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目的 探究肽基精氨酸脱亚胺酶4（PADI4）对基质金属蛋白酶（MMPs）表达的调控机制及其在系统性红斑狼疮（SLE）发展中的潜在作用。方法 采用实时荧光定量逆转录聚合酶链反应（RT-qPCR）检测SLE患者与健康对照（HC）组MMP-14/17/25的mRNA表达水平，应用酶联免疫吸附实验（ELISA）测定其血清蛋白水平。Spearman秩相关分析评价MMPs水平与SLE患者临床指标的相关性。利用PADI4抑制剂GSK484处理原代中性粒细胞，或在PADI4敲减的中性粒细胞样HL-60细胞（dHL-60）中检测MMPs表达水平变化，并通过细胞划痕实验评估细胞迁移能力。结果 SLE患者中性粒细胞MMP-14/17/25的mRNA表达低于HC组（均P<0.01）。血清MMP-14/17/25表达低于HC组（均P<0.01）。MMP-14水平与免疫球蛋白G（IgG）（r=-0.266）、免疫球蛋白A（IgA）（r=-0.286）、球蛋白（GLB）（r=-0.269）呈负相关（均P<0.05），MMP-17水平（r=-0.269）及MMP-25水平（r=-0.244）与尿蛋白（UTP）均呈负相关（均P<0.05）。GSK484（10 μmol/L）抑制PADI4活性后，与对照组相比，中性粒细胞MMP-14/17/25蛋白表达水平上调（均P<0.05），同时细胞划痕迁移率增加（P<0.01）。敲减PADI4表达后，MMP-14/17/25 mRNA表达水平较对照组上调（均P<0.05）。结论 MMP-14/17/25在SLE患者中性粒细胞和血清中低表达，受PADI4负向调控。PADI4可能通过抑制MMPs表达削弱细胞迁移功能，进而参与SLE疾病发展。MMPs或可作为SLE病情监测及靶向干预的潜在新靶点。
Abstract：Objective To investigate the regulatory mechanism of peptidylarginine deiminase 4 (PADI4) on matrix metalloproteinase (MMPs) expression and its potential role in the development of systemic lupus erythematosus (SLE). Methods The mRNA expression levels of MMP-14/17/25 in SLE patients and healthy controls (HC) were measured by real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-qPCR)， and their serum protein levels were measured by enzyme-linked immunosorbent assay (ELISA). Spearman's rank correlation analysis was used to evaluate the correlations between MMPs levels and clinical parameters in SLE patients. Primary neutrophils were treated with the PADI4 inhibitor GSK484， or MMPs expression levels were examined in PADI4-knockdown neutrophil-like HL-60 (dHL-60) cells， and cell migration ability was assessed by wound healing assay. Results The mRNA expression levels of MMP-14/17/25 in neutrophils from SLE patients were lower than those in the HC (all P<0.01). Serum levels of these three MMPs were also lower than those in the HC (all P<0.01). MMP-14 levels were negatively correlated with immunoglobulin G (IgG) (r=-0.266)， immunoglobulin A (IgA) (r=-0.286)， and globulin (GLB)(r=-0.269) (all P<0.05)， while both MMP-17 (r =-0.269) and MMP-25(r =-0.244) levels were negatively correlated with urinary protein (UTP) (all P<0.05). After treatment with GSK484 (10 μmol/L) to inhibit PADI4 activity， the protein expression levels of MMP-14/17/25 in neutrophils were higher than those in the Vehicle group (all P<0.05)， and the cell migration rate in wound healing assay was also greater than that in the Vehicle group (P<0.01). Furthermore， after knockdown of PADI4 expression， the mRNA expression levels of MMP-14/17/25 were higher than those in the Vehicle group (all P<0.05). Conclusion MMP-14/17/25 are downregulated in SLE and negatively regulated by PADI4. PADI4 may contribute to SLE progression by suppressing MMPs expression and neutrophil migration. These findings suggest that MMPs may serve as novel biomarkers and therapeutic targets for SLE.
[1] Dai X， Fan Y， Zhao X. Systemic lupus erythematosus: updated insights on the pathogenesis， diagnosis， prevention and therapeutics[J]. Sig Transduct Target Ther， 2025， 10: 102. doi:10.1038/s41392-025-02168-0.
[2] Shih Y C， Chen P Y， Ko T M， et al. MMP-9 deletion attenuates arteriovenous fistula neointima through reduced perioperative vascular inflammation[J]. IJMS， 2021， 22(11): 5448. doi:10.3390/ijms22115448.
