Our previous studies reveal that CCL18-CCR8 chemokine axis is upregulated in patients of immunoglobulin G4-related disease (IgG4-RD), suggesting that the CCL18–CCR8 axis is implicated in the etiology of IgG4-RD, although whether this axis has a potential as a therapeutic target remains unclear. Our purpose was to clarify the pathogenic roles and therapeutic potential of the murine CCL8 (analog of human CCL18)–CCR8 axis by using an animal model of IgG4-RD (LAT Y136F knockin mice; LAT mice). We compared the infiltration of inflammatory cells and the fibrosis of the salivary glands of 6-week-old LAT mice and littermate mice. The expressions of Ccl8 and Ccr8 were also compared. Next, we investigated the therapeutic effects of intravenous administration of anti-CCL8 neutralizing antibody in LAT mice against inflammation and fibrosis of the salivary glands. We also investigated the effects of stimulation with recombinant mouse CCL8 on the collagen production in a mouse fibroblast cell line (NIH/3 T3) in vitro. When compared with the littermates, the LAT mice showed apparent infiltration of inflammatory cells and fibrosis in the salivary glands. The focus and fibrosis score in the salivary glands were significantly higher in the LAT mice than in the littermates. The expression levels of Ccl8 in the spleen and of Ccr8 in the salivary glands were significantly higher in the LAT mice than in the littermates. Anti-CCL8 antibody significantly improved the focus and fibrosis score in the salivary glands of the LAT mice. In vitro, stimulation with recombinant mouse CCL8 significantly increased the expression of collagen and ERK1/2 phosphorylation in NIH/3 T3. We clarified the overexpression and therapeutic potential of the mouse CCL8–CCR8 axis in LAT mice, which could play a crucial role in fibrosis via ERK1/2 phosphorylation, as well as the chemotaxis of inflammatory cells. The human CCL18–CCR8 axis might be a novel therapeutic target for IgG4-RD.

中文翻译：

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CCL8-CCR8 轴在 IgG4 相关唾液腺炎小鼠模型中的致病作用和治疗潜力

我们之前的研究表明，CCL18-CCR8 趋化因子轴在免疫球蛋白 G4 相关疾病 (IgG4-RD) 患者中上调，这表明 CCL18-CCR8 轴与 IgG4-RD 的病因有关，尽管该轴是否具有潜在的作为治疗靶点尚不清楚。我们的目的是通过使用 IgG4-RD（LAT Y136F 敲入小鼠；LAT 小鼠）的动物模型来阐明鼠 CCL8（人类 CCL18 的类似物）-CCR8 轴的致病作用和治疗潜力。我们比较了 6 周龄 LAT 小鼠和同窝小鼠的炎症细胞浸润和唾液腺纤维化。还比较了 Ccl8 和 Ccr8 的表达。下一个，我们研究了在 LAT 小鼠中静脉注射抗 CCL8 中和抗体对唾液腺炎症和纤维化的治疗效果。我们还研究了在体外用重组小鼠 CCL8 刺激对小鼠成纤维细胞系 (NIH/3 T3) 中胶原蛋白产生的影响。与同窝小鼠相比，LAT 小鼠在唾液腺中表现出明显的炎症细胞浸润和纤维化。LAT 小鼠唾液腺的病灶和纤维化评分显着高于同窝小鼠。LAT 小鼠脾脏中 Ccl8 和唾液腺中 Ccr8 的表达水平显着高于同窝小鼠。抗 CCL8 抗体显着改善了 LAT 小鼠唾液腺的病灶和纤维化评分。体外，用重组小鼠 CCL8 刺激显着增加了 NIH/3 T3 中胶原蛋白的表达和 ERK1/2 磷酸化。我们阐明了 LAT 小鼠中小鼠 CCL8-CCR8 轴的过表达和治疗潜力，它可以通过 ERK1/2 磷酸化以及炎症细胞的趋化性在纤维化中起关键作用。人 CCL18-CCR8 轴可能是 IgG4-RD 的新治疗靶点。