Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity.
Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity.
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DOI：
10.1172/jci19229
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发表时间：
2005-01
期刊：
影响因子：
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通讯作者：
L. Smythies;M. Sellers;R. Clements;Meg Mosteller-Barnum;G. Meng;W. Benjamin;J. Orenstein;Phillip D. Smith
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文献类型：
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作者：
L. Smythies;M. Sellers;R. Clements;Meg Mosteller-Barnum;G. Meng;W. Benjamin;J. Orenstein;Phillip D. Smith
肠道巨噬细胞被认为与粘膜炎症反应有关，与其他组织的巨噬细胞相比，很少受到研究的关注。本研究表明，人类肠道巨噬细胞不表达先天反应受体，包括LPS （CD14）、Fcalpha （CD89）、Fcgamma （CD64、CD32、CD16）、CR3 （CD11b/CD18）和CR4 （CD11c/CD18）受体；生长因子受体IL-2 （CD25）和IL-3 (CD123)；和整合素LFA-1 （CD11a/CD18）。此外，常驻肠道巨噬细胞也不产生促炎细胞因子，包括IL-1、IL-6、IL-10、IL-12、RANTES、tgf - β和tnf - α，以响应一系列炎症刺激，但保持旺盛的吞噬和杀菌活性。因此，肠巨噬细胞在表型和功能上与血液单核细胞明显不同，尽管肠巨噬细胞来源于血液单核细胞。为了解释这一悖论，我们发现肠道基质细胞衍生的产物下调单核细胞受体的表达，并通过tgf - β下调细胞因子的产生，但不下调吞噬或杀菌活性，从而引发肠道巨噬细胞的表型和功能特征。这些发现表明了一种机制，即招募到肠粘膜的血液单核细胞保留了强烈的清道夫和宿主防御功能，但获得了深刻的“炎症能量”，从而促进了正常肠粘膜炎症特征的缺失，尽管免疫刺激细菌非常接近。
Intestinal macrophages, which are thought to orchestrate mucosal inflammatory responses, have received little investigative attention compared with macrophages from other tissues. Here we show that human intestinal macrophages do not express innate response receptors, including the receptors for LPS (CD14), Fcalpha (CD89), Fcgamma (CD64, CD32, CD16), CR3 (CD11b/CD18), and CR4 (CD11c/CD18); the growth factor receptors IL-2 (CD25) and IL-3 (CD123); and the integrin LFA-1 (CD11a/CD18). Moreover, resident intestinal macrophages also do not produce proinflammatory cytokines, including IL-1, IL-6, IL-10, IL-12, RANTES, TGF-beta, and TNF-alpha, in response to an array of inflammatory stimuli but retain avid phagocytic and bacteriocidal activity. Thus, intestinal macrophages are markedly distinct in phenotype and function from blood monocytes, although intestinal macrophages are derived from blood monocytes. To explain this paradox, we show that intestinal stromal cell-derived products downregulate both monocyte receptor expression and, via TGF-beta, cytokine production but not phagocytic or bacteriocidal activity, eliciting the phenotype and functional profile of intestinal macrophages. These findings indicate a mechanism in which blood monocytes recruited to the intestinal mucosa retain avid scavenger and host defense functions but acquire profound "inflammatory anergy," thereby promoting the absence of inflammation characteristic of normal intestinal mucosa despite the close proximity of immunostimulatory bacteria.