It is crucial that we understand how mucosal healing is regulated because it predicts sustained remission and resection-free survival in patients with IBD.4x4Neurath, M.F. Current and emerging therapeutic targets for IBD. Nate Rev Gastroenterol Hepatol. 2017;
Crossref | PubMed | Scopus (108) | Google ScholarSee all References Injury triggers an inflammatory response that protects against invading pathogens and also activates repair signals that are essential for healing.6x6Karin, M. and Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature. 2016;
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Crossref | PubMed | Scopus (161) | Google ScholarSee all References However, our current understanding of inflammation-driven repair mechanisms are limited. Here, we studied the role of CD74 signaling in mucosal healing during colitis, finding that CD74 activation does not drive tissue destruction, but protects the host by promoting mechanisms that restore epithelial lining and mucosal integrity during intestinal inflammation.
The renewal of the intestinal epithelium is critical for mucosal healing and is regulated by signaling pathways that control the proliferation of intestinal epithelial cells.5x5Neurath, M.F. and Travis, S.P. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut. 2012;
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Crossref | PubMed | Scopus (50) | Google ScholarSee all References CD74 signaling was not essential for intestinal homeostasis under steady-state conditions. However, CD74 signaling was strongly activated during the inflammatory response to mucosal injury with overexpression of CD74 most noticeable in the proliferating crypt epithelial cells. PI3K/Akt and ERK signaling are well-characterized pathways that mediate cell proliferation.35x35Vivanco, I. and Sawyers, C.L. The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nat Rev Cancer. 2002;
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Crossref | PubMed | Google ScholarSee all References In this study, we show that CD74, the receptor for MIF cytokine, triggers activation of Akt and ERK to promote regeneration. Through Akt and ERK, intestinal CD74 signaling enhances epithelial cell proliferation, promoting recovery of mucosal injury. Thus, MIF–CD74–Akt and ERK pathways link inflammation to epithelial cell regeneration, mucosal healing, and repair.
Mucosal healing is essential for proper response to IBD therapy. Anti–tumor necrosis factor (TNF) agents have drastically changed the way to treat IBD, leading to mucosal healing in IBD patients.39x39Neurath, M. New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol. 2014;
Crossref | PubMed | Scopus (167) | Google ScholarSee all References Unfortunately, more than half of patients with IBD do not respond to anti-TNF therapy, by mechanisms that are not completely understood. In a recent genetic study, a CD74 polymorphism was associated with anti-TNF treatment failure in patients with IBD,40x40Yoon, S.M., Haritunians, T., Chhina, S., Liu, Z., Yang, S., Landers, C., Li, D., Ye, B.D., Shih, D., and Vasiliauskas, E.A. Colonic phenotypes are associated with poorer response to anti-TNF therapies in patients with IBD. Inflamm Bowel Dis. 2017;
Crossref | PubMed | Scopus (7) | Google ScholarSee all References generating the hypothesis that failure could be more likely to occur in the setting of defective CD74 signaling. It would be interesting to determine whether CD74 gene variants can be used to predict success in a personalized medicine approach to the management of IBD.
New treatments for IBD are needed because many patients do not respond to the clinically approved drugs.4x4Neurath, M.F. Current and emerging therapeutic targets for IBD. Nate Rev Gastroenterol Hepatol. 2017;
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Crossref | PubMed | Scopus (15) | Google ScholarSee all References Enhancing or stimulating the CD74 pathway may be a potential therapeutic strategy for facilitating mucosal healing in IBD. Stimulation of CD74 with exogenous MIF might induce mucosal healing. However, administration of MIF has the potential to lead to an excessive inflammatory state. This is because MIF is capable of stimulating receptors other than CD74, such as CXCR2 and CXCR4.42x42Bernhagen, J., Krohn, R., Lue, H., Gregory, J.L., Zernecke, A., Koenen, R.R., Dewor, M., Georgiev, I., Schober, A., and Leng, L. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 2007;
Crossref | PubMed | Scopus (740) | Google ScholarSee all References,43x43Weber, C., Kraemer, S., Drechsler, M., Lue, H., Koenen, R.R., Kapurniotu, A., Zernecke, A., and Bernhagen, J. Structural determinants of MIF functions in CXCR2-mediated inflammatory and atherogenic leukocyte recruitment. Proc Natl Acad Sci U S A. 2008;
Crossref | PubMed | Scopus (100) | Google ScholarSee all References Recent studies have expanded our knowledge of the specific amino acids that enable the interaction between MIF and its receptors, thus, constructing MIF mutant proteins that selectively stimulate CD74 might become possible.44x44Lacy, M., Kontos, C., Brandhofer, M., Hille, K., Gröning, S., Sinitski, D., Bourilhon, P., Rosenberg, E., Krammer, C., Thavayogarajah, T., Pantouris, G., Bakou, M., Weber, C., Lolis, E., Bernhagen, J., and Kapurniotu, A. Identification of an Arg-Leu-Arg tripeptide that contributes to the binding interface between the cytokine MIF and the chemokine receptor CXCR4. Sci Rep. 2018;
Crossref | Scopus (12) | Google ScholarSee all References Therefore, new therapies might arise from identifying CD74 agonists that promote the regenerative process while avoiding an exaggerated inflammatory response, which is an area of ongoing research.
In conclusion, we report the observation that CD74 is increased in inflamed tissue in patients with IBD, a disease that affects millions of people worldwide, and provide evidence using human studies, mouse models, and cellular models that CD74 signaling is essential for inflammation-driven repair. These results potentially can be leveraged to create new therapeutic opportunities to address the unmet medical needs for IBD patients.