title: Impaired SNX9 Expression in Immune Cells during Chronic Inflammation: Prognostic and Diagnostic Implications.
abstract: 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.
authors.affiliation: Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel; and ImProDia Ltd., Herzliya Pituah 46723, Israel.
authors.forename: Eliran
authors.initials: E
authors.lastname: Ish-Shalom
authors.affiliation: Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel; and.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Meirow
authors.affiliation: Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel; and.
authors.forename: Moshe
authors.initials: M
authors.lastname: Sade-Feldman
authors.affiliation: Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Kanterman
authors.affiliation: Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel; and.
authors.forename: Lynn
authors.initials: L
authors.lastname: Wang
authors.affiliation: ImProDia Ltd., Herzliya Pituah 46723, Israel.
authors.forename: Olga
authors.identifier: http://orcid.org/0000-0003-2017-1926
authors.initials: O
authors.lastname: Mizrahi
authors.affiliation: Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel; and ImProDia Ltd., Herzliya Pituah 46723, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Klieger
authors.affiliation: Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel; and michalb@ekmd.huji.ac.il.
authors.forename: Michal
authors.initials: M
authors.lastname: Baniyash
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology; D014408:Biomarkers, Tumor / Q000097:blood; D017252:CD3 Complex / Q000096:biosynthesis*; D049109:Cell Proliferation; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016867:Immunocompromised Host / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D007893:Leishmania donovani / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000469:parasitology; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D022423:Myeloid Cells / Q000276:immunology*; D058305:Sorting Nexins / Q000096:biosynthesis* / Q000097:blood; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C400533:SNX9 protein, human; D058305:Sorting Nexins