Tubular GM-CSF Promotes Late MCP-1/CCR2-Mediated Fibrosis and Inflammation after Ischemia/Reperfusion Injury.
Tubular GM-CSF Promotes Late MCP-1/CCR2-Mediated Fibrosis and Inflammation after Ischemia/Reperfusion Injury.
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DOI：
10.1681/asn.2019010068
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发表时间：
2019-07
期刊：
影响因子：
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通讯作者：
Leyuan Xu;D. Sharkey;L. Cantley
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文献类型：
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作者：
Leyuan Xu;D. Sharkey;L. Cantley
背景：双侧肾脏缺血再灌注损伤（IRI）后，单核细胞浸润肾脏并分化为促炎巨噬细胞，以响应初始肾脏损伤，然后转变为促进肾脏修复的形式。然而，在单侧IRI （U-IRI）的情况下，我们之前已经表明巨噬细胞持续存在超过修复时间，并可能促进纤维化。方法采用巨噬细胞与小管细胞共培养的方法，在U-IRI小鼠损伤后14天检测巨噬细胞归巢/存活信号。将基因工程缺失Ccr2的小鼠和野生型小鼠分别处理±Ccr2拮抗剂RS102895，并在损伤后14天和30天进行U-IRI，以量化巨噬细胞积累、肾脏纤维化和炎症。结果U-IRI后肾小管损伤不能解决，导致肾小管细胞持续表达粒细胞-巨噬细胞集落刺激因子，直接刺激巨噬细胞表达单核细胞趋化蛋白-1 （Mcp-1）。U-IRI后14天从野生型肾脏分离的CD45+免疫细胞分析显示MCP-1受体Ccr2的高水平表达。在缺乏Ccr2的小鼠和用RS102895处理的野生型小鼠中，U-IRI后巨噬细胞、树突状细胞和T细胞的数量减少，促纤维化生长因子和促炎细胞因子的表达也减少。这导致细胞外基质和肾损伤标志物的减少。结论gm - csf诱导的MCP-1/CCR2信号通路在损伤小管细胞与浸润性免疫细胞和肌成纤维细胞之间的相互作用中起重要作用，并在U-IRI晚期促进持续炎症和小管损伤伴进行性间质纤维化。
BACKGROUND After bilateral kidney ischemia/reperfusion injury (IRI), monocytes infiltrate the kidney and differentiate into proinflammatory macrophages in response to the initial kidney damage, and then transition to a form that promotes kidney repair. In the setting of unilateral IRI (U-IRI), however, we have previously shown that macrophages persist beyond the time of repair and may promote fibrosis. METHODS Macrophage homing/survival signals were determined at 14 days after injury in mice subjected to U-IRI and in vitro using coculture of macrophages and tubular cells. Mice genetically engineered to lack Ccr2 and wild-type mice were treated ±CCR2 antagonist RS102895 and subjected to U-IRI to quantify macrophage accumulation, kidney fibrosis, and inflammation 14 and 30 days after the injury. RESULTS Failure to resolve tubular injury after U-IRI results in sustained expression of granulocyte-macrophage colony-stimulating factor by renal tubular cells, which directly stimulates expression of monocyte chemoattractant protein-1 (Mcp-1) by macrophages. Analysis of CD45+ immune cells isolated from wild-type kidneys 14 days after U-IRI reveals high-level expression of the MCP-1 receptor Ccr2. In mice lacking Ccr2 and wild-type mice treated with RS102895, the numbers of macrophages, dendritic cells, and T cell decreased following U-IRI, as did the expression of profibrotic growth factors and proimflammatory cytokines. This results in a reduction in extracellular matrix and kidney injury markers. CONCLUSIONS GM-CSF-induced MCP-1/CCR2 signaling plays an important role in the cross-talk between injured tubular cells and infiltrating immune cells and myofibroblasts, and promotes sustained inflammation and tubular injury with progressive interstitial fibrosis in the late stages of U-IRI.