Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis
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
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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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 6

The intestinal inflammatory microenvironment affects macrophage differentiation and induces an IL-23–producing phenotype.

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The intestinal inflammatory microenvironment affects macrophage differen...
(A) Morphological findings of in vitro–differentiated macrophages from peripheral CD14+ monocytes of normal controls with or without LPMC-CM. Scale bar: 20 μm. (B) Flow cytometry for the surface phenotypes of LPMC-CM–induced in vitro–differentiated macrophages. The shaded histogram shows profiles of indicated Ab staining and the open histogram shows staining with isotype controls. The data shown are representative of 5 independent experiments. (C) Cytokine production by LPMC-CM–induced in vitro–differentiated macrophages stimulated with heat-killed E. coli for 24 hours. Data represent mean ± SEM from 6 independent experiments. (D) Cytokine production by macrophages differentiated from normal and CD monocytes with or without UC- and CD-CM. Data represent mean ± SEM from 5 independent experiments. All data used at least 3 different CM from individual patients and at least 3 different monocytes from individual patients and controls. Statistical analysis was performed using Kruskal-Wallis 1-way ANOVA and the Tukey-Kramer test for multiple comparisons. **P < 0.01, ***P < 0.001 versus M-CSF induced macrophages; #P< 0.01, ##P < 0.01 comparison between normal control monocytes and monocytes from CD patients.