Leucine-rich α-2-glycoprotein-1 (LRG1) is a novel pro-fibrotic factor that modulates Transforming Growth Factor-β (TGF -β) signaling. However, its role in the corneal fibrotic response remains unknown. In the present study, we found that the LRG1 level increased in alkali-burned mouse corneas. In the LRG1-treated alkali-burned corneas, there were higher fibrogenic protein expression and neutrophils infiltration. LRG1 promoted neutrophils chemotaxis and CXCL-1 secretion. Conversely, LRG1-specific siRNA reduced fibrogenic protein expression and neutrophil infiltration in the alkali-burned corneas. The clearance of neutrophils effectively attenuated the LRG1-enhanced corneal fibrotic response, while the presence of neutrophils enhanced the effect of LRG1 on the fibrotic response in cultured TKE2 cells. In addition, the topical application of LRG1 elevated Interleukin-6 (IL-6) and p-Stat3 levels in the corneal epithelium and in isolated neutrophils. The clearance of neutrophils inhibited the expression of p-Stat3 and IL-6 promoted by LRG1 in alkali-burned corneas. Moreover, neutrophils significantly increased the production of IL-6 and p-Stat3 promoted by LRG1 in TKE2 cells. Furthermore, the inhibition of Stat3 signaling by S3I-201 decreased neutrophil infiltration and alleviated the LRG1-enhanced corneal fibrotic response in the alkali-burned corneas. S3I-201 also reduced LRG1 or neutrophils induced fibrotic response in TKE2 cells. In conclusion, LRG1 promotes the corneal fibrotic response by stimulating neutrophils infiltration via the modulation of the IL-6/Stat3 signaling pathway. Therefore, LRG1 could be targeted as a promising therapeutic strategy for patients with corneal fibrosis.

中文翻译：

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LRG1通过在碱灼伤的小鼠角膜中通过Stat3信号传导诱导中性粒细胞趋化性来促进角膜纤维化反应

富含亮氨酸的 α-2-糖蛋白-1 (LRG1) 是一种新型促纤维化因子，可调节转化生长因子-β (TGF-β) 信号传导。然而，它在角膜纤维化反应中的作用仍然未知。在本研究中，我们发现碱烧伤的小鼠角膜中 LRG1 水平增加。在 LRG1 处理的碱烧角膜中，纤维化蛋白表达和中性粒细胞浸润较高。LRG1 促进中性粒细胞趋化性和 CXCL-1 分泌。相反，LRG1 特异性 siRNA 减少了碱灼伤角膜中的纤维化蛋白表达和中性粒细胞浸润。中性粒细胞的清除有效减弱了 LRG1 增强的角膜纤维化反应，而中性粒细胞的存在增强了 LRG1 对培养的 TKE2 细胞纤维化反应的影响。此外，LRG1 的局部应用提高了角膜上皮和分离的中性粒细胞中白细胞介素 6 (IL-6) 和 p-Stat3 的水平。中性粒细胞的清除抑制了 LRG1 促进的 p-Stat3 和 IL-6 在碱灼伤角膜中的表达。此外，中性粒细胞显着增加了 TKE2 细胞中 LRG1 促进的 IL-6 和 p-Stat3 的产生。此外，S3I-201 对 Stat3 信号的抑制减少了中性粒细胞浸润并减轻了碱烧伤角膜中 LRG1 增强的角膜纤维化反应。S3I-201 还减少了 TKE2 细胞中 LRG1 或中性粒细胞诱导的纤维化反应。总之，LRG1 通过调节 IL-6/Stat3 信号通路刺激中性粒细胞浸润来促进角膜纤维化反应。所以，