Fasciola hepatica GST mu-class suppresses the cytokine storm induced by E. coli-lipopolysaccharide, whereas it modulates the dynamic of peritoneal macrophages in a mouse model and suppresses the classical activation of macrophages

Abstract

ABSTRACT Fasciola hepatica is known to suppress antigen-specific Th1 responses in concurrent bacterial infections while promoting the Th2/Treg regulatory responses. We have recently demonstrated that a single intraperitoneal injection with native F. hepatica glutathione S-transferase (nFhGST) mu-class can suppress the cytokine storm and increase the survival rate in a mouse model of septic shock (V. Aguayo, B. N. Valdes Fernandez, M. Rodrigues-Valentin, C. Ruiz-Jimenez, et al., Sci Rep 9:2275, 2019, https://doi.org/10.1038/s41598-018-37652-x). Knowing that the peritoneal macrophages play essential roles in the defense against microbial agents, the present study aimed to determine whether nFhGST could modulate the dynamics of these cells. The remarkable findings in this article are: (i) nFhGST suppressed serum IL-12, TNF-α, and IFN-γ in BALB/c septic mice while preventing the disappearance of large peritoneal macrophages and significantly increasing the population of these cells in the peritoneal cavity of lipopolysaccharide (LPS)-treated animals; (ii) nFhGST significantly suppressed the high levels of LPS-induced IL-10, which is considered a key cytokine in the pathophysiology of sepsis (H. P. Wu, C. K. Chen, K. Chung, J. C. Tseng, et al., Inflamm Res 58:385-393, 2009, https://doi.org/10.1007/s00011-009-0003-0); (iii) nFhGST suppressed the classical activation of macrophages in vitro by expressing high levels of Ym-1, a typical M2-type marker, promoting the production of IL-37, and prevented the production of TNF-α, iNOS2, and nitric oxide, which are typical markers of M1-type macrophages; and (iv) nFhGST suppressed the bacterial phagocytosis by macrophages, thus partially affecting the capacity of macrophages to destroy microbial pathogens. These findings demonstrate that nFhGST is an excellent modulator of the peritoneal macrophage content in vivo, reinforcing the notion of nFhGST as an anti-inflammatory drug against sepsis in animal models. IMPORTANCE Sepsis is the consequence of a systemic bacterial infection that exacerbates the immune cell’s activation via bacterial products, resulting in the augmented release of inflammatory mediators. A critical factor in the pathogenesis of sepsis is the primary component of the outer membrane of Gram-negative bacteria known as lipopolysaccharide (LPS), which is sensed by TLR4. For this reason, scientists have aimed to develop antagonists able to block TLR4 and, thereby the cytokine storm. We report here that a mixture of mu-class isoforms from the F. hepatica GST protein family administered intraperitoneally 1 h prior to a lethal LPS injection can modulate the dynamics and abundance of large peritoneal macrophages in the peritoneal cavity of septic mice while significantly suppressing the LPS-induced cytokine storm in a mouse model of septic shock. These results suggest that native F. hepatica glutathione S-transferase is a promising candidate for drug development against endotoxemia and other inflammatory diseases.

Keywords

• Fasciola hepatica
• sepsis
• glutathione S-transferase mu-class
• cytokine storm
• alternative activation of macrophages