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

Abstract

In this study, we uncovered a mechanistic link between intestinal inflammation and repair. We showed that cluster of differentiation 74 signaling is strongly activated during intestinal inflammation, and promotes mucosal healing by enhancing intestinal epithelial cell proliferation by activating the protein kinase B and extracellular signal-regulated kinase pathways. 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, CD74receptor 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.

Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair

“…At the cellular level, MIF stimulation of CD74 on intestinal epithelial cells increased cell proliferation and wound closure, an effect that was lost in CD74-deficient cells. Mechanistically, MIF, which also is increased in colitis, stimulated the CD74 receptor, activating proproliferative Akt and ERK pathways (58). So while dispensable in steady state conditions, CD74 appears to be necessary for reparative inflammation.…”

“…CD74 gene expression is increased in patients with IBD (56,57), which occurs in the inflamed areas compared with noninflamed and healthy intestine (Figure 2). CD74 overexpression was most noticeable in proliferating crypt epithelial cells of patients with IBD and amebic colitis, a condition often misdiagnosed as IBD (58,59). CD74 is almost undetectable in the epithelium of non-inflamed human and mice intestine when analyzed by immunohistochemistry (58,60,61).…”

“…CD74 overexpression was most noticeable in proliferating crypt epithelial cells of patients with IBD and amebic colitis, a condition often misdiagnosed as IBD (58,59). CD74 is almost undetectable in the epithelium of non-inflamed human and mice intestine when analyzed by immunohistochemistry (58,60,61). Therefore, it was not too surprising to find that CD74 deficient mice had normal colon, histology, and barrier integrity, and lacked spontaneous colitis in the absence of pathologic insults (58).…”

CD74, a novel predictor for bronchopulmonary dysplasia in preterm infants

“…CD74 is a protein coding gene that associates with major histocompatibility complex class II (MHCII) regulating antigen presentation for immune response. [ 17 , 18 ] Furthermore, the protein encoded by CD74 is a type of cell surface receptor for the cytokine macrophage migration inhibitory factor bounding, initiates survival pathways, and cell proliferation. This protein also interacts with amyloid precursor protein and suppresses the production of amyloid beta.…”

Host Protective Mechanisms to Intestinal Amebiasis

“…While CBA and C3H strains remain infected for up to several weeks after the challenge – with colitis evidenced by immune infiltration, epithelial ulceration, and submucosal edema – the C57BL/6 and BALB/c strains were resistant to amebic infection [ 41 , 89 ]. Discoveries from the mouse model include the findings that deletion of CREM , the leptin receptor, and CD74, each individually increased susceptibility to infection [ 36 , 39 , 90 ]. It is important to mention here that children with polymorphisms in the leptin receptor and the CREM gene were found to have more symptomatic amebic infections [ 35 , 39 ].…”