Distinct different contributions of the alternative and classical complement activation pathway for the innate host response during sepsis.
Distinct different contributions of the alternative and classical complement activation pathway for the innate host response during sepsis.
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DOI：
10.4049/jimmunol.1002741
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发表时间：
2011-03-01
期刊：
影响因子：
--
通讯作者：
Riedemann NC
中科院分区：
文献类型：
--
作者：
Dahlke K;Wrann CD;Sommerfeld O;Sossdorf M;Recknagel P;Sachse S;Winter SW;Klos A;Stahl GL;Ma YX;Claus RA;Reinhart K;Bauer M;Riedemann NC
补体激活代表了对入侵微生物的关键先天防御机制，但对脓毒症期间不同补体激活途径对宿主反应的单独贡献明显缺乏了解。因此，我们研究了缺乏替代（fD-/-）或经典（C1 q-/-）补体激活途径的小鼠在盲肠结扎和穿孔（CLP）诱导的脓毒症期间不同的先天宿主免疫反应。与对照小鼠相比，两种基因敲除小鼠品系均显示出显著降低的存活率和增加的器官功能障碍。令人惊讶的是，fD−/−小鼠在CLP后6 h表现出与对照小鼠一样的补偿性细菌清除能力，而C1 q −/−小鼠在该时间点已经被细菌生长压倒。有趣的是，在CLP后24小时，fD−/−小鼠未能以与对照小鼠相当的方式清除细菌。然而，两种基因敲除小鼠品系在脓毒症期间均显示受损的C3裂解。调查这种差异的潜在原因，我们能够证明，尽管在脓毒症发作早期细菌清除能力正常，但与对照组和C1 q −/−小鼠相比，fD−/−小鼠显示炎性细胞因子产生增加，中性粒细胞募集到肺部和血液中，表明对这些免疫反应的潜在控制丧失。进一步的体外实验显示，在fD−/−小鼠的分离中性粒细胞中，NF-κB活化能力显著增加，支持这一假设。我们的研究结果提供了证据的新概念，替代补体激活途径发挥了明显不同的贡献，先天性宿主反应在脓毒症相比，经典的途径。
Complement activation represents a crucial innate defense mechanism to invading microorganisms, but there is an eminent lack of understanding of the separate contribution of the different complement activation pathways to the host response during sepsis. We therefore investigated different innate host immune responses during cecal ligation and puncture (CLP)-induced sepsis in mice lacking either the alternative (fD−/−) or classical (C1q−/−) complement activation pathway. Both knockout mice strains showed a significantly reduced survival and increased organ dysfunction when compared with control mice. Surprisingly, fD−/− mice demonstrated a compensated bacterial clearance capacity as control mice at 6 h post CLP, whereas C1q−/− mice were already overwhelmed by bacterial growth at this time point. Interestingly, at 24 h after CLP, fD−/− mice failed to clear bacteria in a way comparable to control mice. However, both knockout mice strains showed compromised C3 cleavage during sepsis. Investigating potential causes for this discrepancy, we were able to demonstrate that despite normal bacterial clearance capacity early during the onset of sepsis, fD−/− mice displayed increased inflammatory cytokine generation and neutrophil recruitment into lungs and blood when compared with both control- and C1q−/− mice, indicating a potential loss of control over these immune responses. Further in vitro experiments revealed a strongly increased Nf-κB activation capacity in isolated neutrophils from fD−/− mice, supporting this hypothesis. Our results provide evidence for the new concept that the alternative complement activation pathway exerts a distinctly different contribution to the innate host response during sepsis when compared with the classical pathway.
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