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 5

Intestinal macrophage-derived IL-23 induced IFN-γ production by LPMCs, and LP CD4+ T cells synergize with TNF-α in patients with CD.

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Intestinal macrophage-derived IL-23 induced IFN-γ production by LPMCs, a...
(A) IL-23–induced proinflammatory cytokine production by LPMCs from normal control subject or inflamed mucosa of patients with IBD. Data represent mean ± SEM (normal control, n = 5; UC, n = 8; CD, n = 8). *P < 0.05 versus normal control; ##P < 0.01 versus UC; ζP < 0.05, ζζP < 0.01 versus unstimulated controls. (B) Synergistic effect of TNF-α and IL-6 on the IL-23–induced IFN-γ production by LPMCs and LP CD4+ T cells from inflamed mucosa of patients with CD. Data represent mean ± SEM from 4 individuals. (C) Analysis of the suppressive effect of anti-p40 or anti–TNF-α Abs on the commensal bacteria-induced IFN-γ production by LPMCs from inflamed mucosa of CD patients. α-p40 Ab, α–IL-12/IL-23p40 Ab. Data represent mean ± SEM from at least 4 individuals. Statistical analysis was performed using Kruskal-Wallis 1-way ANOVA and the Tukey-Kramer test for multiple comparisons.