Reprogramming of Monocytes by GM-CSF Contributes to Regulatory Immune Functions during Intestinal Inflammation
Reprogramming of Monocytes by GM-CSF Contributes to Regulatory Immune Functions during Intestinal Inflammation
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DOI：
10.4049/jimmunol.1401482
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发表时间：
2015-03-01
影响因子：
4.4
通讯作者：
Foell, Dirk
中科院分区：
文献类型：
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作者：
Daebritz, Jan;Weinhage, Toni;Foell, Dirk
人类和小鼠研究表明，GM-CSF在肠道炎症中发挥有益作用。为了探索GM-CSF是否通过单核细胞介导其作用，我们分析了GM-CSF对体外单核细胞的作用，并评估了GM-CSF激活的单核细胞（GMaMs）在体内的免疫调节潜力。我们使用微阵列技术和功能测定来表征体外GMaM，并使用结肠炎小鼠模型来研究体内GMaM功能。GM-CSF在体外激活单核细胞以增加粘附、迁移、趋化性和氧化爆发，并引发单核细胞对次级微生物刺激的应答。此外，GMaM在体外加速上皮愈合。最重要的是，在实验性T细胞诱导的结肠炎的小鼠模型中，GMaMs显示出治疗活性并保护小鼠免受结肠炎。这伴随着体内固有层单核细胞中IL-4、IL-10和IL-13的产生增加以及IFN-γ的产生减少。证实了这一发现，GMaM吸引T细胞并通过在体外上调T细胞中的IL-4、IL-10和IL-13来形成它们向Th 2的分化。GM-CSF在克罗恩病中的有益作用可能通过单核细胞的重编程介导，以同时改善细菌清除和诱导伤口愈合，以及调节适应性免疫以限制过度炎症。
Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF-activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell-induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-gamma in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn's disease may possibly be mediated through reprogramming of monocytes to simultaneously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation.