Granulocyte Macrophage Colony-Stimulating Factor-Activated CD39(+)/CD73(+) Murine Monocytes Modulate Intestinal Inflammation via Induction of Regulatory T Cells.
Granulocyte Macrophage Colony-Stimulating Factor-Activated CD39(+)/CD73(+) Murine Monocytes Modulate Intestinal Inflammation via Induction of Regulatory T Cells.
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DOI：
10.1016/j.jcmgh.2015.04.005
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发表时间：
2015-07
影响因子：
7.2
通讯作者：
Varga G
中科院分区：
文献类型：
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作者：
Weinhage T;Däbritz J;Brockhausen A;Wirth T;Brückner M;Belz M;Foell D;Varga G
粒细胞巨噬细胞集落刺激因子(GM-CSF)治疗活动期克罗恩病的临床疗效。为了探讨单核细胞是否在体内介导GM-CSF效应，我们使用了葡聚糖硫酸钠(DSS)诱导的慢性结肠炎小鼠模型。用GM-CSF体外激活小鼠骨髓来源的单核细胞，分析GM-CSF激活的单核细胞的基因表达、表型和功能。在DSS反复循环诱导的慢性结肠炎模型上评价了GMAM的治疗效果。静脉注射单核细胞，通过临床监测、组织学、内窥镜、免疫组织化学和结肠炎性标志物的表达，在体内评价其免疫调节功能。体内显像法测定注射后单核细胞在肠道内的分布。GMAM表达的抗炎分子水平明显更高。细胞吞噬和黏附能力下降，产生的活性氧也增加。GMAM上调CD39和CD73，使腺苷三磷酸转化为腺苷，并与GMAM和幼稚T细胞共培养中Foxp3+(叉头盒蛋白P3阳性)调节性T细胞(Treg)的诱导相一致。在DSS诱导的慢性结肠炎中，过继转移GMAM导致显著的临床改善，表现为体重减轻、炎性浸润、溃疡和结肠收缩。与对照单核细胞相比，GMAM在炎症的肠道中迁移更快，持续时间更长，它们的存在在体内诱导了Treg的产生。GM-CSF通过包括Treg诱导在内的机制导致特异性单核细胞激活，从而调节实验性结肠炎。我们论证了单核细胞表达CD39和CD73诱导Treg的可能机制。
Granulocyte macrophage colony-stimulating factor (GM-CSF) treatment induces clinical response in patients with active Crohn’s disease. To explore whether monocytes mediate GM-CSF effects in vivo, we used a mouse model of chronic colitis induced by dextran sulfate sodium (DSS). Murine bone marrow-derived monocytes were activated with GM-CSF in vitro, and gene expression, phenotype, and function of GM-CSF-activated monocytes (GMaM) were analyzed. Therapeutic effects of GMaM were assessed in a model of chronic colitis induced by repeated cycles of DSS. Monocytes were administered intravenously and their immunomodulatory functions were evaluated in vivo by clinical monitoring, histology, endoscopy, immunohistochemistry, and expression of inflammatory markers in the colon. The distribution of injected monocytes in the intestine was measured by in vivo imaging. GMaM expressed significantly higher levels of anti-inflammatory molecules. Production of reactive oxygen species was also increased while phagocytosis and adherence were decreased. GMaM up-regulated CD39 and CD73, which allows the conversion of adenosine triphosphate into adenosine and coincided with the induction of Foxp3+ (forkhead-box-protein P3 positive) regulatory T cells (Treg) in cocultures of GMaM and naive T cells. In chronic DSS-induced colitis, adoptive transfer of GMaM led to significant clinical improvement, as demonstrated by reduced weight loss, inflammatory infiltration, ulceration, and colon shrinkage. As GMaM migrated faster and persisted longer in the inflamed intestine compared with control monocytes, their presence induced Treg generation in vivo. GM-CSF leads to specific monocyte activation that modulates experimental colitis via mechanisms that include the induction of Treg. We demonstrate a possible mechanism of Treg induction through CD39 and CD73 expression on monocytes.