EP4 Receptor-Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis.
EP4 Receptor-Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis.
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DOI：
10.1371/journal.pgen.1005542
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发表时间：
2015-10
期刊：
影响因子：
4.5
通讯作者：
Chiba T
中科院分区：
文献类型：
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作者：
Nakatsuji M;Minami M;Seno H;Yasui M;Komekado H;Higuchi S;Fujikawa R;Nakanishi Y;Fukuda A;Kawada K;Sakai Y;Kita T;Libby P;Ikeuchi H;Yokode M;Chiba T
前列腺素E2在维持结肠稳态中起重要作用。最近鉴定的前列腺素E受体（EP）4相关蛋白（EPRAP）是体外巨噬细胞中EP 4信号传导的抗炎功能所必需的。为了研究EPRAP在体内的作用，我们研究了EPRAP对结肠炎和结肠炎相关肿瘤发生的影响。在小鼠中，EPRAP缺乏加剧了葡聚糖硫酸钠（DSS）治疗诱导的结肠炎。野生型（WT）或EPRAP缺陷型接受者移植EPRAP缺陷型骨髓比WT或EPRAP缺陷型接受者WT骨髓更严重的DSS诱导的结肠炎。在结肠炎相关肿瘤发生的背景下，全身性EPRAP无效突变和骨髓中的EPRAP缺陷都增强了氧化偶氮甲烷（AOM）/DSS治疗诱导的肠息肉形成。给予EP 4选择性激动剂，ONO-AE 1 -329，改善了WT中DSS诱导的结肠炎，但在EPRAP缺陷小鼠中没有。EPRAP缺陷增加了p105、MEK和ERK磷酸化形式的水平，导致DSS诱导的结肠炎中基质巨噬细胞的激活。DSS处理的EPRAP缺陷小鼠的巨噬细胞相对于WT小鼠表现出促炎基因表达的显著增加。相反，在巨噬细胞中强制表达EPRAP可改善DSS诱导的结肠炎和AOM/DSS诱导的肠息肉形成。这些数据表明，巨噬细胞中的EPRAP在抑制结肠炎症中起关键作用。同时，溃疡性结肠炎患者结肠间质中也有EPRAP阳性巨噬细胞聚集。因此，EPRAP可能是炎症性肠病和相关肠道肿瘤发生的潜在治疗靶点。炎症性肠病（IBD）是西方国家最流行和最严重的胃肠道疾病之一，与癌症的发展有关。EP 4受体信号传导可以抑制肠道炎症，并显示出作为IBD新疗法开发的靶点的希望。然而，迄今为止，缺乏详细的分子靶点阻碍了有效药物的开发。本研究的重点是EPRAP，一种新的EP 4受体相关蛋白，涉及其信号通路。EPRAP基因突变小鼠的产生允许在体内探索EPRAP功能。此外，EPRAP定位于溃疡性结肠炎患者的间质巨噬细胞。本研究揭示了巨噬细胞中的EPRAP在EP 4受体信号传导介导的肠道炎症抑制中起重要作用。因此，巨噬细胞EP 4-EPRAP轴包含IBD的新治疗靶标。
Prostaglandin E2 plays important roles in the maintenance of colonic homeostasis. The recently identified prostaglandin E receptor (EP) 4–associated protein (EPRAP) is essential for an anti-inflammatory function of EP4 signaling in macrophages in vitro. To investigate the in vivo roles of EPRAP, we examined the effects of EPRAP on colitis and colitis-associated tumorigenesis. In mice, EPRAP deficiency exacerbated colitis induced by dextran sodium sulfate (DSS) treatment. Wild-type (WT) or EPRAP-deficient recipients transplanted with EPRAP-deficient bone marrow developed more severe DSS-induced colitis than WT or EPRAP-deficient recipients of WT bone marrow. In the context of colitis-associated tumorigenesis, both systemic EPRAP null mutation and EPRAP-deficiency in the bone marrow enhanced intestinal polyp formation induced by azoxymethane (AOM)/DSS treatment. Administration of an EP4-selective agonist, ONO-AE1-329, ameliorated DSS-induced colitis in WT, but not in EPRAP-deficient mice. EPRAP deficiency increased the levels of the phosphorylated forms of p105, MEK, and ERK, resulting in activation of stromal macrophages in DSS-induced colitis. Macrophages of DSS-treated EPRAP-deficient mice exhibited a marked increase in the expression of pro-inflammatory genes, relative to WT mice. By contrast, forced expression of EPRAP in macrophages ameliorated DSS-induced colitis and AOM/DSS-induced intestinal polyp formation. These data suggest that EPRAP in macrophages functions crucially in suppressing colonic inflammation. Consistently, EPRAP-positive macrophages were also accumulated in the colonic stroma of ulcerative colitis patients. Thus, EPRAP may be a potential therapeutic target for inflammatory bowel disease and associated intestinal tumorigenesis. Inflammatory bowel disease (IBD) is one of the most prevalent and serious gastrointestinal diseases in Western countries and associates with cancer development. EP4 receptor signaling can suppress intestinal inflammation and shows promise as a target for the development of novel therapies for IBD. To date, however, the lack of detailed molecular targets has hampered the development of effective drugs. This study focused on EPRAP, a novel EP4 receptor–associated protein, implicated in its signaling pathway. The generation of EPRAP-gene mutated mice permitted exploration of EPRAP functions in vivo. In addition, EPRAP was localized in stromal macrophages of ulcerative colitis patients. This study revealed that EPRAP in macrophage participates critically in EP4 receptor signaling-mediated inhibition of intestinal inflammation. The macrophage EP4–EPRAP axis thus comprises a novel therapeutic target for IBD.