Matrix Metalloproteinase 8 Deficiency in Mice Exacerbates Inflammatory Arthritis Through Delayed Neutrophil Apoptosis and Reduced Caspase 11 Expression
Matrix Metalloproteinase 8 Deficiency in Mice Exacerbates Inflammatory Arthritis Through Delayed Neutrophil Apoptosis and Reduced Caspase 11 Expression
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DOI：
10.1002/art.27757
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发表时间：
2010-12-01
影响因子：
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通讯作者：
Overall, Christopher M.
中科院分区：
文献类型：
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作者：
Cox, Jennifer H.;Starr, Amanda E.;Overall, Christopher M.
Objective.中性粒细胞的积累通过细胞浸润和细胞清除来平衡，其控制在类风湿性关节炎（RA）和其他慢性炎性疾病的发病机制中是关键的。在嗜中性粒细胞特异性蛋白酶中，基质金属蛋白酶8（MMP-8;也称为嗜中性粒细胞胶原酶或胶原酶2）传统上被认为是胶原降解的关键，因此细胞迁移和浸润。本研究旨在探讨MMP-8在自发性RA小鼠模型中的作用。将MMP-8（-/-）小鼠回交到Fas缺陷型MRL/lpr背景上，所述Fas缺陷型MRL/lpr背景是以包括自发性自身免疫性关节炎的全身性自身免疫性为特征的小鼠品系。用弗氏完全佐剂诱导关节炎，并评估临床疾病和组织学参数。MMP-8（-/-）小鼠具有比它们的MMP-8（+/+）对应物更早和更严重的关节炎症，伴随着滑膜组织中大量中性粒细胞的积累，考虑到通常认为MMP-8具有重要的细胞外基质降解功能，这是一个意想不到的结果。通过CLIP-CHIP微阵列对MMP-8（-/-）小鼠中性粒细胞进行蛋白酶和蛋白酶抑制剂分析，发现除了细胞凋亡引发剂半胱天冬酶11的低表达外，蛋白酶水平几乎没有额外变化。这在未刺激的、脂多糖处理的和干扰素-γ处理的MMP-8（-/-）小鼠中性粒细胞中的蛋白质水平得到证实。MMP-8（-/-）小鼠中性粒细胞中caspase 11下游的凋亡执行者caspase 3的活性因此降低，与野生型小鼠细胞相比，转化为减少的中性粒细胞凋亡和细胞积聚。我们的研究结果表明，MMP-8是不是必不可少的中性粒细胞迁移关节炎和其他可能的自身免疫性疾病。相反，MMP-8对于中性粒细胞凋亡的正常速率是重要的，因此调节细胞清除。由于MMP-8缺乏导致中性粒细胞浸润的过度积累，这是由于延迟的细胞凋亡和与显著增加的中性粒细胞浸润相关的并发病理变化，因此MMP-8被抑制，并因此成为治疗关节炎的药物抗靶标。
Objective. Neutrophil accumulation is balanced by both cell infiltration and cell clearance, the controls of which are pivotal in the pathogenesis of rheumatoid arthritis (RA) and other chronic inflammatory diseases. Of the neutrophil-specific proteases, matrix metalloproteinase 8 (MMP-8; also known as neutrophil collagenase or collagenase 2) is traditionally viewed as being crucial for collagen degradation and hence cell migration and infiltration. This study was undertaken to examine the role of MMP-8 in a murine model of spontaneous RA.Methods. MMP-8(-/-) mice were backcrossed onto the Fas-defective MRL/lpr background, a mouse strain characterized by systemic autoimmunity including spontaneous autoimmune arthritis. Arthritis was induced with Freund's complete adjuvant and clinical disease and histologic parameters were assessed.Results. MMP-8(-/-) mice had earlier and more severe joint inflammation than their MMP-8(+/+) counterparts, coupled with a massive accumulation of neutrophils in synovial tissue, an unexpected result considering the commonly held view that MMP-8 has important extracellular matrix-degradative functions. Protease and protease inhibitor analysis of MMP-8(-/-) mouse neutrophils by CLIP-CHIP microarray revealed very little additional change in protease levels except for low expression of the apoptosis initiator caspase 11. This was confirmed at the protein level in unstimulated, lipopolysaccharide-treated, and interferon-gamma-treated MMP-8(-/-) mouse neutrophils. Downstream of caspase 11, the activity of the apoptosis executioner caspase 3 was consequently reduced in MMP-8(-/-) mouse neutrophils, translating to reduced neutrophil apoptosis and cell accumulation compared with wild-type mouse cells.Conclusion. Our findings indicate that MMP-8 is not essential for neutrophil migration in arthritis and likely other autoimmune diseases. Rather, MMP-8 is important for normal rates of neutrophil apoptosis and hence regulates cell clearance. Because MMP-8 deficiency leads to an exaggerated accumulation of neutrophil infiltrates due to delayed apoptosis and concurrent pathologic changes associated with dramatically increased neutrophil infiltration, MMP-8 is antiinflammatory and therefore a drug antitarget in the treatment of arthritis.