Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis
Nobuhiko Kamada, … , Kiyoko S. Akagawa, Toshifumi Hibi
Nobuhiko Kamada, … , Kiyoko S. Akagawa, Toshifumi Hibi
Published May 22, 2008
Citation Information: J Clin Invest. 2008;118(6):2269-2280. https://doi.org/10.1172/JCI34610.
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Research Article Inflammation

Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ 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-α, 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-α compared with those in normal controls or patients with ulcerative colitis. In addition, the CD14+ macrophages contributed to IFN-γ production rather than IL-17 production by lamina propria mononuclear cells (LPMCs) dependent on IL-23 and TNF-α. Furthermore, the IFN-γ produced by LPMCs triggered further abnormal macrophage differentiation with an IL-23–hyperproducing phenotype. Collectively, these data suggest that this IL-23/IFN-γ–positive feedback loop induced by abnormal intestinal macrophages contributes to the pathogenesis of chronic intestinal inflammation in patients with CD.

Authors

Nobuhiko Kamada, Tadakazu Hisamatsu, Susumu Okamoto, Hiroshi Chinen, Taku Kobayashi, Toshiro Sato, Atsushi Sakuraba, Mina T. Kitazume, Akira Sugita, Kazutaka Koganei, Kiyoko S. Akagawa, Toshifumi Hibi

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Figure 7

IFN-γ in CD-CM promotes IL-23–hyperproducing proinflammatory macrophage differentiation.

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IFN-γ in CD-CM promotes IL-23–hyperproducing proinflammatory macrophage ...
(A) Quantification of IFN-γ and IL-6 in LPMC-CM. Data are shown as mean ± SEM from 3 individual normal controls and 4 individual patients with IBD used for macrophage differentiation experiments. (B) Flow cytometry for the surface phenotypes of IFN-γ–induced in vitro–differentiated macrophages. The shaded histogram shows the profiles of the indicated Ab staining and the open histogram shows staining with isotype controls. (C) Production of IL-12/IL-23p40 and IL-23 by bacteria-stimulated macrophages differentiated with or without IFN-γ. Data represent mean ± SEM from 3 independent experiments. (D) Effect of IFN-γ signal blocking using anti–IFN-γ Ab (α-IFNγ Ab) (1 μg/ml) combination with anti–IFN-γ receptor 1 Ab (α-IFNγR Ab) (10 μg/ml) or same amount of those isotype controls (mouse IgG; mouse IgG2A for α-IFNγ Ab, and mouse IgG1 for α-IFNγR Ab) from CD-CM on macrophage differentiation. Statistical analysis was performed using paired t test. Data represent mean ± SEM from 5 independent experiments. *P < 0.05 compared with controls.