Annexin 1-deficient neutrophils exhibit enhanced transmigration in vivo and increased responsiveness in vitro.
The role of the endogenous anti-inflammatory mediator annexin 1 (AnxA1) in controlling polymorphonuclear leukocyte (PMN) trafficking and activation was addressed using the recently generated AnxA1 null mouse. In the zymosan peritonitis model, AnxA1 null mice displayed a higher degree (50-70%) of PMN recruitment compared with wild-type littermate mice, and this was associated with reduced numbers of F4/80+ cells. Intravital microscopy analysis of the cremaster microcirculation inflamed by zymosan (6 h time-point) indicated a greater extent of leukocyte emigration, but not rolling or adhesion, in AnxA1 null mice. Real-time analysis of the cremaster microcirculation did not show spontaneous activation in the absence of AnxA1; however, superfusion with a direct-acting PMN activator (1 nM platelet-activating factor) revealed a subtle yet significant increase in leukocyte emigration, but not rolling or adhesion, in this genotype. Changes in the microcirculation were not secondary to alterations in hemodynamic parameters. The phenotype of the AnxA1 null PMN was investigated in two in vitro assays of cell activation (CD11b membrane expression and chemotaxis): the data obtained indicated a higher degree of cellular responses irrespective of the stimulus used. In conclusion, we have used a combination of inflammatory protocols and in vitro assays to address the specific counter-regulatory role of endogenous AnxA1, demonstrating its inhibitory control on PMN activation and the consequent impact on the inflamed microcirculation.
Bart's and The London, Queen Mary School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK.
Bristi E
BE
Chatterjee
Simon
S
Yona
Guglielmo
G
Rosignoli
Rebecca E
RE
Young
Sussan
S
Nourshargh
Roderick J
RJ
Flower
Mauro
M
Perretti
D000818:Animals; D017305:Annexin A1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D015054:Zymosan / Q000008:administration & dosage / Q000494:pharmacology
D017305:Annexin A1; D039481:CD11b Antigen; D010972:Platelet Activating Factor; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015054:Zymosan