Abstract
Parasitic helminths can reside in humans owing to their ability to disrupt host protective immunity. Receptor for advanced glycation end products (RAGE), which is highly expressed in host skin, mediates inflammatory responses by regulating the expression of pro-inflammatory cytokines and endothelial adhesion molecules. In this study, we evaluated the effects of venestatin, an EF-hand Ca2+-binding protein secreted by the parasitic helminth Strongyloides venezuelensis, on RAGE activity and immune responses. Our results demonstrated that venestatin bound to RAGE and downregulated the host immune response. Recombinant venestatin predominantly bound to the RAGE C1 domain in a Ca2+-dependent manner. Recombinant venestatin effectively alleviated RAGE-mediated inflammation, including footpad edema in mice, and pneumonia induced by an exogenous RAGE ligand. Infection experiments using S. venezuelensis larvae and venestatin silencing via RNA interference revealed that endogenous venestatin promoted larval migration from the skin to the lungs in a RAGE-dependent manner. Moreover, endogenous venestatin suppressed macrophage and neutrophil accumulation around larvae. Although the invasion of larvae upregulated the abundance of RAGE ligands in host skin tissues, mRNA expression levels of tumor necrosis factor-α, cyclooxygenase-2, endothelial adhesion molecules vascular cell adhesion protein-1, intracellular adhesion molecule-1, and E-selectin were suppressed by endogenous venestatin. Taken together, our results indicate that venestatin suppressed RAGE-mediated immune responses in host skin induced by helminthic infection, thereby promoting larval migration. The anti-inflammatory mechanism of venestatin may be targeted for the development of anthelminthics and immunosuppressive agents for the treatment of RAGE-mediated inflammatory diseases.
Highlights
Parasitic helminths are highly prevalent worldwide, in developing countries, with over two billion people infected around the globe [1]
We determined that venestatin, an EF-hand Ca2+-binding protein secreted by the parasitic nematode Strongyloides venezuelensis, bound to receptor for advanced glycation end products (RAGE), a host pro-inflammatory receptor, which downregulated RAGE-mediated inflammatory responses
S. venezuelensis larvae successfully migrated to their niche owing to the anti-inflammatory functions of venestatin
Summary
Parasitic helminths are highly prevalent worldwide, in developing countries, with over two billion people infected around the globe [1]. Helminths have evolved effective strategies to regulate the protective immune response in the host [5], thereby establishing successful tissue migration to their reproductive niche and facilitating chronic parasitism. Helminths dampen or overcome the host immune response by secreting a variety of immunomodulators [6,7]. Various immunomodulators were identified from helminth genomes and proteomes, showing potential for immunologic tolerance to both innate and adaptive responses [8]. These immunomodulators may have dual effects on health. On one hand, they may suppress immunological disorders such as allergy and autoimmunity. They may suppress immune defense mechanisms by antagonizing vaccine efficacy and resistance to microbial infections [9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
