| TREML4调控NF-κB通路介导中性粒细胞胞外陷阱加重类风湿关节炎的机制研究 |
| 投稿时间：2025-01-08 修订日期：2025-02-06 点此下载全文 |
| 引用本文：张倩,牟晓月,金都,叶恒力.TREML4调控NF-κB通路介导中性粒细胞胞外陷阱加重类风湿关节炎的机制研究[J].医学研究杂志,2025,54(7):85-90 |
| DOI：
10.11969/j.issn.1673-548X.2025.07.016 |
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| 基金项目:浙江省医药卫生科技计划项目(2022RC294) |
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| 中文摘要:目的 探究髓样细胞表达的触发受体4(triggering receptor expressed on Myeloid cells-like 4,TREML4)调控核因子κB(nuclear factor-kappaB,NF-κB)通路介导中性粒细胞胞外陷阱(neutrophil extracellular traps,NETs)加重类风湿关节炎(rheumatoid arthritis,RA)的作用机制。方法 在DBA/1J小鼠皮下注射弗氏佐剂和牛Ⅱ型胶原诱导RA模型。使用佛波酯(phorbol 12-myristate 13-acetate,PMA)诱导中性粒细胞形成NETs。观察小鼠关节肿胀程度等形态学指标,使用苏木精-伊红(hematoxylin-eosin staining,HE)观察踝关节的病理情况,使用酶链免疫吸附试验(enzyme- linked immunosorbent assay,ELISA)检测血清中的炎性细胞因子白介素-1β(interleukin-1β,IL-1β)、白介素-6(interleukin-6,IL-6)和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α),使用Western blot法检测髓过氧化物酶(myeloperoxidase,MPO)和瓜氨酸化组蛋白H3(citrullinated histone H3,CitH3)以评估小鼠踝关节NETs的释放情况,使用Western blot法检测TREML4、NF-κB通路相关蛋白下游核因子κB抑制因子α(nuclear factor kappa B inhibitor α,IκBα)和NF-κB p65的表达情况,使用免疫荧光检测中性粒细胞中MPO和CitH3的分布情况以评估NETs的形成。结果 相比于对照组小鼠,RA组小鼠的关节出现肿胀、骨质侵蚀、免疫细胞过度浸润及软骨损伤,血清中炎性细胞因子IL-6、TNF-α和IL-1β增加(P＜0.01),IκBα表达降低(P＜0.01),NF-κB p65表达增加,差异有统计学意义(P＜0.01)。相比于正常组中性粒细胞,PMA组中性粒细胞形成的NETs数量增加,TREML4和NF-κB p65表达增加,IκBα表达降低,差异有统计学意义(P＜0.01)。相比于PMA+si-NC组中性粒细胞,PMA+si-TREML4组中性粒细胞形成的NETs数量降低,TREML4和NF-κB p65表达降低,IκBα表达增加,差异有统计学意义(P＜0.01)。结论 TREML4能够调控NF-κB通路介导的NETs形成以促进RA。 |
| 中文关键词:类风湿关节炎 TREML4 NF-κB通路 中性粒细胞胞外陷阱 |
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| TREML4 Regulates NF-κB Pathway to Aggravate Rheumatoid Arthritis by Neutrophil Extracellular Traps. |
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| Abstract:Objective To explore the mechanism by which the triggering receptor expressed on Myeloid cells-like 4 (TREML4) regulates nuclear factor-kappaB (NF-κB) pathway mediates neutrophil extracellular traps (NETs) aggravating rheumatoid arthritis (RA). Methods RA model was induced by subcutaneous injection of Freund adjuvant and bovine collagen type II in DBA/1J mice. We used phorbol 12-myristate 13-acetate (PMA) to induce neutrophils to form NETs. We observed the degree of joint swelling and other morphological indicators, used hematoxylin-eosin staining (HE) staining to observe the pathology of the ankle joint, used enzyme- linked immunosorbent assay (ELISA) to measure the levels of inflammatory factors interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in serum, used western blot to detect the expression of myeloperoxidase (MPO) and citrullinated histone H3 (CitH3) for assess the release of NETs in the ankle joint of mice, used western blot to detect the expression of TREML4 and NF-κB pathway-associated proteins nuclear factor kappa B inhibitor α (IκBα) and NF-κB p65, used immunofluorescence to detect the distribution of MPO and CitH3 in neutrophils to assess the formation of NETs. Results Compared with the control group, the RA group exhibited joint swelling, bone erosion, excessive infiltration of immune cells and cartilage damage, and the serum inflammatory factors IL-6, TNF-α and IL-1β were significantly increased (P＜0.01), the expression of IκBα was significantly decreased (P＜0.01), and the expression of NF-κB p65 was significantly increased (P＜0.01). Compared with control group, the number of NETs formed by neutrophils in PMA group was significantly increased, the expression of TREML4 and NF-κB p65 was significantly increased (P＜0.01), and the expression of IκBα was significantly decreased (P＜0.01). Compared with the PMA+si-NC group, the number of NETs formed by neutrophils in the PMA+si-TREML4group was significantly reduced (P＜0.01), the expression of TREML4 and NF-κB p65 was significantly decreased (P＜0.01), and the expression of IκBα was significantly increased (P＜0.01). ConclusionTREML4 can regulate the formation of NETs mediated by NF-κB pathway to aggravate RA. |
| keywords:Rheumatoid arthritis TREML4 NF-κB pathway Neutrophil extracellular traps |
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