Regulation of inflammation and fibrosis by macrophages in lymphedema
Regulation of inflammation and fibrosis by macrophages in lymphedema
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DOI：
10.1152/ajpheart.00598.2014
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发表时间：
2015-05-01
影响因子：
4.8
通讯作者：
Mehrara, Babak J.
中科院分区：
文献类型：
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作者：
Ghanta, Swapna;Cuzzone, Daniel A.;Mehrara, Babak J.
淋巴水肿是癌症治疗的常见并发症，其特征是炎症、纤维化和脂肪沉积。我们以前已经表明，巨噬细胞浸润增加，在小鼠模型的水肿。由于巨噬细胞是淋巴管生成和纤维化的调节因子，因此本研究旨在使用耗竭实验确定这些细胞在水肿中的作用。从患单侧上肢乳腺癌相关性水肿的患者中获得正常和水肿组织的匹配活检标本，并使用免疫组化评估巨噬细胞积聚。此外，我们使用小鼠尾部水肿模型来量化巨噬细胞积聚并分析条件性巨噬细胞耗竭的结果。临床水肿活检的组织学分析显示巨噬细胞浸润显著增加。同样，在小鼠尾部模型中，淋巴损伤增加了巨噬细胞的数量，有利于M2分化。使用CD 11b-白喉毒素受体小鼠骨髓重建的致命照射野生型小鼠进行慢性巨噬细胞消耗并没有减少肿胀、脂肪沉积或总体炎症。水肿形成后巨噬细胞耗竭显著增加了纤维化和CD 4+细胞的积聚，促进了Th 2分化，同时降低了淋巴转运能力和VEGF-C表达。我们的研究结果表明，巨噬细胞的家水肿组织和分化成M2表型。此外，我们的研究结果表明，巨噬细胞在水肿中具有抗纤维化作用，并直接或间接调节CD 4（+）细胞的积累和Th 2分化。最后，我们的研究结果表明，水肿相关的巨噬细胞是VEGF-C的主要来源，淋巴损伤后受损的巨噬细胞反应导致淋巴功能下降。
Lymphedema, a common complication of cancer treatment, is characterized by inflammation, fibrosis, and adipose deposition. We have previously shown that macrophage infiltration is increased in mouse models of lymphedema. Because macrophages are regulators of lymphangiogenesis and fibrosis, this study aimed to determine the role of these cells in lymphedema using depletion experiments. Matched biopsy specimens of normal and lymphedema tissues were obtained from patients with unilateral upper extremity breast cancer-related lymphedema, and macrophage accumulation was assessed using immunohistochemistry. In addition, we used a mouse tail model of lymphedema to quantify macrophage accumulation and analyze outcomes of conditional macrophage depletion. Histological analysis of clinical lymphedema biopsies revealed significantly increased macrophage infiltration. Similarly, in the mouse tail model, lymphatic injury increased the number of macrophages and favored M2 differentiation. Chronic macrophage depletion using lethally irradiated wild-type mice reconstituted with CD11b-diphtheria toxin receptor mouse bone marrow did not decrease swelling, adipose deposition, or overall inflammation. Macrophage depletion after lymphedema had become established significantly increased fibrosis and accumulation of CD4(+) cells and promoted Th2 differentiation while decreasing lymphatic transport capacity and VEGF-C expression. Our findings suggest that macrophages home to lymphedematous tissues and differentiate into the M2 phenotype. In addition, our findings suggest that macrophages have an antifibrotic role in lymphedema and either directly or indirectly regulate CD4(+) cell accumulation and Th2 differentiation. Finally, our findings suggest that lymphedema-associated macrophages are a major source of VEGF-C and that impaired macrophage responses after lymphatic injury result in decreased lymphatic function.