Intestinal-epithelial LSD1 controls goblet cell maturation and effector responses required for gut immunity to bacterial and helminth infection

Naveen Parmar; Kyle Burrows; Pia M Vornewald; Håvard T Lindholm; Rosalie T Zwiggelaar; Alberto Díez-Sánchez; Mara Martín-Alonso; Madeleine Fosslie; Bruce A Vallance; John Arne Dahl; Colby Zaph; Menno J Oudhoff

doi:10.1371/journal.ppat.1009476

Intestinal-epithelial LSD1 controls goblet cell maturation and effector responses required for gut immunity to bacterial and helminth infection

PLoS Pathog. 2021 Mar 31;17(3):e1009476. doi: 10.1371/journal.ppat.1009476. eCollection 2021 Mar.

Authors

Affiliations

¹ CEMIR-Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
² The Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
³ Department of Immunology, University of Toronto, Toronto, Canada.
⁴ Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁵ Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital Research Institute, Vancouver, British Columbia.
⁶ Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.

Abstract

Infectious and inflammatory diseases in the intestine remain a serious threat for patients world-wide. Reprogramming of the intestinal epithelium towards a protective effector state is important to manage inflammation and immunity and can be therapeutically targeted. The role of epigenetic regulatory enzymes within these processes is not yet defined. Here, we use a mouse model that has an intestinal-epithelial specific deletion of the histone demethylase Lsd1 (cKO mice), which maintains the epithelium in a fixed reparative state. Challenge of cKO mice with bacteria-induced colitis or a helminth infection model both resulted in increased pathogenesis. Mechanistically, we discovered that LSD1 is important for goblet cell maturation and goblet-cell effector molecules such as RELMß. We propose that this may be in part mediated by directly controlling genes that facilitate cytoskeletal organization, which is important in goblet cell biology. This study therefore identifies intestinal-epithelial epigenetic regulation by LSD1 as a critical element in host protection from infection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Citrobacter rodentium
Enterobacteriaceae Infections / immunology*
Goblet Cells / immunology*
Goblet Cells / metabolism
Histone Demethylases / immunology*
Histone Demethylases / metabolism
Intestinal Mucosa / immunology
Intestinal Mucosa / metabolism*
Mice
Mice, Knockout
Trichuriasis / immunology*
Trichuris

Substances

Histone Demethylases
KDM1a protein, mouse

Grants and funding

Funding of this work was provided by the Norwegian Research Council (Centre of Excellence grant 223255/F50, and ‘Young Research Talent’ 274760 to MJO) and the Norwegian Cancer Society (182767 to MJO). MMA is the recipient of a Marie Skłodowska-Curie IF (DLV-794391). This work was also supported by the South‐Eastern Norway Regional Health Authority, Early Career Grant 2016058, and the Research Council of Norway “Young Research Talent” grant to JAD. KB is a Banting Fellow. MF is supported by the Norwegian Research Council (grant no. 275286). CZ is supported by the Australian National Health and Medical Research Council (APP1104433 and APP1104466). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.