
authors.lastname: Finlay
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: richard.flavell@yale.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D001343:Autophagy; D003092:Colitis / Q000276:immunology / Q000382:microbiology; D003106:Colon / Q000276:immunology* / Q000382:microbiology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D020397:Goblet Cells / Q000166:cytology / Q000276:immunology*; D058847:Inflammasomes / Q000276:immunology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009093:Mucus / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology*
chemical_list: D058847:Inflammasomes; C559901:Nod-like receptor pyrin domain-containing protein 6, mouse; D011956:Receptors, Cell Surface