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S100A8 警报素可支持周围型脊柱关节炎滑膜微环境中成纤维细胞产生白细胞介素 6 和金属蛋白酶 9。

S100A8 alarmin supports IL-6 and metalloproteinase-9 production by fibroblasts in the synovial microenvironment of peripheral spondyloarthritis.

机构信息

Biochemistry Department, Universidad Nacional de San Luis, San Luis, ;Argentina.

Instituto Multidisciplinario de Investigaciones Biológicas-San Luis (IMIBIO-SL), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de San Luis (UNSL), San Luis, Argentina.

出版信息

Front Immunol. 2023 Jan 9;13:1077914. doi: 10.3389/fimmu.2022.1077914. eCollection 2022.

DOI:10.3389/fimmu.2022.1077914
PMID:36700196
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9868917/
Abstract

INTRODUCTION

Spondyloarthritis (SpA) is a common autoinflammatory disease. S100A8/ S100A9 alarmin is strongly expressed in the synovial sublining layers of psoriatic arthritis. S100A8/ S100A9 is the most abundant protein in rheumatoid arthritis synovial fluid (SF) and has a key role in promoting IL-6 expression in fibroblast-like synoviocytes (FLS). The molecular mechanisms and the role of S100-alarmins in the synovial microenvironment of SpA have never been demonstrated.

METHODS AND RESULTS

Here, we confirm the effect of the synovial microenvironment of peripheral SpA on interleukin-6 (IL-6) and metalloproteinase (MMP)-9 production by FLS. MMP-9 expression and activity were detected, which were reduced in the presence of anti-IL-6R. Analyzing cell signaling mechanisms, we found that stimulation with IL-6 co-triggered MMP-9 and IL-10 secretion. MMP-9 secretion depended on JNK and p38 MAPKs, whereas IL-10 secretion was dependent on the JAK pathway as a potential feedback mechanism controlling IL-6-induced MMP-9 expression. Using a proteomic approach, we identified S100A8 in the peripheral SpA SF. This presence was confirmed by immunoblotting. S100A8 increased the IL-6 secretion via ERK and p38 MAPK pathways. Furthermore, anti-S100A8/A9 reduced both IL-6 and MMP-9 production induced by SpA SF in FLS.

DISCUSSION

Our data reveal a marked relationship between S100A8 alarmin with IL-6 and MMP-9 secretion by FLS in the real synovial microenvironment of peripheral SpA. These results identify a mechanism linking S100A8 to the pathogenesis of peripheral SpA.

摘要

简介

脊柱关节炎（SpA）是一种常见的自身炎症性疾病。S100A8/S100A9 警报素在银屑病关节炎的滑膜下衬里层中强烈表达。S100A8/S100A9 是类风湿关节炎滑膜液（SF）中最丰富的蛋白质，在成纤维样滑膜细胞（FLS）中促进白细胞介素 6（IL-6）表达方面发挥关键作用。S100-警报素在 SpA 滑膜微环境中的分子机制及其作用从未被证明过。

方法和结果

在这里，我们证实了外周 SpA 的滑膜微环境对 FLS 产生白细胞介素 6（IL-6）和金属蛋白酶（MMP）-9 的影响。检测到 MMP-9 的表达和活性，在存在抗 IL-6R 的情况下，其表达和活性降低。分析细胞信号转导机制，我们发现 IL-6 刺激共同触发 MMP-9 和 IL-10 的分泌。MMP-9 的分泌依赖于 JNK 和 p38 MAPKs，而 IL-10 的分泌依赖于 JAK 途径，作为一种潜在的反馈机制，控制 IL-6 诱导的 MMP-9 表达。使用蛋白质组学方法，我们在外周 SpA SF 中鉴定出 S100A8。免疫印迹法证实了这一点的存在。S100A8 通过 ERK 和 p38 MAPK 途径增加了 IL-6 的分泌。此外，抗 S100A8/A9 减少了 SpA SF 诱导的 FLS 中 IL-6 和 MMP-9 的产生。

讨论

我们的数据揭示了在真实的外周 SpA 滑膜微环境中，S100A8 警报素与 FLS 中 IL-6 和 MMP-9 分泌之间的显著关系。这些结果确定了将 S100A8 与外周 SpA 发病机制联系起来的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/0cd2c35b2bd5/fimmu-13-1077914-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/86555076de17/fimmu-13-1077914-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/337e7b96a50c/fimmu-13-1077914-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/bc5f51a6a2d4/fimmu-13-1077914-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/00cc5e254604/fimmu-13-1077914-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/0cd2c35b2bd5/fimmu-13-1077914-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/86555076de17/fimmu-13-1077914-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/337e7b96a50c/fimmu-13-1077914-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/bc5f51a6a2d4/fimmu-13-1077914-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/00cc5e254604/fimmu-13-1077914-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d257/9868917/0cd2c35b2bd5/fimmu-13-1077914-g005.jpg

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