Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice.
Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)-induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54-95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24-48 h). Combined treatment increased median survival to 96 h (range 24-240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24-48 h] and 48 h [24-96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis.
Department of Traumatology, Center of Surgery, University of Ulm, Ulm 89081, Germany;
Markus
M
Huber-Lang
Department of Immunology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo N-0027, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo N-0027, Norway;
Andreas
A
Barratt-Due
The Interventional Centre, Oslo University Hospital, Oslo N-0027, Norway; Department of Anesthesiology, Oslo University Hospital, Oslo N-0027, Norway;
Søren E
SE
Pischke
Research Institute of Internal Medicine, Oslo University Hospital, Oslo N-0027, Norway;
Øystein
Ø
Sandanger
Department of Immunology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo N-0027, Norway;
Per H
PH
Nilsson
Centre for Ecology and Hydrology, Wallingford, Oxfordshire OX10 8BB, United Kingdom;
Miles A
MA
Nunn
Department of Traumatology, Center of Surgery, University of Ulm, Ulm 89081, Germany;
Stephanie
S
Denk
Department of Epidemiology and Biostatistics, University of Ulm, Ulm 89081, Germany;
Wilhelm
W
Gaus
Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway;
Terje
T
Espevik
Department of Immunology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo N-0027, Norway; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Research Laboratory, Nordland Hospital Bodø, University of Tromsø, Tromsø 9019, Norway; and Faculty of Health Sciences, University of Tromsø, Tromsø 9019, Norway t.e.mollnes@medisin.uio.no.
Tom E
TE
Mollnes
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology*; D003182:Complement C5 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008297:Male; D051379:Mice; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D013997:Time Factors
D057134:Antibodies, Neutralizing; D003182:Complement C5; D016207:Cytokines; D018950:Lipopolysaccharide Receptors