Agr2-associated ER stress promotes adherent-invasive E. coli dysbiosis and triggers CD103+ dendritic cell IL-23-dependent ileocolitis

Monica Viladomiu; Manirath Khounlotham; Belgin Dogan; Svetlana F Lima; Ahmed Elsaadi; Emre Cardakli; Jim G Castellanos; Charles Ng; Jeremy Herzog; Alexi A Schoenborn; Melissa Ellermann; Bo Liu; Shiying Zhang; Ajay S Gulati; R Balfour Sartor; Kenneth W Simpson; Steven M Lipkin; Randy S Longman

doi:10.1016/j.celrep.2022.111637

Agr2-associated ER stress promotes adherent-invasive E. coli dysbiosis and triggers CD103⁺ dendritic cell IL-23-dependent ileocolitis

Cell Rep. 2022 Nov 15;41(7):111637. doi: 10.1016/j.celrep.2022.111637.

Authors

Monica Viladomiu¹, Manirath Khounlotham¹, Belgin Dogan², Svetlana F Lima¹, Ahmed Elsaadi¹, Emre Cardakli¹, Jim G Castellanos¹, Charles Ng³, Jeremy Herzog⁴, Alexi A Schoenborn⁵, Melissa Ellermann⁴, Bo Liu⁴, Shiying Zhang², Ajay S Gulati⁵, R Balfour Sartor⁴, Kenneth W Simpson⁶, Steven M Lipkin⁷, Randy S Longman⁸

Affiliations

¹ Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA.
² College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
³ Department of Pathology, Weill Cornell Medicine, New York, NY 10021, USA.
⁴ Departments of Medicine and Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Department of Pediatrics, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA; College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
⁷ Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: stl2012@med.cornell.edu.
⁸ Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA; Jill Roberts Center for IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: ral2006@med.cornell.edu.

Abstract

Endoplasmic reticulum (ER) stress is associated with Crohn's disease (CD), but its impact on host-microbe interaction in disease pathogenesis is not well defined. Functional deficiency in the protein disulfide isomerase anterior gradient 2 (AGR2) has been linked with CD and leads to epithelial cell ER stress and ileocolitis in mice and humans. Here, we show that ileal expression of AGR2 correlates with mucosal Enterobactericeae abundance in human inflammatory bowel disease (IBD) and that Agr2 deletion leads to ER-stress-dependent expansion of mucosal-associated adherent-invasive Escherichia coli (AIEC), which drives Th17 cell ileocolitis in mice. Mechanistically, our data reveal that AIEC-induced epithelial cell ER stress triggers CD103⁺ dendritic cell production of interleukin-23 (IL-23) and that IL-23R is required for ileocolitis in Agr2^-/- mice. Overall, these data reveal a specific and reciprocal interaction of the expansion of the CD pathobiont AIEC with ER-stress-associated ileocolitis and highlight a distinct cellular mechanism for IL-23-dependent ileocolitis.

Keywords: AIEC; Agr2; CP: Immunology; CP: Microbiology; ER stress; IL-23; Th17; ileitis.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Crohn Disease* / genetics
Crohn Disease* / microbiology
Dendritic Cells
Dysbiosis*
Escherichia coli
Escherichia coli Infections*
Humans
Interleukin-23
Mice
Mucoproteins* / genetics
Oncogene Proteins

Substances

Interleukin-23
Mucoproteins
Oncogene Proteins
Agr2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding