Distinct different contributions of the alternative and classical complement activation pathway for the innate host response during sepsis.

Department of Anesthesiology and Intensive Care Therapy, Jena University Hospital, Friedrich Schiller University Jena, 07747 Jena, Germany.

Journal of immunology (Baltimore, Md. : 1950) 2011 Mar 1

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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.

Citation

Katja Dahlke, Christiane D Wrann, Oliver Sommerfeld, Maik Sossdorf, Peter Recknagel, Svea Sachse, Sebastian W Winter, Andreas Klos, Gregory L Stahl, Yuanyuan Xu Ma, Ralf A Claus, Konrad Reinhart, Michael Bauer, Niels C Riedemann. Distinct different contributions of the alternative and classical complement activation pathway for the innate host response during sepsis. Journal of immunology (Baltimore, Md. : 1950). 2011 Mar 1;186(5):3066-75