[3] Chen Z， Wang H， Xia Y， et al. Therapeutic potential of mesenchymal cell–derived miRNA-150-5p–expressing exosomes in rheumatoid arthritis mediated by the modulation of MMP14 and VEGF[J]. J Immunol， 2018， 201(8): 2472-82. doi:10.4049/jimmunol.1800304.
[4] 方全钢， 刘海芸， 万 静， 等. MMP25和E-cadherin在类风湿关节炎中的诊断价值[J]. 江西医药， 2024， 59(2): 143-7， 154. doi:10.3969/j.issn.1006-2238.2024.02.001.
[5] 马 洁， 汪晓庆， 周廷栋， 等. 肽基精氨酸脱亚胺酶4调控IL-8分泌参与系统性红斑狼疮发病的研究[J]. 安徽医科大学学报， 2025， 60(10): 1874-8， 1886. doi:10.19405/j.cnki.issn1000-1492.2025.10.013.
[6] Nakamura K， Nakayama H， Sasaki S， et al. Mycobacterium avium-intracellulare complex promote release of pro-inflammatory enzymes matrix metalloproteinases by inducing neutrophil extracellular trap formation[J]. Sci Rep， 2022， 12: 5181. doi:10.1038/s41598-022-09017-y.
[7] González-García A， Cusácovich I， Ruiz-Irastorza G. Treatment of systemic lupus erythematosus: new therapeutic options[J]. Rev Clínica Espa?ola Engl Ed， 2023， 223(10): 629-39. doi:10.1016/j.rceng.2023.11.001.
[8] Lazar S， Kahlenberg J M. Systemic lupus erythematosus: new diagnostic and therapeutic approaches[J]. Annu Rev Med， 2023， 74: 339-52. doi:10.1146/annurev-med-043021-032611.
[9] Wang G， Chen S， Xie Z， et al. TGFβ attenuates cartilage extracellular matrix degradation via enhancing FBXO6-mediated MMP14 ubiquitination[J]. Ann Rheumatic Dis， 2020， 79(8): 1111-20. doi:10.1136/annrheumdis-2019-216911.
[10] Chalkia A， Gakiopoulou H， Theochari I， et al. TGF-β1/smad signalling in proliferative glomerulonephritis associated with autoimmune diseases[J]. MJR， 2022， 33(2): 176. doi:10.31138/mjr.33.2.176.
[11] Han K Y， Dugas-Ford J， Seiki M， et al. Evidence for the involvement of MMP14 in MMP2 processing and recruitment in exosomes of corneal fibroblasts[J]. Invest Ophthalmol Vis Sci， 2015， 56(9): 5323-9. doi:10.1167/iovs.14-14417.
[12] Gonzalez-Molina J， Gramolelli S， Liao Z， et al. MMP14 in sarcoma: a regulator of tumor microenvironment communication in connective tissues[J]. Cells， 2019， 8(9): 991. doi:10.3390/cells8090991.
[13] Xiao C， Wang Y， Cheng Q， et al. Increased expression of MMP17 predicts poor clinical outcomes in epithelial ovarian cancer patients[J]. Medicine， 2022， 101(34): e30279. doi:10.1097/md.0000000000030279.
[14] English W R， Velasco G， Stracke J O， et al. Catalytic activities of membrane-type 6 matrix metalloproteinase (MMP25)[J]. FEBS Lett， 2001， 491(1-2): 137-42. doi:10.1016/S0014-5793(01)02150-0.
[15] Hanata N， Shoda H， Hatano H， et al. Peptidylarginine deiminase 4 promotes the renal infiltration of neutrophils and exacerbates the TLR7 agonist-induced lupus mice[J]. Front Immunol， 2020， 11: 1095. doi:10.3389/fimmu.2020.01095.
[16] 余武汉， 陈 浪， 李腾飞， 等. 中性粒细胞胞外诱捕网对组织器官损害的研究进展[J]. 中国普通外科杂志， 2021， 30(12): 1485-94. doi:10.7659/j.issn.1005-6947.2021.12.013.
基本信息:
中图分类号:R593.241
引用信息:
[1]罗颖,汪晓庆,马洁,等.PADI4负向调控中性粒细胞MMP-14/17/25表达在系统性红斑狼疮中的机制[J].安徽医科大学学报().
基金信息:
安徽高校自然科学研究项目（编号：KJ2021ZD0029）; 安徽省高校科研项目（编号：2024AH050787）
2026-07-24
2026-07-24
2026-07-24