title: Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9.
abstract: Many host-factors are inducibly expressed during the development of inflammatory bowel disease (IBD), each having their unique properties, such as immune activation, bacterial clearance, and tissue repair/remodeling. Dysregulation/imbalance of these factors may have pathogenic effects that can contribute to colitis-associated cancer (CAC). Previous reports showed that IBD patients inducibly express colonic chitinase 3-like 1 (CHI3L1) that is further upregulated during CAC development. However, little is known about the direct pathogenic involvement of CHI3L1 in vivo. Here we demonstrate that CHI3L1 (aka Brp39) knockout (KO) mice treated with azoxymethane (AOM)/dextran sulphate sodium (DSS) developed severe colitis but lesser incidence of CAC as compared to that in wild-type (WT) mice. Highest CHI3L1 expression was found during the chronic phase of colitis, rather than the acute phase, and is essential to promote intestinal epithelial cell (IEC) proliferation in vivo. This CHI3L1-mediated cell proliferation/survival involves partial downregulation of the pro-apoptotic S100A9 protein that is highly expressed during the acute phase of colitis, by binding to the S100A9 receptor, RAGE (Receptor for Advanced Glycation End products). This interaction disrupts the S100A9-associated expression positive feedback loop during early immune activation, creating a CHI3L1hi S100A9low colonic environment, especially in the later phase of colitis, which promotes cell proliferation/survival of both normal IECs and tumor cells.
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Daren
authors.initials: D
authors.lastname: Low
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Renuka
authors.initials: R
authors.lastname: Subramaniam
authors.affiliation: Laboratory of Cardiovascular Science, National Institutes on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Division of Mucosal Immunology, Graduate School, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Aomatsu
authors.affiliation: Department of Immunology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizoguchi
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Aylwin
authors.initials: A
authors.lastname: Ng
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Arianna K
authors.initials: AK
authors.lastname: DeGruttola
authors.affiliation: Department of Microbiology and Immunology, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunology, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.affiliation: Division of Mucosal Immunology, Graduate School, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Andoh
authors.affiliation: Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Center for The Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Emiko
authors.initials: E
authors.lastname: Mizoguchi
mesh_terms: D000818:Animals; D040502:Calgranulin B / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D000071451:Chitinase-3-Like Protein 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D003092:Colitis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism
chemical_list: C084533:CHI3L1 protein, human; D040502:Calgranulin B; C509289:Chil1 protein, mouse; D000071451:Chitinase-3-Like Protein 1; D064568:S100 Calcium Binding Protein beta Subunit; C576329:S100A9 protein, mouse; C579160:S100B protein, human
keywords: RAGE; bone marrow chimeras; colitis-associated cancer; intestinal epithelial cells; mammalian chitinase