Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood.
It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis.
Clark
Stephen R
SR
Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
Ma
Adrienne C
AC
Tavener
Samantha A
SA
McDonald
Braedon
B
Goodarzi
Zahra
Z
Kelly
Margaret M
MM
Patel
Kamala D
KD
Chakrabarti
Subhadeep
S
McAvoy
Erin
E
Sinclair
Gary D
GD
Keys
Elizabeth M
EM
Allen-Vercoe
Emma
E
Devinney
Rebekah
R
Doig
Christopher J
CJ
Green
Francis H Y
FH
Kubes
Paul
P
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001419:Bacteria / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology*; D004848:Epithelium / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology*; D018805:Sepsis / Q000276:immunology / Q000382:microbiology* / Q000503:physiopathology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D000410:Alanine Transaminase