Synergy between a plasminogen cascade and MMP-9 in autoimmune disease.
Synergy between a plasminogen cascade and MMP-9 in autoimmune disease.
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DOI：
10.1172/jci23977
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发表时间：
2005-04
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影响因子：
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通讯作者：
Zhi Liu;Ning Li;L. Diaz;M. Shipley;R. Senior;Z. Werb
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作者：
Zhi Liu;Ning Li;L. Diaz;M. Shipley;R. Senior;Z. Werb
纤溶酶原/纤溶酶（Plg/plasmin）系统和MMPs的细胞外蛋白水解是自身免疫性和炎症性疾病中组织损伤所必需的。在自身免疫性疾病大疱性类天疱疮（BP）的实验模型中，我们证明了Plg级联与MMP-9/明胶酶B在体内的真皮-表皮分离过程中协同作用。用半粒内体抗原BP180抗体诱导小鼠BP。缺乏MMP-9的小鼠对实验性BP有抗性，而缺乏Plg以及组织Plg激活剂（tPA）和尿激酶Plg激活剂（uPA）的小鼠在BP180抗体诱导下出现延迟且强度较小的水疱形成。Plg缺陷小鼠局部重组Plg或活性形式的MMP-9 (actMMP-9)，而不是MMP-9的前酶形式（proMMP-9），发生BP。相比之下，proMMP-9或actMMP-9，而不是Plg，重建了mmp -9缺陷小鼠对皮肤病的易感性。此外，注射致病性IgG的mmp -3缺陷小鼠出现相同程度的BP，皮肤中actimmp -9的表达水平与WT对照组相似。因此，在BP中，Plg/纤溶蛋白系统对MMP-9的激活和随后的真皮-表皮分离具有上位性。
Extracellular proteolysis by the plasminogen/plasmin (Plg/plasmin) system and MMPs is required for tissue injury in autoimmune and inflammatory diseases. We demonstrate that a Plg cascade synergizes with MMP-9/gelatinase B in vivo during dermal-epidermal separation in an experimental model of bullous pemphigoid (BP), an autoimmune disease. BP was induced in mice by antibodies to the hemidesmosomal antigen BP180. Mice deficient in MMP-9 were resistant to experimental BP, while mice deficient in Plg and both tissue Plg activator (tPA) and urokinase Plg activator (uPA) showed delayed and less intense blister formation induced by antibodies to BP180. Plg-deficient mice reconstituted locally with Plg or the active form of MMP-9 (actMMP-9), but not the proenzyme form of MMP-9 (proMMP-9), developed BP. In contrast, proMMP-9 or actMMP-9, but not Plg, reconstituted susceptibility of MMP-9-deficient mice to the skin disease. In addition, MMP-3-deficient mice injected with pathogenic IgG developed the same degree of BP and expressed levels of actMMP-9 in the skin similar to those of WT controls. Thus, the Plg/plasmin system is epistatic to MMP-9 activation and subsequent dermal-epidermal separation in BP.