Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences University of Glasgow, Glasgow, Scotland, UK.
Orthopaedic Research Institute, Department of Orthopaedic Surgery, St George Hospital Campus, University of New South Wales, New South Wales, Australia.
Sci Rep. 2019 Feb 6;9(1):1463. doi: 10.1038/s41598-018-37684-3.
Alarmins S100A8 and S100A9 are endogenous molecules released in response to environmental triggers and cellular damage. They are constitutively expressed in immune cells such as monocytes and neutrophils and their expression is upregulated under inflammatory conditions. The molecular mechanisms that regulate inflammatory pathways in tendinopathy are largely unknown therefore identifying early immune effectors is essential to understanding the pathology. Based on our previous investigations highlighting tendinopathy as an alarmin mediated pathology we sought evidence of S100A8 & A9 expression in a human model of tendinopathy and thereafter, to explore mechanisms whereby S100 proteins may regulate release of inflammatory mediators and matrix synthesis in human tenocytes. Immunohistochemistry and quantitative RT-PCR showed S100A8 & A9 expression was significantly upregulated in tendinopathic tissue compared with control. Furthermore, treating primary human tenocytes with exogenous S100A8 & A9 significantly increased protein release of IL-6, IL-8, CCL2, CCL20 and CXCL10; however, no alterations in genes associated with matrix remodelling were observed at a transcript level. We propose S100A8 & A9 participate in early pathology by modulating the stromal microenvironment and influencing the inflammatory profile observed in tendinopathy. S100A8 and S100A9 may participate in a positive feedback mechanism involving enhanced leukocyte recruitment and release of pro-inflammatory cytokines from tenocytes that perpetuates the inflammatory response within the tendon in the early stages of disease.
警报素 S100A8 和 S100A9 是对环境触发和细胞损伤作出反应而释放的内源性分子。它们在免疫细胞（如单核细胞和中性粒细胞）中持续表达，在炎症条件下其表达上调。因此，确定早期免疫效应物对于理解病理学至关重要，而肌腱病中调节炎症途径的分子机制在很大程度上尚不清楚。基于我们之前的研究强调了肌腱病作为警报素介导的病理学，我们在肌腱病的人类模型中寻找 S100A8 和 S100A9 表达的证据，然后探讨 S100 蛋白可能调节人类肌腱细胞中炎症介质释放和基质合成的机制。免疫组织化学和定量 RT-PCR 显示，与对照组相比，S100A8 和 S100A9 在肌腱病组织中的表达显著上调。此外，用外源性 S100A8 和 S100A9 处理原代人肌腱细胞显著增加了白细胞介素 6、白细胞介素 8、CCL2、CCL20 和 CXCL10 的蛋白释放；然而，在转录水平上没有观察到与基质重塑相关的基因发生变化。我们提出 S100A8 和 S100A9 通过调节基质微环境并影响肌腱病中观察到的炎症特征参与早期病理学。S100A8 和 S100A9 可能参与涉及增强白细胞募集和从肌腱细胞释放促炎细胞因子的正反馈机制，从而在疾病的早期阶段使肌腱内的炎症反应持续存在。
