Protection of mice against septic shock induced by lethal intraperitoneal dose of LPS by a recombinant <i>Fasciola hepatica</i> fatty acid binding protein

Sepsis caused by Gram-negative bacteria is a severe systemic infection characterized by an excessive inflammatory response triggered by lipopolysaccharide (LPS), a potent endotoxin of these bacteria, often leading to organ failure and high mortality. Despite improved outcomes with antibiotic therapy, controlling persistent inflammation remains a major therapeutic challenge. Interestingly, helminth-derived molecules, such as the recombinant protein Fh15 from <i>Fasciola hepatica</i>, have been demonstrated to suppress inflammatory responses in experimental models of sepsis. This study aimed to evaluate the capacity of Fh15 to effectively attenuate cytokine storms and improve survival in mice, alongside analyzing its effects on macrophage phenotype and function to better understand its potential as an anti-inflammatory biotherapeutic. Our results demonstrate that a single intraperitoneal injection of an optimized dose of 100 μg Fh15 (~5 mg/kg body weight), administered 1 h after a lethal (LD100) LPS challenge, significantly improved survival and markedly suppressed the cytokine storm in mice. This treatment was associated with a substantial reduction in C-reactive protein (CRP) levels, along with an increase in IL-37. In addition, a 100 μg Fh15 dose (~5 mg/kg body weight [BW]) effectively controlled LPS-induced IL-10 overproduction, potentially preventing immunosuppression that may contribute to mortality. Fh15 also significantly reduced the expression of macrophage activation markers, including CD14, tumor necrosis factor-alpha (TNF-α), nitric oxide synthase-2 (NOS2), CD38, and IL-12p70, potentially impairing macrophage maturation, phagocytic activity, and their capacity to activate Th1 cells. These findings demonstrate the potential of Fh15 to modulate key inflammatory pathways involved in sepsis and support its potential as a novel recombinant protein-based anti-inflammatory therapy.IMPORTANCESepsis remains a leading cause of mortality worldwide, primarily driven by an overwhelming inflammatory response triggered by bacterial components such as lipopolysaccharide (LPS). This excessive immune activation, characterized by cytokine storms and macrophage overactivation, leads to organ failure and death. Current therapeutic strategies, including antibiotic treatment, often fail to address the persistent inflammation that contributes to sepsis severity. In this study, we proposed Fh15, a recombinant protein derived from <i>Fasciola hepatica</i>, as a potent immunomodulatory agent capable of attenuating the cytokine storm, improving survival, and modulating macrophage activity in a mouse model of septic shock. These findings underscore the potential of Fh15 as a novel anti-inflammatory agent, offering a promising therapeutic approach to manage endotoxemia and reduce sepsis-related mortality.