Double Blockade of CD14 and Complement C5 Abolishes the Cytokine Storm and Improves Morbidity and Survival in Polymicrobial Sepsis in Mice

Abstract

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.

Prognostic value of CD4+CD25+ Tregs as a valuable biomarker for patients with sepsis in ICU

“…The concept of PCT clearance for assessing the prognosis of sepsis introduces the dynamic change of PCT that is more meaningful than the absolute value of PCT. [14,16,17] Our study has shown similar results. Analysis of endotoxins showed that median values on day 7 are also significantly different between the two groups as 0.1240 EU/mL (0.0443 EU/mL, 0.2320 EU/ mL) vs. 0.4813 EU/mL (0.2387 EU/mL, 0.7412 EU/mL) (Z=-2.583, P=0.010).…”

“…The main cause of early death of patients with sepsis is early excessive activation of the immune system to release large amounts of cytokines (cytokine storm) that damage multi-organ systems. [13,14] Later deaths are due to reduced antibody-dependent cell-mediated cytotoxicity (ADCC), immunosuppression, decreased ability to clear pathogens, [5] and increased function of CD4 + CD25 + Tregs suppressing activation of effect T cells. [11,15] Our study has shown that the median ratio of CD4 + CD25…”

Park7 interacts with p47phox to direct NADPH oxidase-dependent ROS production and protect against sepsis

“…Extravagant inflammation reactions are autodestructive and result in distant organ damage or failure, whereas an insufficient response due to immune anergy or tolerance can propagate further infection [2]. Some septic patients die at the early stage of sepsis characterized by an uncontrolled activation of the immune responses [3], but most patients die at the late stage with significant immunosuppression, marked by an impaired activation of the immune responses and hypoinflammation [4][5][6]. Therefore, understanding the immune pathophysiology of the late stage will be mandatory for discovering novel therapeutic options.…”

Human Endothelial Cell Activation by Escherichia coli and Staphylococcus aureus Is Mediated by TNF and IL-1β Secondarily to Activation of C5 and CD14 in Whole Blood

“…In a number of different models, we have previously shown that combined inhibition of CD14 and key complement components can attenuate inflammation induced by Gram-negative bacteria (15,16,20,(30)(31)(32)(33)(34), Gram-positive bacteria (14), and polymicrobial stimuli (17). We therefore intended to evaluate to what extent inhibiting whole blood inflammation would affect EC activation by using CD14-and C5-blocking Abs.…”

“…Furthermore, in a murine sepsis model, we have recently shown that combined inhibition reduces both inflammation and mortality (17).…”