Intravascular danger signals guide neutrophils to sites of sterile inflammation.
Neutrophils are recruited from the blood to sites of sterile inflammation, where they contribute to wound healing but may also cause tissue damage. By using spinning disk confocal intravital microscopy, we examined the kinetics and molecular mechanisms of neutrophil recruitment to sites of focal hepatic necrosis in vivo. Adenosine triphosphate released from necrotic cells activated the Nlrp3 inflammasome to generate an inflammatory microenvironment that alerted circulating neutrophils to adhere within liver sinusoids. Subsequently, generation of an intravascular chemokine gradient directed neutrophil migration through healthy tissue toward foci of damage. Lastly, formyl-peptide signals released from necrotic cells guided neutrophils through nonperfused sinusoids into the injury. Thus, dynamic in vivo imaging revealed a multistep hierarchy of directional cues that guide neutrophil localization to sites of sterile inflammation.
McDonald
Braedon
B
Immunology Research Group, University of Calgary, Alberta T2N 4N1, Canada.
Pittman
Keir
K
Menezes
Gustavo B
GB
Hirota
Simon A
SA
Slaba
Ingrid
I
Waterhouse
Christopher C M
CC
Beck
Paul L
PL
Muruve
Daniel A
DA
Kubes
Paul
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002448:Cell Adhesion; D054426:Chemokine CXCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D003463:Cues; D004730:Endothelium, Vascular / Q000502:physiology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007700:Kinetics; D008099:Liver / Q000098:blood supply / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016177:Macrophage-1 Antigen / Q000502:physiology; D051379:Mice; D008853:Microscopy / Q000379:methods; D018613:Microscopy, Confocal; D055806:Microvessels / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000502:physiology; D010455:Peptides / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction
D002352:Carrier Proteins; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; C469988:Fpr1 protein, mouse; D016177:Macrophage-1 Antigen; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C546469:P2rx7 protein, mouse; D010455:Peptides; D044042:Receptors, Formyl Peptide; D023063:Receptors, Interleukin-8B; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate