Chronic inflammation is associated with immunosuppression and downregulated expression of the TCR CD247. In searching for new biomarkers that could validate the impaired host immune status under chronic inflammatory conditions, we discovered that sorting nexin 9 (SNX9), a protein that participates in early stages of clathrin-mediated endocytosis, is downregulated as well under such conditions. SNX9 expression was affected earlier than CD247 by the generated harmful environment, suggesting that it is a potential marker sensing the generated immunosuppressive condition. We found that myeloid-derived suppressor cells, which are elevated in the course of chronic inflammation, are responsible for the observed SNX9 reduced expression. Moreover, SNX9 downregulation is reversible, as its expression levels return to normal and immune functions are restored when the inflammatory response and/or myeloid-derived suppressor cells are neutralized. SNX9 downregulation was detected in numerous mouse models for pathologies characterized by chronic inflammation such as chronic infection (Leishmania donovani), cancer (melanoma and colorectal carcinoma), and an autoimmune disease (rheumatoid arthritis). Interestingly, reduced levels of SNX9 were also observed in blood samples from colorectal cancer patients, emphasizing the feasibility of its use as a diagnostic and prognostic biomarker sensing the host's immune status and inflammatory stage. Our new discovery of SNX9 as being regulated by chronic inflammation and its association with immunosuppression, in addition to the CD247 regulation under such conditions, show the global impact of chronic inflammation and the generated immune environment on different cellular pathways in a diverse spectrum of diseases.
Bibliographical noteFunding Information:
This work was supported by the Israel Science Foundation, the Israeli Ministry of Health, the Joint German-Israeli Research Program, the Israel Cancer Research Fund, the United States-Israel Binational Science Foundation, and by Joseph and Matilda Melnick funds. We thank the Society of Research Associates of the Lautenberg Center, the Concern Foundation of Los Angeles, and the Harold B. Abramson Chair in Immunology for support.We thank Dr. Stefan F. Lichtenthaler from Munich University for providing the anti-SNX9 Abs; Prof. Alberto Mantovani from the University of Milan School of Medicine for providing the anti-Gr-1 Abs; and Dr. Keren Or Amar, Dr. Lora Ashkar, and Prof. David Naor from the Lautenberg Center for help in setting the RA mouse models system. We thank Prof. Ayala Hubert from the Hadassah Medical Center for providing the blood samples of the CRC patients, Prof. Charls Yaffe for providing the mice infected with L. donovani, Dr. Juan Bonifacino for advice on this project, and Prof. Eitan Yafe-Nof for reviewing this manuscript.
© 2015 by The American Association of Immunologists, Inc. All rights reserved.