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An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients
Bryan Heit,
Samantha Tavener,
Eko Raharjo, and
Paul Kubes
Immunology Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Alberta T2N 4N1, Canada
Address correspondence to Paul Kubes, Immunology Research Group, University of Calgary, 3330 Hospital Dr. NW, Alberta T2N 4N1, Canada. Tel.: (403) 220-8558. Fax: (403) 283-1267. E-mail: pkubes{at}ucalgary.ca
Abstract:
Neutrophils must follow both endogenous and bacterial chemoattractantsignals out of the vasculature and through the interstitiumto arrive at a site of infection. By necessity, in the settingof multiple chemoattractants, the neutrophils must prioritize,favoring end target chemoattractants (e.g., fMLP and C5a) emanatingfrom the site of infection over intermediary endogenous chemoattractants(e.g., IL-8 and LTB4) encountered en route to sites of infection.In this study, we propose a hierarchical model of two signalingpathways mediating the decision-making process of the neutrophils,which allows end target molecules to dominate over intermediarychemoattractants. In an under agarose assay, neutrophils predominantlymigrated toward end target chemoattractants via p38 MAPK, whereasintermediary chemoattractant-induced migration was phosphoinositide3-kinase (PI3K)/Akt dependent. When faced with competing gradientsof end target and intermediary chemoattractants, Akt activationwas significantly reduced within neutrophils, and the cellsmigrated preferentially toward end target chemoattractants evenat 1/1,000th that of intermediary chemoattractants. End targetmolecules did not require chemotactic properties, since thep38 MAPK activator, LPS, also inhibited Akt and prevented migrationto intermediary chemoattractants. p38 MAPK inhibitors not onlyreversed this hierarchy, such that neutrophils migrated preferentiallytoward intermediary chemoattractants, but also allowed neutrophilsto be drawn out of a local end target chemoattractant environmentand toward intermediary chemoattractants unexpectedly in anexaggerated (two- to fivefold) fashion. This was entirely relatedto significantly increased magnitude and duration of Akt activation.Finally, end target chemoattractant responses were predominantlyMac-1 dependent, whereas nondominant chemoattractants used primarilyLFA-1. These data provide support for a two pathway signalingmodel wherein the end target chemoattractants activate p38 MAPK,which inhibits intermediary chemoattractant-induced PI3K/Aktpathway, establishing an intracellular signaling hierarchy.
Key Words: p38 MAPK; PI3K gamma; chemotaxis; neutrophils; signal transduction
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Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1.
Mechanisms of Leukotriene B4-Triggered Monocyte Adhesion.
E. B. Friedrich, A. M. Tager, E. Liu, A. Pettersson, C. Owman, L. Munn, A. D. Luster, and R. E. Gerszten (2003)
Arterioscler Thromb Vasc Biol
23, 1761-1767
|Abstract »|Full Text »|PDF »
Reactivation of Formyl Peptide Receptors Triggers the Neutrophil NADPH-oxidase but Not a Transient Rise in Intracellular Calcium.
J. Bylund, A. Bjorstad, D. Granfeldt, A. Karlsson, C. Woschnagg, and C. Dahlgren (2003)
J. Biol. Chem.
278, 30578-30586
|Abstract »|Full Text »|PDF »
Measuring Chemotaxis and Chemokinesis: The Under-Agarose Cell Migration Assay.
