Protection of innate immunity by C5aR antagonist in septic mice

Abstract

Innate immune functions are known to be compromised during sepsis, often with lethal consequences. There is also evidence in rats that sepsis is associated with excessive complement activation and generation of the potent anaphylatoxin C5a. In the presence of a cyclic peptide antagonist (C5aRa) to the C5a receptor (C5aR), the binding of murine 125I-C5a to murine neutrophils was reduced, the in vitro chemotactic responses of mouse neutrophils to mouse C5a were markedly diminished, the acquired defect in hydrogen peroxide (H2O2) production of C5a-exposed neutrophils was reversed, and the lung permeability index (extravascular leakage of albumin) in mice after intrapulmonary deposition of IgG immune complexes was markedly diminished. Mice that developed sepsis after cecal ligation/puncture (CLP) and were treated with C5aRa had greatly improved survival rates. These data suggest that C5aRa interferes with neutrophil responses to C5a, preventing C5a-induced compromise of innate immunity during sepsis, with greatly improved survival rates after CLP.

Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist

“…C5a receptor antagonist has been shown to block the acute phase of injuries in several models including antiphospholipid syndrome, sepsis and liver regeneration following toxic injury (Girardi et al, 2003;Huber-Lang et al, 2002;Strey et al, 2003). When the antagonist injected intraperitoneally into C57BL/6 wild type animals, the cryoinjury site in the brain was histologically similar to (data not shown), and percent inhibition of neutrophil extravastion was not statistically different from, genetically deficient C5 −/− animals ( p>0.8) (Fig.…”

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

“…The importance of C5a has been broadly uncovered in polymicrobial (cecal ligation and puncture)-induced sepsis in rodents (8). Inhibition of C5a or one or both of its receptors (C5aR/C5L2) are all treatment strategies that have demonstrated reduced inflammation and increased survival, notably, also when given after induction of sepsis (44)(45)(46). Recently, the significance of complement was clearly revealed in a baboon model of E. coli-induced sepsis (21).…”

C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist

“…C5a binds its specific G protein-coupled R, C5aR, on a variety of cells, including those of myeloid origin such as neutrophils and monocytes [11][12][13]. C5aR activation on these cells can contribute to the inflammation in many diseases, such as the reverse Arthus reaction [14] and sepsis [15]. Of relevance to the kidney is the finding of C5aR in cultured renal mesangial and proximal tubular epithelial cells [16][17][18], and that C5a signaling through C5aR has been shown to be important in the tubulointerstitial injury in a model of immune complex-mediated glomerulonephritis (GN) [19].…”