Blocking Matrix Metalloproteinase-9 Abrogates Collagen-Induced Arthritis via Inhibiting Dendritic Cell Migration
Blocking Matrix Metalloproteinase-9 Abrogates Collagen-Induced Arthritis via Inhibiting Dendritic Cell Migration
复制标题
阻断基质金属蛋白酶-9 通过抑制树突状细胞迁移消除胶原诱导的关节炎
DOI：
10.4049/jimmunol.1800412
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发表时间：
2018-12-15
影响因子：
4.4
通讯作者：
Sun, Erwei
中科院分区：
文献类型：
--
作者：
He, Juan;Li, Xing;Sun, Erwei
树突状细胞（DC）向淋巴结（LN）转运以呈递抗原是类风湿关节炎（RA）发病机制中的关键步骤。基质金属蛋白酶-9（MMP-9）是DC迁移的关键分子。因此，阻断MMP-9以抑制DC迁移可能是治疗RA的新策略。在这项研究中，我们使用抗MMP-9抗体治疗DBA/1 J小鼠胶原诱导的关节炎（CIA），并证明抗MMP-9抗体治疗通过调节DC运输显着抑制CIA的发展。在抗MMP-9抗体治疗的CIA小鼠中，引流LN中的DC数量明显减少。在体外，抗MMP-9抗体和MMP-9抑制剂抑制成熟骨髓来源的DC在Matrigel中响应于CCR 7配体CCL 21的迁移。此外，阻断MMP-9可减少CIA小鼠淋巴结中的T和B细胞数量，但对淋巴结或脾脏中纯化的CD 4（+）T细胞对II型胶原的T细胞反应无直接影响。抗MMP-9抗体对DCs的MHC Ⅱ类分子、CD 40、CD 80、CD 86及趋化因子受体（CCR 5和CCR 7）的表达无明显影响。此外，我们发现在MMP-9（-/-）小鼠和野生型小鼠中，与野生型DC相比，MMP-9（-/-）DC从足垫运输到腘淋巴结的数量显著减少。综上所述，这些结果表明DC衍生的MMP-9是DC迁移的关键因素，阻断MMP-9以抑制DC迁移可能构成未来治疗RA和其他类似自身免疫性疾病的新策略。
Trafficking of dendritic cells (DCs) to lymph nodes (LNs) to present Ags is a crucial step in the pathogenesis of rheumatoid arthritis (RA). Matrix metalloproteinase-9 (MMP-9) is the key molecule for DC migration. Thus, blocking MMP-9 to inhibit DC migration may be a novel strategy to treat RA. In this study, we used anti-MMP-9 Ab to treat collagen-induced arthritis (CIA) in DBA/1J mice and demonstrated that anti-MMP-9 Ab treatment significantly suppressed the development of CIA via the modulation of DC trafficking. In anti-MMP-9 Ab-treated CIA mice, the number of DCs in draining LNs was obviously decreased. In vitro, anti- MMP-9 Ab and MMP-9 inhibitor restrained the migration of mature bone marrow-derived DCs in Matrigel in response to CCR7 ligand CCL21. In addition, blocking MMP-9 decreased T and B cell numbers in LNs of CIA mice but had no direct influence on the T cell response to collagen II by CD4(+) T cells purified from LNs or spleen. Besides, anti-MMP-9 Ab did not impact on the expression of MHC class II, CD40, CD80, CD86, and chemokine receptors (CCR5 and CCR7) of DCs both in vivo and in vitro. Furthermore, we discovered the number of MMP-9(-/-) DCs trafficking from footpads to popliteal LNs was dramatically reduced as compared with wild type DCs in both MMP-9(-/-) mice and wild type mice. Taken together, these results indicated that DC-derived MMP-9 is the crucial factor for DC migration, and blocking MMP-9 to inhibit DC migration may constitute a novel strategy of future therapy for RA and other similar autoimmune diseases.