Proteolysis of human thrombin generates novel host defense peptides.
The coagulation system is characterized by the sequential and highly localized activation of a series of serine proteases, culminating in the conversion of fibrinogen into fibrin, and formation of a fibrin clot. Here we show that C-terminal peptides of thrombin, a key enzyme in the coagulation cascade, constitute a novel class of host defense peptides, released upon proteolysis of thrombin in vitro, and detected in human wounds in vivo. Under physiological conditions, these peptides exert antimicrobial effects against Gram-positive and Gram-negative bacteria, mediated by membrane lysis, as well as immunomodulatory functions, by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, they are protective against P. aeruginosa sepsis, as well as lipopolysaccharide-induced shock. Moreover, the thrombin-derived peptides exhibit helical structures upon binding to lipopolysaccharide and can also permeabilize liposomes, features typical of "classical" helical antimicrobial peptides. These findings provide a novel link between the coagulation system and host-defense peptides, two fundamental biological systems activated in response to injury and microbial invasion.
Papareddy
Praveen
P
Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden.
Rydengård
Victoria
V
Pasupuleti
Mukesh
M
Walse
Björn
B
Mörgelin
Matthias
M
Chalupka
Anna
A
Malmsten
Martin
M
Schmidtchen
Artur
A
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001777:Blood Coagulation / Q000235:genetics / Q000276:immunology*; D015153:Blotting, Western; D002469:Cell Separation; D017124:Conserved Sequence; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D019272:Leukocyte Elastase / Q000378:metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011516:Prothrombin / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D011516:Prothrombin; D019272:Leukocyte Elastase; D013917:Thrombin