A proinflammatory role for proteolytically cleaved annexin A1 in neutrophil transendothelial migration.
Neutrophil extravasation, a critical component of innate immunity must be tightly regulated to prevent inadvertent or prolonged inflammation and subsequent tissue damage. We have shown previously that endothelial ERK1/2 signaling essential for neutrophil transendothelial migration is induced by a soluble factor produced by activated neutrophils. In this study, we demonstrate that the soluble neutrophil factor is a truncated form of annexin A1 (AnxA1) that can be generated by calpain 1 cleavage of the N terminus, thus identifying a novel proinflammatory function to AnxA1. In contrast, neither the full-length protein nor the N-terminal 26 aa peptide, previously shown to be antiinflammatory, were able to activate Erk. Our data suggest that two different fragments of AnxA1 have opposing functions in inflammation. We also provide evidence that C-terminal AnxA1 functions by increasing ICAM1 clustering around adherent neutrophils to anchor them to the endothelium and promote transmigration through the transcellular route.
Williams
Samantha L
SL
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
Milne
Ian R
IR
Bagley
Christopher J
CJ
Gamble
Jennifer R
JR
Vadas
Mathew A
MA
Pitson
Stuart M
SM
Khew-Goodall
Yeesim
Y
D000595:Amino Acid Sequence; D017305:Annexin A1 / Q000378:metabolism / Q000502:physiology*; D002154:Calpain / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology*
D017305:Annexin A1; D018836:Inflammation Mediators; D010446:Peptide Fragments; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002154:Calpain