S100A8 & S100A9: Alarmin mediated inflammation in tendinopathy
S100A8 & S100A9: Alarmin mediated inflammation in tendinopathy
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DOI：
10.1038/s41598-018-37684-3
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发表时间：
2019-02-06
影响因子：
4.6
通讯作者：
Millar, Neal L.
中科院分区：
文献类型：
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作者：
Crowe, Lindsay A. N.;McLean, Michael;Millar, Neal L.
Alarmins S100 A8和S100 A9是响应于环境触发和细胞损伤而释放的内源性分子。它们在免疫细胞如单核细胞和嗜中性粒细胞中组成型表达，并且它们的表达在炎性条件下上调。肌腱病变中调节炎症通路的分子机制在很大程度上是未知的，因此识别早期免疫效应物对于理解病理学至关重要。基于我们以前的研究强调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S100 A8和A9表达的证据，并在此之后探索S100蛋白可以调节人类肌腱细胞中炎症介质释放和基质合成的机制。免疫组化和定量RT-PCR显示，与对照组相比，S100 A8和A9在肌腱病变组织中的表达显著上调。此外，用外源性S100 A8和A9处理原代人腱细胞显著增加了IL-6、IL-8、CCL 2、CCL 20和CXCL 10的蛋白质释放;然而，在转录水平上没有观察到与基质重塑相关的基因的改变。我们提出S100 A8和A9通过调节间质微环境和影响肌腱病中观察到的炎症特征参与早期病理学。S100 A8和S100 A9可能参与正反馈机制，涉及增强白细胞募集和从肌腱细胞释放促炎细胞因子，其在疾病的早期阶段使肌腱内的炎症反应持续。
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.