Echinococcus granulosus cyst fluid inhibits the type I interferon response by promoting ROS in macrophages.

In cystic echinococcosis (CE), Echinococcus granulosus cystic fluid (EgCF) could impede macrophage-mediated immunity. However, whether EgCF is implicated in the type I interferon response remains to be established. Here, we revealed that EgCF reduced 2'3'-cGAMP-induced IFN-ß production in macrophages by inhibiting the cGAS-STING-IRF3 signaling. EgCF also increased the intracellular reactive oxygen species (ROS) levels. Administration of the ROS inhibitor N-acetylcysteine (NAC) restored the cGAS-STING-IRF3 signaling, which, in turn, upregulated IFN-ß expression. The findings disclose that EgCF could increase macrophage ROS levels, thereby blocking cGAS-STING-IRF3 signaling and repressing the IFN-I response.

Echinococcus granulosus cyst fluid inhibits KDM6B-mediated demethylation of trimethylated histone H3 lysine 27 and interleukin-1ß production in macrophages.

BACKGROUND: Echinococcus granulosus can manipulate its host's immune response to ensure its own survival. However, the effect of histone modifications on the regulation of the NOD-like receptor protein 3 (NLRP3) inflammasome and downstream interleukin-1ß (IL-1ß) production in response to the parasite is not fully understood. METHODS: We evaluated IL-1ß secretion through enzyme-linked immunosorbent assay and assessed reactive oxygen species levels using the dichlorodihydrofluorescein diacetate probe. Western blotting and quantitative real-time polymerase chain reaction were performed to examine the expression of NLRP3 and IL-1ß in mouse peritoneal macrophages and Tohoku Hospital Pediatrics-1 cells, a human macrophage cell line. The presence of trimethylated histone H3 lysine 27 (H3K27me3) modification on NLRP3 and IL-1ß promoters was studied by chromatin immunoprecipitation. RESULTS: Treatment with E. granulosus cyst fluid (EgCF) considerably reduced IL-1ß secretion in mouse and human macrophages, although reactive oxygen species production increased. EgCF also suppressed the expression of NLRP3 and IL-1ß. Mechanistically, EgCF prompted the enrichment of repressive H3K27me3 modification on the promoters of both NLRP3 and IL-1ß in macrophages. Notably, the presence of EgCF led to a significant reduction in the expression of the H3K27me3 demethylase KDM6B. CONCLUSIONS: Our study revealed that EgCF inhibits KDM6B expression and H3K27me3 demethylation, resulting in the transcriptional inhibition of NLRP3 and IL-1ß. These results provide new insights into the immune evasion mechanisms of E. granulosus.