GZMK Facilitates Experimental Rheumatoid Arthritis Progression by Interacting with CCL5 and Activating the ERK Signaling.

IF 4.5 2区 医学 Q2 CELL BIOLOGY Inflammation Pub Date : 2024-11-04 DOI:10.1007/s10753-024-02166-4
Liting Xu, Hui Wang, Congcong Sun, Qingyu Zhao, Lili Wang, Qianqian Yan, Jialin Wang, Na Lin, Chunfang Liu
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Abstract

Synovial over-proliferation is a key event in the progression of rheumatoid arthritis (RA) disease. Ferroptosis may be essential for maintaining the balance between synovial proliferation and death. This study aimed to investigate the molecular mechanisms mediating the activation and ferroptosis of collagen-induced arthritis (CIA)-synovial fibroblasts (SFs). Differentially expressed genes (DEGs) in the synovial tissues of CIA rats and normal rats were screened through sequencing. The GSE115662 dataset from the GEO database was analyzed and screened for DEGs. The viability, proliferation, migration, invasion, cell cycle, and apoptosis of CIA-SFs were analyzed by cell counting kit-8, 5-ethynyl-2'-deoxyuridine, flow cytometry, transwell migration, and invasion assays. The ferroptosis of CIA-SFs was assessed using matching reagent kits to detect indicators like reactive oxygen species, ferrous iron, malondialdehyde, glutathione, and superoxide dismutase. The interaction between Granzyme K (GZMK) and C-C motif chemokine 5 (CCL5) was determined by coimmunoprecipitation assay. We found abnormal GZMK expression in the GSE115662 database and mRNA sequencing data. GZMK was overexpressed in CIA-SFs, and GZMK promoted cell proliferation, migration, invasion, inflammation, and decreased cell apoptosis and ferroptosis in CIA-SFs. GZMK could interact with CCL5 to activate the ERK signaling. GZMK and CCL5 knockdown improved by reducing arthritis scores, redness and swelling of paws, and pathological changes in joint synovium of CIA rats. CCL5 overexpression reversed the effects of GZMK silencing on CIA-SFs cell proliferation, migration, invasion, apoptosis, and ferroptosis. We confirmed that GZMK accelerated experimental rheumatoid arthritis progression by interacting with CCL5 and activating the ERK signaling.

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GZMK 通过与 CCL5 相互作用并激活 ERK 信号,促进实验性类风湿性关节炎的进展。
滑膜过度增殖是类风湿性关节炎(RA)病情发展的一个关键因素。铁变态反应可能是维持滑膜增殖和死亡之间平衡的关键。本研究旨在探讨介导胶原诱导的关节炎(CIA)-滑膜成纤维细胞(SFs)的活化和铁变态反应的分子机制。通过测序筛选了CIA大鼠和正常大鼠滑膜组织中的差异表达基因(DEGs)。对 GEO 数据库中的 GSE115662 数据集进行了分析和 DEGs 筛选。通过细胞计数试剂盒-8、5-乙炔基-2'-脱氧尿苷、流式细胞仪、Transwell迁移和侵袭试验分析了CIA-SFs的活力、增殖、迁移、侵袭、细胞周期和凋亡。使用配套试剂盒检测活性氧、亚铁、丙二醛、谷胱甘肽和超氧化物歧化酶等指标,评估了 CIA-SFs 的铁变态反应。粒酶 K(GZMK)与 C-C motif 趋化因子 5(CCL5)之间的相互作用是通过共沉淀法测定的。我们在GSE115662数据库和mRNA测序数据中发现了GZMK的异常表达。GZMK在CIA-SFs中过表达,GZMK在CIA-SFs中促进细胞增殖、迁移、侵袭、炎症,减少细胞凋亡和铁凋亡。GZMK可与CCL5相互作用,激活ERK信号转导。GZMK和CCL5的敲除可减少CIA大鼠关节炎评分、爪子红肿和关节滑膜的病理变化。CCL5 的过表达逆转了 GZMK 沉默对 CIA-SFs 细胞增殖、迁移、侵袭、凋亡和铁蛋白沉积的影响。我们证实,GZMK通过与CCL5相互作用并激活ERK信号传导,加速了实验性类风湿性关节炎的进展。
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来源期刊
Inflammation
Inflammation 医学-免疫学
CiteScore
9.70
自引率
0.00%
发文量
168
审稿时长
3.0 months
期刊介绍: Inflammation publishes the latest international advances in experimental and clinical research on the physiology, biochemistry, cell biology, and pharmacology of inflammation. Contributions include full-length scientific reports, short definitive articles, and papers from meetings and symposia proceedings. The journal''s coverage includes acute and chronic inflammation; mediators of inflammation; mechanisms of tissue injury and cytotoxicity; pharmacology of inflammation; and clinical studies of inflammation and its modification.
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