Monocyte Adhesion, Migration, and Extracellular Matrix Breakdown Are Regulated by Integrin αVβ3 in Mycobacterium tuberculosis Infection.
Monocyte Adhesion, Migration, and Extracellular Matrix Breakdown Are Regulated by Integrin αVβ3 in Mycobacterium tuberculosis Infection.
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DOI：
10.4049/jimmunol.1700128
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发表时间：
2017-08-01
期刊：
影响因子：
--
通讯作者：
Porter JC
中科院分区：
文献类型：
--
作者：
Brilha S;Wysoczanski R;Whittington AM;Friedland JS;Porter JC
在结核病（TB）中，先天性炎症免疫反应驱动组织破坏、发病率和死亡率。单核细胞分泌基质金属蛋白酶（MMPs），其在局部组织破坏和空化中具有关键作用。我们假设，整合素信号可能调节单核细胞MMP分泌在肺结核细胞粘附到细胞外基质（ECM）。结核分枝杆菌刺激的单核细胞与I型胶原和纤连蛋白的粘附使MMP-1基因表达分别增加了2.6倍和4.3倍，分泌分别增加了60%（从1208.1 ± 186到1934.4 ± 135 pg/ml; p < 0.0001）和63%（1970.3 ± 95 pg/ml; p < 0.001）。MMP-10分泌增加了90%，结合到I型胶原和55%的纤连蛋白，而MMP-7增加了57%的胶原。ECM不影响金属蛋白酶-1或-2的组织抑制剂的分泌。整合素αVβ3表面表达在刺激的单核细胞中特异性上调，并在粘附至I型胶原后进一步增加。β3或αV整合素亚基的结合增加M中MMP-1/10的分泌。结核病刺激的单核细胞据我们所知，在一组TB患者中，与对照受试者相比，首次检测到诱导痰中整合素β3 mRNA积累显著增加（p < 0.05）。在transwell系统中，整合素αVβ3与感染的单核细胞上增加的和功能活性的MMP-1区域共定位，αVβ3阻断显著降低I型胶原分解，并损害单核细胞粘附和白细胞迁移（p < 0.0001）。总之，我们的数据表明，M。结核刺激上调单核细胞上整合素αVβ3的表达，其上调MMP-1和MMP-10在与ECM粘附时的分泌。这导致单核细胞募集和胶原酶活性增加，这将驱动炎性组织损伤。
In tuberculosis (TB), the innate inflammatory immune response drives tissue destruction, morbidity, and mortality. Monocytes secrete matrix metalloproteinases (MMPs), which have key roles in local tissue destruction and cavitation. We hypothesized that integrin signaling might regulate monocyte MMP secretion in pulmonary TB during cell adhesion to the extracellular matrix (ECM). Adhesion to type I collagen and fibronectin by Mycobacterium tuberculosis–stimulated monocytes increased MMP-1 gene expression by 2.6-fold and 4.3-fold respectively, and secretion by 60% (from 1208.1 ± 186 to 1934.4 ± 135 pg/ml; p < 0.0001) and 63% (1970.3 ± 95 pg/ml; p < 0.001). MMP-10 secretion increased by 90% with binding to type I collagen and 55% with fibronectin, whereas MMP-7 increased 57% with collagen. The ECM did not affect the secretion of tissue inhibitors of metalloproteinases-1 or -2. Integrin αVβ3 surface expression was specifically upregulated in stimulated monocytes and was further increased after adhesion to type I collagen. Binding of either β3 or αV integrin subunits increased MMP-1/10 secretion in M. tuberculosis–stimulated monocytes. In a cohort of TB patients, significantly increased integrin β3 mRNA accumulation in induced sputum was detected, to our knowledge, for the first time, compared with control subjects (p < 0.05). Integrin αVβ3 colocalized with areas of increased and functionally active MMP-1 on infected monocytes, and αVβ3 blockade markedly decreased type I collagen breakdown, and impaired both monocyte adhesion and leukocyte migration in a transwell system (p < 0.0001). In summary, our data demonstrate that M. tuberculosis stimulation upregulates integrin αVβ3 expression on monocytes, which upregulates secretion of MMP-1 and -10 on adhesion to the ECM. This leads to increased monocyte recruitment and collagenase activity, which will drive inflammatory tissue damage.
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