MMP-1 drives immunopathology in human tuberculosis and transgenic mice
MMP-1 drives immunopathology in human tuberculosis and transgenic mice
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DOI：
10.1172/jci45666
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发表时间：
2011-05-01
影响因子：
15.9
通讯作者：
Friedland, Jon S.
中科院分区：
文献类型：
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作者：
Elkington, Paul;Shiomi, Takayuki;Friedland, Jon S.
结核分枝杆菌可导致肺组织损伤扩散，但驱动这种免疫病理学的机制知之甚少。肺基质的分解涉及基质金属蛋白酶，它具有独特的能力，在中性pH值下降解纤维状胶原蛋白。为了确定基质金属蛋白酶是否在结核病（TB）的免疫病理学中发挥作用，我们分析了基质金属蛋白酶及其抑制剂，金属蛋白酶组织抑制剂（TIMPs），在痰液和支气管肺泡灌洗液从TB患者和症状对照。HIV阴性和HIV阳性结核病患者的MMP-1浓度均显着增加，而HIV阴性结核病患者的TIMP浓度较低。在原代人单核细胞中，M.结核感染选择性上调MMP 1基因表达和分泌，特异性MMP抑制剂Ro 32 -3555抑制M.结核病驱动的MMP-1活性。由于小鼠MMP-1直系同源物在肺中不表达，因此感染M.结核病不发展与人类相当的组织破坏，我们用M.目的：探讨MMP-1是否引起肺免疫病理学改变。在MMP-1转基因小鼠中，M.结核感染增加了MMP-1的表达，导致肺肉芽肿中的肺泡破坏和显著更大的胶原分解。总之，MMP-1可以驱动TB中的组织破坏，并且代表限制免疫病理学的治疗靶标。
Mycobacterium tuberculosis can cause lung tissue damage to spread, but the mechanisms driving this immunopathology are poorly understood. The breakdown of lung matrix involves MMPs, which have a unique ability to degrade fibrillar collagens at neutral pH. To determine whether MMPs play a role in the immunopathology of tuberculosis (TB), we profiled MMPs and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs), in sputum and bronchoalveolar lavage fluid from patients with TB and symptomatic controls. MMP-1 concentrations were significantly increased in both HIV-negative and HIV-positive patients with TB, while TIMP concentrations were lower in HIV-negative TB patients. In primary human monocytes, M. tuberculosis infection selectively upregulated MMP1 gene expression and secretion, and Ro32-3555, a specific M MP inhibitor, suppressed M. tuberculosis-driven MMP-1 activity. Since the mouse MMP-1 ortholog is not expressed in the lung and mice infected with M. tuberculosis do not develop tissue destruction equivalent to humans, we infected transgenic mice expressing human MMP-1 with M. tuberculosis to investigate whether MMP-1 caused lung imrnunopathology. In the MMP-1 transgenic mice, M. tuberculosis infection increased MMP-1 expression, resulting in alveolar destruction in lung granulomas and significantly greater collagen breakdown. In summary, MMP-1 may drive tissue destruction in TB and represents a therapeutic target to limit immunopathology.