Infiltrating CCR2+ monocytes and their progenies, fibrocytes, contribute to colon fibrosis by inhibiting collagen degradation through the production of TIMP-1
Infiltrating CCR2+ monocytes and their progenies, fibrocytes, contribute to colon fibrosis by inhibiting collagen degradation through the production of TIMP-1
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DOI：
10.1038/s41598-019-45012-6
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发表时间：
2019-06-12
影响因子：
4.6
通讯作者：
Katayama, Naoyuki
中科院分区：
文献类型：
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作者：
Kuroda, Naoki;Masuya, Masahiro;Katayama, Naoyuki
肠纤维化是炎症性肠病(IBD)的严重并发症。尽管最近IBD的抗炎治疗取得了显著的成功，但肠纤维化的发生率和肠道切除的必要性并没有显著改变。为了阐明造血细胞在肠纤维化中的作用，我们制备了骨髓(BM)嵌合小鼠(嵌合体)，这些嵌合小鼠来自增强型绿色荧光蛋白(EGFP)转基因小鼠或CC趋化因子受体2(CCR2)缺陷小鼠。移植2个月后，用偶氮甲烷/葡聚糖硫酸钠处理骨髓嵌合体。在慢性炎症过程中，CCR2(+)BM来源的单核细胞和纤维细胞浸润到结肠和CC趋化因子配体2的产生增加，导致EGFP BM嵌合体的结肠纤维化。在CCR2缺失的BM嵌合体中，结肠固有层中的单核细胞和纤维细胞数量显著减少，结肠纤维化减轻。在结肠组织中，两种嵌合体组织金属蛋白酶抑制物(TIMP)-1的表达差异有统计学意义，而I型胶原、转化生长因子-β1和基质金属蛋白酶的表达无明显差异。CCR2(+)单核细胞和成纤维细胞高表达TIMP1mRNA。我们的结果表明，CCR2(+)单核细胞及其后代纤维细胞通过产生TIMP-1抑制胶原降解，从而促进结肠纤维化。
Intestinal fibrosis is a serious complication in inflammatory bowel disease (IBD). Despite the remarkable success of recent anti-inflammatory therapies for IBD, incidence of intestinal fibrosis and need for bowel resection have not significantly changed. To clarify the contribution of haematopoietic-derived cells in intestinal fibrosis, we prepared bone marrow (BM) chimeric mice (chimeras), which were reconstituted with BM cells derived from enhanced green fluorescent protein (EGFP)-transgenic mice or CC chemokine receptor 2 (CCR2)-deficient mice. After 2 months of transplantation, BM chimeras were treated with azoxymethane/dextran sodium sulphate. During chronic inflammation, CCR2(+) BM-derived monocyte and fibrocyte infiltration into the colon and CC chemokine ligand 2 production increased, leading to colon fibrosis in EGFP BM chimeras. In CCR2-deficient BM chimeras, monocyte and fibrocyte numbers in the colonic lamina propria significantly decreased, and colon fibrosis was attenuated. In colon tissue, mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 but not of collagen I, transforming growth factor-beta 1 or matrix metalloproteinases was significantly different between the two chimeras. CCR2(+) monocytes and fibrocytes showed high Timp1 mRNA expression. Our results suggest that infiltrating CCR2(+) monocytes and their progenies, fibrocytes, promote colon fibrosis by inhibiting collagen degradation through TIMP-1 production.