Targeting Complement C5a Receptor 1 for the Treatment of Immunosuppression in Sepsis

Complement factor C5a was originally identified as a powerful promoter of inflammation through activation of the C5a receptor 1 (C5ar1). Recent evidence suggests involvement of C5a not only in pro- but also in anti-inflammatory signaling. The present study aims to unveil the role of C5ar1 as potential therapeutic target in a murine sepsis model. Our study discloses a significantly increased survival in models of mild to moderate but not severe sepsis of C5ar1-deficient mice. The decreased mortality of C5ar1-deficient mice is accompanied by improved pathogen clearance and largely preserved liver function. C5ar1-deficient mice exhibited a significantly increased production of the pro-inflammatory mediator interferon-gamma (IFN-gamma) and a decreased production of the anti-inflammatory cytokine interleukin-10 (IL-10). Together, these data uncover C5a signaling as a mediator of immunosuppressive processes during sepsis and describe the C5ar1 and related changes of the IFN-gamma to IL-10 ratio as markers for the immunological (dys)function accompanying sepsis.

Automated summary

In a murine sepsis model, C5ar1-deficient mice show increased survival rates with improved pathogen clearance and preserved liver function. These mice exhibit increased production of the pro-inflammatory mediator IFN-γ and decreased production of the anti-inflammatory cytokine IL-10.