Abstract
The production of IL-1-family cytokines such as IL-1β and IL-18 is finely regulated by inflammasome activation after the recognition of pathogens associated molecular pattern (PAMPs) and danger associated molecular patterns (DAMPs). However, little is known about the helminth-derived molecules capable of activating the inflammasome. In the case of the helminth trematode Fasciola hepatica, the secretion of different cathepsin L cysteine peptidases (FhCL) is crucial for the parasite survival. Among these enzymes, cathepsin L3 (FhCL3) is expressed mainly in the juvenile or invasive stage. The ability of FhCL3 to digest collagen has demonstrated to be critical for intestinal tissue invasion during juvenile larvae migration. However, there is no information about the interaction of FhCL3 with the immune system. It has been shown here that FhCL3 induces a non-canonical inflammasome activation in dendritic cells (DCs), leading to IL-1β and IL-18 production without a previous microbial priming. Interestingly, this activation was depending on the cysteine protease activity of FhCL3 and the NLRP3 receptor, but independent of caspase activation. We also show that FhCL3 is internalized by DCs, promoting pro-IL-1β cleavage to its mature and biologically active form IL-1β, which is released to the extracellular environment. The FhCL3-induced NLRP3 inflammasome activation conditions DCs to promote a singular adaptive immune response, characterized by increased production of IFN-γ and IL-13. These data reveal an unexpected ability of FhCL3, a helminth-derived molecule, to activate the NLRP3 inflammasome, which is independent of the classical mechanism involving caspase activation.
Highlights
Fasciolosis, caused by the helminth parasite F. hepatica is a chronic disease that affects the liver of cattle all over the world
It has been established that the F. hepatica proteins cathepsin L1 (FhCL1), gluthation transferase (FhGST), and Kunitz type molecule (FhKTM) have a modulating effect on dendritic cells (DCs), which leads to the suppression of the adaptive immune responses Th1 and/or Th17 [9, 10]
Despite the evidences showing that different molecules from F. hepatica, such as cysteine protease cathepsin L1 (FhCL1), glutathione transferase (FhGST), and Kunitz type molecule (KTM) are able to regulate DCs activation [9, 10], there is no information about the capacity of FhCL3, which is expressed in the invasive stage of this parasite, to modulate DCs functions
Summary
Fasciolosis, caused by the helminth parasite F. hepatica is a chronic disease that affects the liver of cattle all over the world. In our laboratory, it has been demonstrated a correlation between PDL-2 expression in macrophages and the promotion of Th2 response, which in turn inhibits Th1 profile during infection with F. hepatica [11]. These results suggest that there would be molecules within the products derived from the parasite, that promote inflammatory type responses. According to this hypothesis, data from other authors have demonstrated that a mucin-like peptide derived from F. hepatica has immunostimulatory properties, increasing the ability of DCs to promote IFN-γ responses in allogeneic splenocytes [12]
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