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Recombinant Fasciola hepatica Fatty Acid Binding Protein Downregulates Inflammatory Cytokines/Chemokines in a Mouse Model of Septic Shock and Shows a Wide Spectrum of Action

Sepsis is the leading cause of death from infections. It involves, both pathogen and host factors and it is characterized by an exacerbation of inflammatory cytokines and chemokines and organ dysfunction and failure. Recently, we reported that a recombinant Fasciola hepatica fatty acid binding protein, termed Fh15, is capable of suppressing the LPS induced expression of inflammatory cytokines such as IL‐1β and TNFα in murine bone marrow derived macrophages in vitro. We also demonstrated that such anti‐inflammatory effect is achieved by targeting specifically the CD14 co‐receptor, which results in a complete suppression of TLR4 activation and makes macrophages irresponsive to subsequent LPS‐stimuli. In the current study, we evaluated the capacity of Fh15 to suppress the TLR4‐activation in vitro, as well as its capacity to therapeutically suppress the cytokine storm in a mouse model of septic shock. We also tested the ability of Fh15 to suppress the activation of multiple TLRs in response to Gram‐positive and Gram‐negative whole bacteria extracts in vitro. For in vivo studies, we used female BALB/c mice that received a lethal intraperitoneal (i.p.) injection of LPS‐E. coli and 1h later received a single i.p. injection with 50μg Fh15. Animals were sacrificed 12h after the LPS challenge. For in vitro experiments, we used THP1‐CD14 cells, which were cultured with Fh15 prior to stimulation with optimized concentrations of 1×108 cells of Klebsiella pneumoniae and Enterococcus faecalis. Results demonstrated that, although Fh15 was unable to stimulate the secretion of any inflammatory cytokine, it significantly suppressed the levels of serum IFNγ (p=0.0425), TNFα (p=0.0008), IL‐1β (p=0.0021) in all animals exposed to lethal doses of LPS. Fh15 also significantly suppressed the levels in serum of two macrophage inflammatory proteins MIP‐1α (p=0.0027) and MIP‐1β (p<0.0001), two chemotactic chemokines that play relevant roles in the inflammatory process. Moreover, we also demonstrated that Fh15 inhibits the stimulation of various TLRs in response to whole bacteria extracts, suggesting that Fh15 could have a broad spectrum of action. These results support the possibility of using Fh15 as an excellent alternative for an anti‐inflammatory drug in pre‐clinical studies in the near future.