He Guiliang, Ma Mengru, Yang Wei, Wang Hao, Zhang Yong, Gao Ming-Qing
College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.
Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China.
Int J Biol Sci. 2017 May 5;13(5):604-614. doi: 10.7150/ijbs.19591. eCollection 2017.
Fibroblasts constitute the majority of the stromal cells within bovine mammary gland, yet the functional contributions of these cells to mastitis and fibrosis and the mechanism are poorly understood. In this study, we demonstrate that inflammation-associated fibroblasts (INFs) extracted from bovine mammary glands with clinical mastitis had different expression pattern regarding to several extracellular matrix (ECM) proteins, chemokines and cytokines compared to normal fibroblasts (NFs) from dairy cows during lactation. The INFs induced epithelial-mesenchymal transition (EMT) and inflammatory responses of mammary epithelial cells in a vitro co-culture model. These functional contributions of INFs to normal epithelial cells were mediated through their ability to secrete stromal cell-derived factor 1 (SDF-1). SDF-1 was highly secreted/expressed by INFs, lipopolysaccharide (LPS) -treated NFs, lipoteichoic acid (LTA) -treated NFs, as well as mastitic tissue compared to their counterparts. Exogenous SDF-1 promoted EMT on epithelial cells through activating NF-κB pathway, induced inflammation response and inhibited proliferation of epithelial cells. In addition, SDF-1 was able to induce mastitis and slight fibrosis of mouse mammary gland, which was attenuated by a specific inhibitor of the receptor of SDF-1. Our findings indicate that stromal fibroblasts within mammary glands with mastitis contribute to EMT and inflammatory responses of epithelial cells through the secretion of SDF-1, which could result in the inflammation spread and fibrosis within mammary gland.
成纤维细胞构成了牛乳腺中大部分的基质细胞，但这些细胞对乳腺炎和纤维化的功能贡献及其机制尚不清楚。在本研究中，我们证明，与泌乳期奶牛的正常成纤维细胞（NFs）相比，从患有临床乳腺炎的牛乳腺中提取的炎症相关成纤维细胞（INFs）在几种细胞外基质（ECM）蛋白、趋化因子和细胞因子方面具有不同的表达模式。在体外共培养模型中，INFs诱导乳腺上皮细胞发生上皮-间质转化（EMT）和炎症反应。INFs对正常上皮细胞的这些功能贡献是通过其分泌基质细胞衍生因子1（SDF-1）的能力介导的。与相应的对照相比，INFs、脂多糖（LPS）处理的NFs、脂磷壁酸（LTA）处理的NFs以及乳腺炎组织中SDF-1的分泌/表达水平都很高。外源性SDF-1通过激活NF-κB途径促进上皮细胞的EMT，诱导炎症反应并抑制上皮细胞增殖。此外，SDF-1能够诱导小鼠乳腺发生乳腺炎和轻微纤维化，而SDF-1受体的特异性抑制剂可减轻这种情况。我们的研究结果表明，患有乳腺炎的乳腺中的基质成纤维细胞通过分泌SDF-1促进上皮细胞的EMT和炎症反应，这可能导致乳腺内炎症扩散和纤维化。
