CD74 Signaling Links Inflammation to Intestinal Epithelial Cell Regeneration and Promotes Mucosal Healing.

Abstract

BACKGROUND & AIMS:

The inflammatory response to intestinal damage promotes healing through mechanisms that are incompletely understood. Gene expression of cluster of differentiation 74 (CD74), the receptor for cytokine macrophage migration inhibitory factor, is increased in patients with inflammatory bowel disease (IBD), however, the role of CD74 signaling in intestinal inflammation remains poorly understood. The aim of this study was to determine the functional role of CD74 signaling in intestinal inflammation.

METHODS:

We studied the characteristics of CD74 protein expression in human IBD and experimental colitis. The functional role of CD74 signaling in the intestine was investigated using cellular models; wild-type, CD74-/-, and bone marrow chimera mice; neutralizing anti-CD74 antibodies; flow cytometry; immunohistochemistry; immunofluorescence; immunoblotting; and clustered regularly interspaced short palindromic repeats and associated protein 9 technology.

RESULTS:

In IBD patients and experimental colitis, CD74-receptor protein expression was increased in inflamed intestinal tissue, prominently in the crypt epithelial cells. By using distinct but complementary chemical and non-chemically induced mouse models of colitis with genetic and antibody neutralization approaches, we found that CD74 signaling was necessary for gut repair. Mechanistically, we found that the macrophage migration inhibitory factor cytokine, which also is increased in colitis, stimulated the CD74 receptor, enhancing intestinal epithelial cell proliferation through activation of the protein kinase B and the extracellular signal-regulated kinase pathways. Our data also suggest that CD74 signaling in immune cells was not essential for mucosal healing.

CONCLUSIONS:

CD74 signaling is strongly activated during intestinal inflammation and protects the host by promoting epithelial cell regeneration, healing, and maintaining mucosal barrier integrity. Enhancing the CD74 pathway may represent a unique therapeutic strategy for promoting healing in IBD.

• Authors: Laura Farr, Swagata Ghosh, Nona Jiang, Koji Watanabe, Mahmut Parlak, Richard Bucala, Shannon Moonah
• Journal: Cellular and molecular gastroenterology and hepatology (Cell Mol Gastroenterol Hepatol) Vol. 10 Issue 1 Pg. 101-112 ( 2020) ISSN: 2352-345X [Electronic] United States
• PMID: 32004754 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Differentiation, B-Lymphocyte
• Histocompatibility Antigens Class II
• Macrophage Migration-Inhibitory Factors
• invariant chain
• Intramolecular Oxidoreductases
• MIF protein, human
• Mif protein, mouse

Topics

• Animals
• Antigens, Differentiation, B-Lymphocyte (genetics, metabolism)
• Biopsy
• Bone Marrow Transplantation
• Cell Line, Tumor
• Colitis, Ulcerative (genetics, immunology, parasitology, pathology)
• Crohn Disease (immunology, pathology)
• Datasets as Topic
• Disease Models, Animal
• Entamoeba histolytica (pathogenicity)
• Epithelial Cells (immunology, pathology)
• Gene Expression Profiling
• Histocompatibility Antigens Class II (genetics, metabolism)
• Humans
• Intestinal Mucosa (cytology, immunology, pathology)
• Intramolecular Oxidoreductases (metabolism)
• Macrophage Migration-Inhibitory Factors (metabolism)
• Mice
• Mice, Knockout
• Permeability
• Primary Cell Culture
• Regeneration (immunology)
• Signal Transduction (genetics, immunology)
• Transplantation Chimera