A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis.
A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis.
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DOI：
10.1097/mib.0000000000000731
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发表时间：
2016-06
影响因子：
4.9
通讯作者：
Ostanin DV
中科院分区：
文献类型：
--
作者：
Becker F;Kurmaeva E;Gavins FN;Stevenson EV;Navratil AR;Jin L;Tsunoda I;Orr AW;Alexander JS;Ostanin DV
炎症相关淋巴管生成(IAL)常见于炎症性肠病。据信，血管紧张素转换酶通过促进液体和免疫细胞的清除来限制炎症。虽然单核细胞/巨噬细胞(M-Φ)在炎症性肠病的肠道病理中起重要作用，但其在肠道中的作用从未被机械地研究过。我们研究了单核细胞/M-Φ在肠炎症和肠易激综合征发生发展中的作用。由于炎性单核细胞表达CC趋化因子受体2(CCR2)，我们选用了CCR2白喉毒素受体转基因小鼠(CCR2)和−/−小鼠，前者可以通过注射白喉毒素来去除单核细胞，后者减少了循环单核细胞。急性结肠炎和慢性结肠炎分别用葡聚糖硫酸钠和过继转移CD4+CD45RBHigh T细胞诱导。肠炎症通过流式细胞仪、免疫荧光、疾病活动性和组织病理学进行评估，而IAL通过淋巴管形态和密度进行评估。我们证明了肠道MΦ表达血管内皮生长因子-C/D。在急性结肠炎中，单核细胞耗竭的小鼠对肠道损伤有保护作用，表现为IAL减少，而将野生型单核细胞转移到CCR2−/−小鼠体内后，这种情况被逆转。在慢性结肠炎中，CCR2缺乏并没有减轻炎症，而是降低了IAL。我们提出M-Φ在(1)促进急性炎症和(2)促进IAL中的双重作用。我们的数据表明，肠道炎症和IAL可以独立发生，因为即使存在炎症，在没有单核细胞/MΦ的情况下，IAL也会减少。未来炎症性肠病的治疗可能独立地利用IAL的促进和M-Φ的抑制，以恢复淋巴清除和减少炎症。
Inflammation-associated lymphangiogenesis (IAL) is frequently observed in inflammatory bowel diseases. IAL is believed to limit inflammation by enhancing fluid and immune cell clearance. Although monocytes/macrophages (MΦ) are known to contribute to intestinal pathology in inflammatory bowel disease, their role in intestinal IAL has never been studied mechanistically. We investigated contributions of monocytes/MΦ to the development of intestinal inflammation and IAL. Because inflammatory monocytes express CC chemokine receptor 2 (CCR2), we used CCR2 diphtheria toxin receptor transgenic (CCR2.DTR) mice, in which monocytes can be depleted by diphtheria toxin injection, and CCR2−/− mice, which have reduced circulating monocytes. Acute or chronic colitis was induced by dextran sodium sulfate or adoptive transfer of CD4+CD45RBhigh T cells, respectively. Intestinal inflammation was assessed by flow cytometry, immunofluorescence, disease activity, and histopathology, whereas IAL was assessed by lymphatic vessel morphology and density. We demonstrated that intestinal MΦ expressed vascular endothelial growth factor-C/D. In acute colitis, monocyte-depleted mice were protected from intestinal injury and showed reduced IAL, which was reversed after transfer of wild-type monocytes into CCR2−/− mice. In chronic colitis, CCR2 deficiency did not attenuate inflammation but reduced IAL. We propose a dual role of MΦ in (1) promoting acute inflammation and (2) contributing to IAL. Our data suggest that intestinal inflammation and IAL could occur independently, because IAL was reduced in the absence of monocytes/MΦ, even when inflammation was present. Future inflammatory bowel disease therapies might exploit promotion of IAL and suppression of MΦ independently, to restore lymphatic clearance and reduce inflammation.