The Role of Mannose-Binding Lectin-Associated Serine Protease-3 in Activation of the Alternative Complement Pathway
The Role of Mannose-Binding Lectin-Associated Serine Protease-3 in Activation of the Alternative Complement Pathway
复制标题
DOI：
10.4049/jimmunol.1100280
复制
发表时间：
2011-10-01
影响因子：
4.4
通讯作者：
Fujita, Teizo
中科院分区：
文献类型：
--
作者：
Iwaki, Daisuke;Kanno, Kazuko;Fujita, Teizo
甘露糖结合凝集素（MBL）相关的丝氨酸蛋白酶（MASP）负责激活凝集素补体途径。三种类型的MASP（MASP-1、MASP-2和MASP-3）与血清中的MBL和纤维胶凝蛋白复合。尽管已知MASP-1和MASP-2有助于补体活化，但MASP-3的功能仍不清楚。在本研究中，我们使用重组小鼠MASP-3（rMASP-3）和几种不同类型的MASP缺陷型小鼠研究了MASP-3活化及其底物的机制。获得了在制备过程中不自动活化的酶原rMASP-3。在MBL-A的存在下，通过与金黄色葡萄球菌孵育激活重组酶，但MBL-C不存在。体内研究揭示了MASP-1/3缺陷型小鼠和所有MASP（MASP-1/2/3）缺陷型小鼠对S.这些小鼠中的金黄色葡萄球菌和细菌清除率低于野生型和MASP-2缺陷型小鼠中的那些。与野生型血清相比，来自所有MASP缺陷型小鼠的血清显示出在细菌上显著较低的C3沉积活性，并且向缺陷型血清中添加rMASP-3恢复了C3沉积。所有MASP缺陷小鼠血清中的低C3沉积可能是由低水平因子B活化引起的，而添加rMASP-3可改善该活化。此外，rMASP-3在体外直接活化因子B和D。这些结果表明，与MBL复合的MASP-3通过与细菌靶标孵育转化为活性形式，并且活化的MASP-3触发了旁路补体途径的初始活化步骤。免疫学杂志，2011，187：3751-3758。
Mannose-binding lectin (MBL)-associated serine proteases (MASPs) are responsible for activation of the lectin complement pathway. Three types of MASPs (MASP-1, MASP-2, and MASP-3) are complexed with MBL and ficolins in serum. Although MASP-1 and MASP-2 are known to contribute to complement activation, the function of MASP-3 remains unclear. In this study, we investigated the mechanism of MASP-3 activation and its substrate using the recombinant mouse MASP-3 (rMASP-3) and several different types of MASP-deficient mice. A proenzyme rMASP-3 was obtained that was not autoactivated during preparation. The recombinant enzyme was activated by incubation with Staphylococcus aureus in the presence of MBL-A, but not MBL-C. In vivo studies revealed the phagocytic activities of MASP-1/3-deficient mice and all MASPs (MASP-1/2/3)-deficient mice against S. aureus and bacterial clearance in these mice were lower than those in wild-type and MASP-2-deficient mice. Sera from all MASPs-deficient mice showed significantly lower C3 deposition activity on the bacteria compared with that of wild-type serum, and addition of rMASP-3 to the deficient serum restored C3 deposition. The low C3 deposition in sera from all MASPs-deficient mice was probably caused by the low level factor B activation that was ameliorated by the addition of rMASP-3. Furthermore, rMASP-3 directly activated factors B and D in vitro. These results suggested that MASP-3 complexed with MBL is converted to an active form by incubation with bacterial targets, and that activated MASP-3 triggered the initial activation step of the alternative complement pathway. The Journal of Immunology, 2011, 187: 3751-3758.