Becker Felix, Kurmaeva Elvira, Gavins Felicity N E, Stevenson Emily V, Navratil Aaron R, Jin Long, Tsunoda Ikuo, Orr A Wayne, Alexander Jonathan S, Ostanin Dmitry V
*Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana; †Department of General and Visceral Surgery, University Hospital Muenster, Germany; ‡Department of Medicine, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center-Shreveport, Louisiana; Departments of §Neurology, ‖Microbiology and Immunology, ¶Cellular Biology and Anatomy; and **Pathology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana.
Inflamm Bowel Dis. 2016 Jun;22(6):1326-45. doi: 10.1097/MIB.0000000000000731.
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 CD4CD45RB 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.
炎症相关的淋巴管生成（IAL）在炎症性肠病中经常被观察到。IAL被认为通过增强液体和免疫细胞清除来限制炎症。虽然已知单核细胞/巨噬细胞（MΦ）在炎症性肠病的肠道病理中起作用，但其在肠道IAL中的作用从未进行过机制研究。我们研究了单核细胞/MΦ对肠道炎症和IAL发展的贡献。
由于炎症单核细胞表达CC趋化因子受体2（CCR2），我们使用了CCR2白喉毒素受体转基因（CCR2.DTR）小鼠（其中单核细胞可通过注射白喉毒素而被清除）和循环单核细胞减少的CCR2小鼠。分别通过葡聚糖硫酸钠或CD4CD45RB T细胞的过继转移诱导急性或慢性结肠炎。通过流式细胞术、免疫荧光、疾病活动度和组织病理学评估肠道炎症，而通过淋巴管形态和密度评估IAL。
我们证明肠道MΦ表达血管内皮生长因子-C/D。在急性结肠炎中，单核细胞清除的小鼠免受肠道损伤，并且IAL减少，在将野生型单核细胞转移到CCR2小鼠后这种情况得到逆转。在慢性结肠炎中，CCR2缺陷并未减轻炎症，但减少了IAL。
我们提出MΦ在（1）促进急性炎症和（2）促成IAL方面具有双重作用。我们的数据表明肠道炎症和IAL可能独立发生，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。未来的炎症性肠病治疗可能会分别利用促进IAL和抑制MΦ来恢复淋巴清除并减轻炎症。
