Exosites mediate the anti-inflammatory effects of a multifunctional serpin from the saliva of the tick Ixodes ricinus.
Serine protease inhibitors (serpins) are a structurally related but functionally diverse family of ubiquitous proteins. We previously described Ixodes ricinus immunosuppressor (Iris) as a serpin from the saliva of the tick I. ricinus displaying high affinity for human leukocyte elastase. Iris also displays pleotropic effects because it interferes with both the immune response and hemostasis of the host. It thus inhibits lymphocyte proliferation and the secretion of interferon-gamma or tumor necrosis factor-alpha by peripheral blood mononuclear cells, and also platelet adhesion, coagulation and fibrinolysis. Its ability to interfere with coagulation and fibrinolysis, but not platelet adhesion, depends on the integrity of its antiproteolytic reactive center loop domain. Here, we dissect the mechanisms underlying the interaction of recombinant Iris with peripheral blood mononuclear cells. We show that Iris binds to monocytes/macrophages and inhibits their ability to secrete tumor necrosis factor-alpha. Recombinant Iris also has a protective role in endotoxemic shock. The anti-inflammatory ability of Iris does not depend on its antiprotease activity. Moreover, we pinpoint the exosites involved in this activity.
Laboratoire de Biologie Moléculaire des Ectoparasites, Université Libre de Bruxelles, Gosselies, Belgium.
Pierre-Paul
PP
Prevot
Alain
A
Beschin
Laurence
L
Lins
Jérôme
J
Beaufays
Amélie
A
Grosjean
Léa
L
Bruys
Benoît
B
Adam
Michel
M
Brossard
Robert
R
Brasseur
Karim
K
Zouaoui Boudjeltia
Luc
L
Vanhamme
Edmond
E
Godfroid
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018884:Ixodes / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D012463:Saliva / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D012772:Shock, Septic / Q000276:immunology / Q000517:prevention & control; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; C515507:Iris protein, Ixodes ricinus; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D015843:Serpins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D019272:Leukocyte Elastase