title: Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis.
abstract: Intestinal macrophages play a central role in regulation of immune responses against commensal bacteria. In general, intestinal macrophages lack the expression of innate-immune receptor CD14 and do not produce proinflammatory cytokines against commensal bacteria. In this study, we identified what we believe to be a unique macrophage subset in human intestine. This subset expressed both macrophage (CD14, CD33, CD68) and DC markers (CD205, CD209) and produced larger amounts of proinflammatory cytokines, such as IL-23, TNF-alpha, and IL-6, than typical intestinal resident macrophages (CD14-CD33+ macrophages). In patients with Crohn disease (CD), the number of these CD14+ macrophages were significantly increased compared with normal control subjects. In addition to increased numbers of cells, these cells also produced larger amounts of IL-23 and TNF-alpha compared with those in normal controls or patients with ulcerative colitis. In addition, the CD14+ macrophages contributed to IFN-gamma production rather than IL-17 production by lamina propria mononuclear cells (LPMCs) dependent on IL-23 and TNF-alpha. Furthermore, the IFN-gamma produced by LPMCs triggered further abnormal macrophage differentiation with an IL-23-hyperproducing phenotype. Collectively, these data suggest that this IL-23/IFN-gamma-positive feedback loop induced by abnormal intestinal macrophages contributes to the pathogenesis of chronic intestinal inflammation in patients with CD.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Susumu
authors.initials: S
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chinen
authors.forename: Taku
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sakuraba
authors.forename: Mina T
authors.initials: MT
authors.lastname: Kitazume
authors.forename: Akira
authors.initials: A
authors.lastname: Sugita
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Koganei
authors.forename: Kiyoko S
authors.initials: KS
authors.lastname: Akagawa
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D002454:Cell Differentiation; D002469:Cell Separation; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis*; D008264:Macrophages / Q000378:metabolism*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D009092:Mucous Membrane / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D053759:Interleukin-23; D018950:Lipopolysaccharide Receptors; D063268:Sialic Acid Binding Ig-like Lectin 3; D007371:Interferon-gamma