Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via lL-23/IFN-γ axis
Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via lL-23/IFN-γ axis
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独特的CD14+肠道巨噬细胞通过IL - 23/IFN - γ轴促进克罗恩病的发病机制
DOI：
10.1172/jci34610
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发表时间：
2008-06-01
影响因子：
15.9
通讯作者：
Hibi, Toshifumi
中科院分区：
文献类型：
--
作者：
Kamada, Nobuhiko;Hisamatsu, Tadakazu;Hibi, Toshifumi
肠道巨噬细胞在调节针对共生细菌的免疫反应中发挥核心作用。一般而言，肠道巨噬细胞缺乏先天免疫受体CD 14的表达，并且不产生针对肠道细菌的促炎细胞因子。在这项研究中，我们确定了我们认为是人类肠道中独特的巨噬细胞亚群。该亚群表达巨噬细胞（CD 14、CD 33、CD 68）和DC标志物（CD 205、CD 209），并产生比典型肠道驻留巨噬细胞（CD 14-CD 33（+）巨噬细胞）更大量的促炎细胞因子，如IL-23、TNF-α和IL-6。在克罗恩病（CD）患者中，这些CD 14（+）巨噬细胞的数量与正常对照组相比显著增加。除了细胞数量增加外，与正常对照组或溃疡性结肠炎患者相比，这些细胞还产生大量的IL-23和TNF-α。此外，CD 14（+）巨噬细胞促进IFN-γ的产生，而不是依赖于IL-23和TNF-α的固有层单核细胞（LPMC）产生IL-17。此外，由LPMC产生的IFN-γ引发了进一步的异常巨噬细胞分化，具有IL-23高产生表型。总的来说，这些数据表明，这种由异常肠巨噬细胞诱导的IL-23/IFN-γ正反馈回路有助于CD患者慢性肠道炎症的发病机制。
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 pro-inflammatory 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.