Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.
Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo. The serine proteases and extracellular nucleosomes enhance tissue factor- and factor XII-dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.
Massberg
Steffen
S
Deutsches Herzzentrum, Technische Universität, Munich, Germany.
Grahl
Lenka
L
von Bruehl
Marie-Luise
ML
Manukyan
Davit
D
Pfeiler
Susanne
S
Goosmann
Christian
C
Brinkmann
Volker
V
Lorenz
Michael
M
Bidzhekov
Kiril
K
Khandagale
Avinash B
AB
Konrad
Ildiko
I
Kennerknecht
Elisabeth
E
Reges
Katja
K
Holdenrieder
Stefan
S
Braun
Siegmund
S
Reinhardt
Christoph
C
Spannagl
Michael
M
Preissner
Klaus T
KT
Engelmann
Bernd
B
D000818:Animals; D001777:Blood Coagulation / Q000235:genetics* / Q000502:physiology; D001779:Blood Coagulation Factors / Q000378:metabolism / Q000502:physiology; D056649:Cathepsin G / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005337:Fibrin / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics* / Q000502:physiology; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D009707:Nucleosomes / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000502:physiology; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D020521:Stroke / Q000235:genetics / Q000378:metabolism
D001779:Blood Coagulation Factors; D008074:Lipoproteins; D009707:Nucleosomes; C045071:leukocyte procoagulant activity; C051928:lipoprotein-associated coagulation inhibitor; D005337:Fibrin; D057057:Serine Proteases; D056649:Cathepsin G; D019272:Leukocyte Elastase