M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis.
M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis.
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DOI：
10.1371/journal.pone.0078128
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Barrachina MD
中科院分区：
文献类型：
--
作者：
Cosín-Roger J;Ortiz-Masiá D;Calatayud S;Hernández C;Alvarez A;Hinojosa J;Esplugues JV;Barrachina MD
巨噬细胞，表现出很大的可塑性，是发炎组织的重要组成部分，并构成再生反应的基本要素。已有报道称，上皮Wnt信号传导参与巨噬细胞的增殖和分化机制以及Wnt配体的表达。我们的目的是确定巨噬细胞表型是否决定Wnt配体的表达，巨噬细胞表型在上皮激活Wnt信号传导中的影响以及该途径在溃疡性结肠炎中的相关性。将人单核细胞衍生的巨噬细胞和U937衍生的巨噬细胞极化为M1或M2表型，并通过qPCR分析Wnt 1和Wnt 3a的表达。在与Caco-2细胞共培养系统中，分析巨噬细胞和Wnt 1对β-catenin、Tcf-4、c-Myc和细胞分化标志物表达的影响。免疫组化检测UC患者受损和非受损黏膜中CD 68、CD 206、CD 86、Wnt 1、β-catenin和c-Myc的表达。我们还通过qPCR测定了Lgr 5和c-Myc的mRNA表达，并通过western blot测定了β-catenin的蛋白水平。结果表明，M2（无M1）通过Wnt 1激活共培养上皮细胞中的Wnt信号通路，从而损害肠上皮细胞分化。在慢性与新诊断患者的受损粘膜中观察到CD 206+巨噬细胞数量的显著增加。CD 206免疫染色与Wnt 1共定位于粘膜中，这些细胞与上皮细胞中经典Wnt信号通路的激活和碱性磷酸酶活性的降低相关。我们的研究结果表明，M2巨噬细胞，而不是M1，激活Wnt信号通路，并减少肠上皮细胞分化共培养的上皮细胞。在UC患者的粘膜中，M2巨噬细胞随着慢性增加，并且与上皮Wnt信号传导的激活和肠上皮细胞分化的减少相关。
Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of β-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, β-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of β-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in enterocyte differentiation.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
3.7
作者：
Ortiz-Masià D;Díez I;Calatayud S;Hernández C;Cosín-Roger J;Hinojosa J;Esplugues JV;Barrachina MD
通讯作者：
Barrachina MD
影响因子：
29.4
作者：
Farin, Henner F.;Van Es, Johan H.;Clevers, Hans
通讯作者：
Clevers, Hans
DOI：
10.1073/pnas.0405979102
发表时间：
2005-01-04
影响因子：
11.1
作者：
Pull, SL;Doherty, JM;Stappenbeck, TS
通讯作者：
Stappenbeck, TS
影响因子：
4.9
作者：
Hughes, K. R.;Sablitzky, F.;Mahida, Y. R.
通讯作者：
Mahida, Y. R.