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Originally published online as doi:10.2353/ajpath.2008.070069 on December 13, 2007

Published online before print December 13, 2007
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(American Journal of Pathology. 2008;172:265-273.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070069

Nitric Oxide Regulates Neutrophil Migration through Microparticle Formation

Sarah Nolan, Rachel Dixon, Keith Norman, Paul Hellewell and Victoria Ridger

From the Cardiovascular Research Unit, University of Sheffield, School of Medicine and Biomedical Sciences, Sheffield, United Kingdom

The role of nitric oxide (NO) in regulating neutrophil migration has been investigated. Human neutrophil migration to interleukin (IL)-8 (1 nmol/L) was measured after a 1-hour incubation using a 96-well chemotaxis plate assay. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) significantly (P < 0.001) enhanced IL-8-induced migration by up to 45%. Anti-CD18 significantly (P < 0.001) inhibited both IL-8-induced and L-NAME enhanced migration. Antibodies to L-selectin or PSGL-1 had no effect on IL-8-induced migration but prevented the increased migration to IL-8 induced by L-NAME. L-NAME induced generation of neutrophil-derived microparticles that was significantly (P < 0.01) greater than untreated neutrophils or D-NAME. This microparticle formation was dependent on calpain activity and superoxide production. Only microparticles from L-NAME and not untreated or D-NAME-treated neutrophils induced a significant (P < 0.01) increase in IL-8-induced migration and transendothelial migration. Pretreatment of microparticles with antibodies to L-selectin (DREG-200) or PSGL-1 (PL-1) significantly (P < 0.001) inhibited this effect. The ability of L-NAME-induced microparticles to enhance migration was found to be dependent on the number of microparticles produced and not an increase in microparticle surface L-selectin or PSGL-1 expression. These data show that NO can modulate neutrophil migration by regulating microparticle formation.






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