A novel complement inhibitor sMAP-FH targeting both the lectin and alternative complement pathways
A novel complement inhibitor sMAP-FH targeting both the lectin and alternative complement pathways
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DOI：
10.1096/fj.201902475r
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发表时间：
2020-03-26
期刊：
影响因子：
4.8
通讯作者：
Sekine, Hideharu
中科院分区：
文献类型：
--
作者：
Takasumi, Mika;Omori, Tomoko;Sekine, Hideharu
补体激活的抑制已经成为治疗一系列疾病的选择。凝集素和旁路途径（分别为LP和AP）的激活有助于某些疾病如缺血-再灌注损伤和年龄相关性黄斑变性（AMD）中的状况恶化。在目前的研究中，我们通过融合全长MAp 44或小甘露糖结合凝集素相关蛋白（sMAP）（LP调节剂）与补体因子H（SCR 1/5-FH）（AP调节剂）的N-末端5个短一致重复（SCR）结构域，产生了MAp 44-FH和sMAP-FH途径的双重补体抑制剂。当在小鼠中腹膜内施用时，两种融合蛋白的鼠形式与循环中的内源性甘露糖结合凝集素（MBL）或纤维胶凝蛋白A形成复合物。多重补体活化测定揭示，与MAp 44-FH相比，sMAP-FH在体内以及体外对LP和AP的活化具有显著更高的抑制作用。人形式的sMAP-FH也显示对人血清中LP和AP活化的双重抑制作用。我们的研究结果表明，新的融合蛋白sMAP-FH抑制小鼠和人血清中的LP和AP激活，并可能是一种有效的治疗剂的疾病，其中LP和AP激活显着参与。
Inhibition of the complement activation has emerged as an option for treatment of a range of diseases. Activation of the lectin and alternative pathways (LP and AP, respectively) contribute to the deterioration of conditions in certain diseases such as ischemia-reperfusion injuries and age-related macular degeneration (AMD). In the current study, we generated dual complement inhibitors of the pathways MAp44-FH and sMAP-FH by fusing full-length MAp44 or small mannose-binding lectin-associated protein (sMAP), LP regulators, with the N-terminal five short consensus repeat (SCR) domains of complement factor H (SCR1/5-FH), an AP regulator. The murine forms of both fusion proteins formed a complex with endogenous mannose-binding lectin (MBL) or ficolin A in the circulation when administered in mice intraperitoneally. Multiple complement activation assays revealed that sMAP-FH had significantly higher inhibitory effects on activation of the LP and AP in vivo as well as in vitro compared to MAp44-FH. Human form of sMAP-FH also showed dual inhibitory effects on LP and AP activation in human sera. Our results indicate that the novel fusion protein sMAP-FH inhibits both the LP and AP activation in mice and in human sera, and could be an effective therapeutic agent for diseases in which both the LP and AP activation are significantly involved.