Abstract
Protease inhibitors have important function during homeostasis, inflammation and tissue injury. In this study, we described the role of Schistosoma mansoni SmKI-1 serine protease inhibitor in parasite development and as a molecule capable of regulating different models of inflammatory diseases. First, we determine that recombinant (r) SmKI-1 and its Kunitz domain but not the C-terminal region possess inhibitory activity against trypsin and neutrophil elastase (NE). To better understand the molecular basis of NE inhibition by SmKI-1, molecular docking studies were also conducted. Docking results suggest a complete blockage of NE active site by SmKI-1 Kunitz domain. Additionally, rSmKI-1 markedly inhibited the capacity of NE to kill schistosomes. In order to further investigate the role of SmKI-1 in the parasite, we designed specific siRNA to knockdown SmKI-1 in S. mansoni. SmKI-1 gene suppression in larval stage of S. mansoni robustly impact in parasite development in vitro and in vivo. To determine the ability of SmKI-1 to interfere with neutrophil migration and function, we tested SmKI-1 anti-inflammatory potential in different murine models of inflammatory diseases. Treatment with SmKI-1 rescued acetaminophen (APAP)-mediated liver damage, with a significant reduction in both neutrophil recruitment and elastase activity. In the model of gout arthritis, this protein reduced neutrophil accumulation, IL-1β secretion, hypernociception, and overall pathological score. Finally, we demonstrated the ability of SmKI-1 to inhibit early events that trigger neutrophil recruitment in pleural cavities of mice in response to carrageenan. In conclusion, SmKI-1 is a key protein in S. mansoni survival and it has the ability to inhibit neutrophil function as a promising therapeutic molecule against inflammatory diseases.
Highlights
Immunologic disorders are becoming increasingly prevalent in developed population, with asthma exceeding 10% of children in many countries [1], while the incidence of autoimmune diseases such as type I diabetes [2] as well as of inflammatory bowel disease (IBD)[3] continues to rise
The control of inflammatory responses is extended to pathogen-derived antigens, leading us to study one S. mansoni Kunitz type protease inhibitor (SmKI-1), found in larval and adult phases of the parasite
We demonstrate that SmKI-1 inhibits trypsin and neutrophil elastase (NE)
Summary
Immunologic disorders are becoming increasingly prevalent in developed population, with asthma exceeding 10% of children in many countries [1], while the incidence of autoimmune diseases such as type I diabetes [2] as well as of inflammatory bowel disease (IBD)[3] continues to rise. One possible explanation resides that helminths drive the regulatory arm of the immune system, abrogating the ability of the host to expel the parasites, while dampening reactivity to many inflammatory processes. Larval schistosomes (schistosomula) migrate to the blood vessels where they mature to adult worms and live as pairs in the mesenteric or perivesicular veins for years [6]. These parasite stages (larval and adult), besides surviving inside the host, acquire the ability to modulate human immune responses, what has always called the attention of many scientists worldwide [7, 8]. The control of inflammation seems not to be strictly dependent on parasite infection, since it is extended to some pathogen-derived antigens [9, 11, 12], suggesting some schistosome molecules are useful weapons to control inflammation [13, 14]
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