Inflammatory macrophages switch to CCL17-expressing phenotype and promote peritoneal fibrosis
Inflammatory macrophages switch to CCL17-expressing phenotype and promote peritoneal fibrosis
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DOI：
10.1002/path.5350
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发表时间：
2019-11-22
影响因子：
7.3
通讯作者：
Lin, Shuei-Liong
中科院分区：
文献类型：
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作者：
Chen, Yi-Ting;Hsu, Hao;Lin, Shuei-Liong
腹膜纤维化仍然是接受腹膜透析治疗的肾衰竭患者的一个问题。严重的腹膜纤维化伴包裹性或包裹性腹膜硬化症是毁灭性的，并危及生命。尽管在被诊断为包裹性腹膜硬化症之前，间皮下成纤维细胞是动物模型中产生瘢痕的肌成纤维细胞的主要前体细胞，以及患者腹腔液中M2巨噬细胞(M Phi)衍生的趋化因子已经被确定，但减轻腹膜纤维化仍是一个未得到满足的医学需求，部分原因是M Phi S与成纤维细胞之间的相互作用机制尚不清楚。我们使用次氯酸钠诱导的类似于临床包裹性腹膜硬化症的小鼠模型来研究M phi S是如何激活成纤维细胞和纤维化的。次氯酸钠通过募集单核细胞和激活局部细胞增殖，导致CD11b(高)F4/80(高)驻留M Phi S消失，而CD11b(INT)F4/80(INT)炎症性M Phi S(InM Phi S)积聚。InfM Phi S从次氯酸盐损伤后第2天开始表达趋化因子(C-C基序)配体17、CCL22和精氨酸酶-1。超过75%的InfM Phi S通过CSF1R驱动的Cre重组酶进行基因重组，这为从伤后第2天起通过白喉毒素诱导的M Phi消融减少肌成纤维细胞和纤维化提供了可能性。此外，给予CCL17抗体可减少M phi S、肌成纤维细胞、纤维化程度，改善损伤后的腹膜功能。CCL17在机制上刺激培养的腹膜下成纤维细胞迁移和胶原生成。通过在M-Phi-S细胞中诱导表达红色荧光蛋白和在Col1a1表达细胞中表达绿色荧光蛋白的小鼠的饲养，证实M-Phi-S在损伤前后腹膜中不产生胶原。然而，在来自Col1a1-GFP报告鼠的骨髓的嵌合小鼠的纤维化腹膜中发现了少量的纤维细胞，但它们不能促进肌成纤维细胞的形成。这些数据表明，损伤后InfM Phi S转变为促纤维化表型，并通过CCL17激活腹膜成纤维细胞。阻断CCL17可能为腹膜纤维化患者提供一种新的治疗方法。(C)2019年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Peritoneal fibrosis remains a problem in kidney failure patients treated with peritoneal dialysis. Severe peritoneal fibrosis with encapsulation or encapsulating peritoneal sclerosis is devastating and life-threatening. Although submesothelial fibroblasts as the major precursor of scar-producing myofibroblasts in animal models and M2 macrophage (M phi)-derived chemokines in peritoneal effluents of patients before diagnosis of encapsulating peritoneal sclerosis have been identified, attenuation of peritoneal fibrosis is an unmet medical need partly because the mechanism for cross talk between M phi s and fibroblasts remains unclear. We use a sodium hypochlorite-induced mouse model akin to clinical encapsulated peritoneal sclerosis to study how the peritoneal M phi s activate fibroblasts and fibrosis. Sodium hypochlorite induces the disappearance of CD11b(high)F4/80(high) resident M phi s but accumulation of CD11b(int)F4/80(int) inflammatory M phi s (InfM phi s) through recruiting blood monocytes and activating local cell proliferation. InfM phi s switch to express chemokine (C-C motif) ligand 17 (CCL17), CCL22, and arginase-1 from day 2 after hypochlorite injury. More than 75% of InfM phi s undergo genetic recombination by Csf1r-driven Cre recombinase, providing the possibility to reduce myofibroblasts and fibrosis by diphtheria toxin-induced M phi ablation from day 2 after injury. Furthermore, administration of antibody against CCL17 can reduce M phi s, myofibroblasts, fibrosis, and improve peritoneal function after injury. Mechanistically, CCL17 stimulates migration and collagen production of submesothelial fibroblasts in culture. By breeding mice that are induced to express red fluorescent protein in M phi s and green fluorescence protein (GFP) in Col1a1-expressing cells, we confirmed that M phi s do not produce collagen in peritoneum before and after injury. However, small numbers of fibrocytes are found in fibrotic peritoneum of chimeric mice with bone marrow from Col1a1-GFP reporter mice, but they do not contribute to myofibroblasts. These data demonstrate that InfM phi s switch to pro-fibrotic phenotype and activate peritoneal fibroblasts through CCL17 after injury. CCL17 blockade in patients with peritoneal fibrosis may provide a novel therapy. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.