CD14 inhibition improves survival and attenuates thrombo‐inflammation and cardiopulmonary dysfunction in a baboon model of Escherichia coli sepsis

Abstract

Background During sepsis, gram‐negative bacteria induce robust inflammation primarily via lipopolysacharride (LPS) signaling through TLR4, a process that involves the glycosylphosphatidylinositol (GPI)‐anchored receptor CD14 transferring LPS to the Toll‐like receptor 4/myeloid differentiation factor 2 (TLR4/MD‐2) complex. Sepsis also triggers the onset of disseminated intravascular coagulation and consumptive coagulopathy. Objectives We investigated the effect of CD14 blockade on sepsis‐induced coagulopathy, inflammation, organ dysfunction, and mortality. Methods We used a baboon model of lethal Escherichia (E) coli sepsis to study two experimental groups (n = 5): (a) E coli challenge; (b) E coli challenge plus anti‐CD14 (23G4) inhibitory antibody administered as an intravenous bolus 30 minutes before the E coli. Results Following anti‐CD14 treatment, two animals reached the 7‐day end‐point survivor criteria, while three animals had a significantly prolonged survival as compared to the non‐treated animals that developed multiple organ failure and died within 30 hours. Anti‐CD14 reduced the activation of coagulation through inhibition of tissue factor‐dependent pathway, especially in the survivors, and enhanced the fibrinolysis due to strong inhibition of plasminogen activator inhibitor 1. The treatment prevented the robust complement activation induced by E coli, as shown by significantly decreased C3b, C5a, and sC5b‐9. Vital signs, organ function biomarkers, bacteria clearance, and leukocyte and fibrinogen consumption were all improved at varying levels. Anti‐CD14 reduced neutrophil activation, cell death, LPS levels, and pro‐inflammatory cytokines (tumor necrosis factor, interleukin (IL)‐6, IL‐1β, IL‐8, interferon gamma, monocyte chemoattractant protein‐1), more significantly in the survivors than non‐surviving animals. Conclusions Our results highlight the crosstalk between coagulation/fibrinolysis, inflammation, and complement systems and suggest a protective role of anti‐CD14 treatment in E coli sepsis.

Simultaneous C5 and CD14 inhibition limits inflammation and organ dysfunction in pig polytrauma

“…STAT1 as well as KLF4 can be triggered by interferon-g (IFN-g), which will induce a pro-inflammatory cellular response (49,50). Complement and/or CD14 inhibition successfully reduced the IFN-g production in mice and baboons' sepsis studies (22,43), thus preventing STAT1 and KLF4 overactivation. Additionally, interferon gamma-induced protein 10 (IP-10), which expression is dependent on STAT1 signaling (51), was significantly reduced in heart, liver, spleen, and kidney by the combined inhibition therapy in porcine Escherichia coli sepsis model (30).…”

“…Substances targeting the complement system or TLR signaling pathways have long been considered potential therapies for various diseases ( 28 , 38 ). The effectiveness of the complement inhibition therapies at the C3 level (compstatin) and C5 level (RA101295), along with CD14 inhibition monotherapy were already proven to be beneficial in porcine and baboon sepsis models ( 39 – 43 ). In these studies, the complement or CD14 inhibition attenuated the sepsis-induced inflammation and coagulopathy ( 42 , 43 ), displayed protective effects on the endothelium, and was associated with improved organ performance ( 39 , 40 ).…”

“…The effectiveness of the complement inhibition therapies at the C3 level (compstatin) and C5 level (RA101295), along with CD14 inhibition monotherapy were already proven to be beneficial in porcine and baboon sepsis models ( 39 – 43 ). In these studies, the complement or CD14 inhibition attenuated the sepsis-induced inflammation and coagulopathy ( 42 , 43 ), displayed protective effects on the endothelium, and was associated with improved organ performance ( 39 , 40 ). While the complement or CD14 inhibition monotherapy proved to be effective, the combined inhibition therapy displayed clear enhanced effects.…”

Olaparib attenuates sepsis-induced acute multiple organ injury via ERK-mediated CD14 expression

“…29,30 Inhibition of CD14 was successful in improving survival by attenuating thrombo-inflammation and cardiopulmonary dysfunction in a baboon model. 31 Furthermore, anti-rabbit CD14 monoclonal antibody exhibits protective effects on organ dysfunction and cell death in rabbits treated with endotoxemia. 22 CD14-deficient mice are more effective in inhibiting the spread of E. coli intraperitoneally inoculated than wildtype mice.…”

Multiple datasets to explore the molecular mechanism of sepsis

“…The mechanisms of immunosuppression in sepsis include immune cell exhaustion and apoptosis, including CD4 + T cells, CD8 + T cells, NK cells, neutrophils, dendritic cells, macrophages, and monocytes, among which T cells are the most affected. The effector function of T cells is impaired, the antigen presentation ability is impaired, and the secretion of cytokines is dysregulated [5][6][7].…”