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 (Mϕ)-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 Mϕs and fibroblasts remains unclear. We use a sodium hypochlorite-induced mouse model akin to clinical encapsulated peritoneal sclerosis to study how the peritoneal Mϕs activate fibroblasts and fibrosis. Sodium hypochlorite induces the disappearance of CD11bhigh F4/80high resident Mϕs but accumulation of CD11bint F4/80int inflammatory Mϕs (InfMϕs) through recruiting blood monocytes and activating local cell proliferation. InfMϕs switch to express chemokine (C-C motif) ligand 17 (CCL17), CCL22, and arginase-1 from day 2 after hypochlorite injury. More than 75% of InfMϕs undergo genetic recombination by Csf1r-driven Cre recombinase, providing the possibility to reduce myofibroblasts and fibrosis by diphtheria toxin-induced Mϕ ablation from day 2 after injury. Furthermore, administration of antibody against CCL17 can reduce Mϕs, 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 Mϕs and green fluorescence protein (GFP) in Col1a1-expressing cells, we confirmed that Mϕs 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 InfMϕs 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. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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炎性巨噬细胞转变为表达CCL17的表型并促进腹膜纤维化。

在腹膜透析治疗的肾衰竭患者中，腹膜纤维化仍然是一个问题。包囊或包囊性腹膜硬化的严重腹膜纤维化是毁灭性的，威胁生命。尽管在动物模型和诊断为包膜性腹膜硬化之前，已确定患者模型腹膜流出物中亚膜成纤维细胞是产生疤痕的成纤维细胞的主要前体和M2巨噬细胞（M）衍生的趋化因子，但腹膜纤维化的减弱仍未满足医学需求Mϕ和成纤维细胞之间的串扰机制尚不清楚。我们使用类似于临床封装的腹膜硬化的次氯酸钠诱导的小鼠模型来研究腹膜Mϕs如何激活成纤维细胞和纤维化。次氯酸钠通过募集血液单核细胞和激活局部细胞增殖，诱导CD11bhigh F4 / 80high常驻Mϕ的消失，但CD11bint F4 / 80int炎性Mϕs（InfMϕs）的积累。从次氯酸盐损伤后的第二天开始，InfM转换为表达趋化因子（CC基序）配体17（CCL17），CCL22和精氨酸酶-1。超过75％的InfMϕ通过Csf1r驱动的Cre重组酶进行基因重组，从伤后第2天起就可以通过白喉毒素诱导的Mϕ消融减少成肌纤维细胞和纤维化。此外，给予抗CCL17抗体可减少Mϕs，成肌纤维细胞，纤维化并改善损伤后的腹膜功能。从机理上讲，CCL17刺激培养中的间皮下成纤维细胞的迁移和胶原蛋白的产生。通过繁殖诱导在Mϕs中表达红色荧光蛋白和在Col1a1表达细胞中表达绿色荧光蛋白（GFP）的小鼠，我们证实了Mϕs在损伤前后的腹膜中均不产生胶原蛋白。但是，在来自Col1a1-GFP报告基因小鼠的具有骨髓的嵌合小鼠的纤维化腹膜中发现了少量的纤维细胞，但它们对成肌纤维细胞没有贡献。这些数据表明，损伤后InfM转换为促纤维化表型并通过CCL17激活腹膜成纤维细胞。腹膜纤维化患者的CCL17阻断可能会提供一种新颖的治疗方法。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 我们证实损伤前后M ands不会在腹膜中产生胶原蛋白。但是，在来自Col1a1-GFP报告基因小鼠的具有骨髓的嵌合小鼠的纤维化腹膜中发现了少量的纤维细胞，但它们对成肌纤维细胞没有贡献。这些数据表明，损伤后InfM转换为促纤维化表型并通过CCL17激活腹膜成纤维细胞。腹膜纤维化患者的CCL17阻断可能会提供一种新颖的治疗方法。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 我们证实损伤前和损伤后Mϕs不会在腹膜中产生胶原蛋白。但是，在来自Col1a1-GFP报告基因小鼠的具有骨髓的嵌合小鼠的纤维化腹膜中发现了少量的纤维细胞，但它们对成肌纤维细胞没有贡献。这些数据表明，损伤后InfM转换为促纤维化表型并通过CCL17激活腹膜成纤维细胞。腹膜纤维化患者的CCL17阻断可能会提供一种新颖的治疗方法。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 这些数据表明，损伤后InfM转换为促纤维化表型并通过CCL17激活腹膜成纤维细胞。腹膜纤维化患者的CCL17阻断可能会提供一种新颖的治疗方法。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 这些数据表明，损伤后，InfM转换为促纤维化表型并通过CCL17激活腹膜成纤维细胞。腹膜纤维化患者的CCL17阻断可能会提供一种新颖的治疗方法。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版