PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant KRAS mice
PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant KRAS mice
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DOI：
10.1080/2162402x.2017.1423168
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发表时间：
2018-01-01
期刊：
影响因子：
7.2
通讯作者：
Burgermeister, Elke
中科院分区：
文献类型：
--
作者：
Gutting, Tobias;Weber, Christian A.;Burgermeister, Elke
为了确定新的癌症免疫治疗枢纽，我们产生了C57BL/6J小鼠，伴随着可药物转录因子PPARγ的缺失和突变的KRASG12V癌基因在肠细胞中的转基因过表达。动物出现小肠上皮增生、跨壁炎症和锯齿状腺瘤，CD3+FOXP3+T细胞和巨噬细胞渗入非恶性粘膜固有层。在锯齿状息肉中，CD3+CD8+T细胞和磷酸化ERK1/2减少，衰老标记物P21和巨噬细胞计数增加，表明组织微环境处于免疫抑制状态。用PPAR伽玛激动剂罗格列酮治疗突变的KRASG12V小鼠后，小鼠的M1巨噬细胞数量增加，IL4表达减少，息肉负荷减少。罗格列酮还促进人THP1来源的巨噬细胞的M1极化，并降低分离的小鼠淋巴细胞中IL4mRNA的表达。因此，在上皮和免疫细胞隔间通过PPARγ抑制致癌驱动基因突变RAS可能是预防或治疗与肠道炎症相关的人类恶性肿瘤的未来目标。
To identify novel hubs for cancer immunotherapy, we generated C57BL/6J mice with concomitant deletion of the drugable transcription factor PPAR gamma and transgenic overexpression of the mutant KRASG12V oncogene in enterocytes. Animals developed epithelial hyperplasia, transmural inflammation and serrated adenomas in the small intestine with infiltration of CD3+ FOXP3+ T-cells and macrophages into the lamina propria of the non-malignant mucosa. Within serrated polyps, CD3+ CD8+ T-cells and phosphorylated ERK1/2 were reduced and the senescence marker P21 and macrophage counts up-regulated, indicative of an immunosuppressive tissue microenvironment. Treatment of mutant KRASG12V mice with the PPAR gamma-agonist rosiglitazone augmented M1 macrophage numbers, reduced IL4 expression and diminished polyp load in mice. Rosiglitazone also promoted M1 polarisation of human THP1-derived macrophages and decreased Il4 mRNA in isolated murine lymphocytes. Thus, inhibition of the oncogenic driver mutant RAS by PPAR gamma in epithelial and immune cell compartments may be a future target for the prevention or treatment of human malignancies associated with intestinal inflammation.