PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils.
Neutrophils encounter and 'prioritize' many chemoattractants in their pursuit of bacteria. Here we tested the possibility that the phosphatase PTEN is responsible for the prioritization of chemoattractants. Neutrophils induced chemotaxis by two separate pathways, the phosphatidylinositol-3-OH kinase (PI(3)K) phosphatase and tensin homolog (PTEN) pathway, and the p38 mitogen-activated protein kinase pathway, with the p38 pathway dominating over the PI(3)K pathway. Pten(-/-) neutrophils could not prioritize chemoattractants and were 'distracted' by chemokines when moving toward bacterial chemoattractants. In opposing gradients, PTEN became distributed throughout the cell circumference, which inhibited all PI(3)K activity, thus permitting 'preferential' migration toward bacterial products via phospholipase A(2) and p38. Such prioritization was defective in Pten(-/-) neutrophils, which resulted in defective bacterial clearance in vivo. Our data identify a PTEN-dependent mechanism in neutrophils to prioritize, 'triage' and integrate responses to multiple chemotactic cues.
Heit
Bryan
B
Institute of Infection and Immunity, University of Calgary, Calgary T2N 4N1, Canada.
Robbins
Stephen M
SM
Downey
Charlene M
CM
Guan
Zhiwen
Z
Colarusso
Pina
P
Miller
B Joan
BJ
Jirik
Frank R
FR
Kubes
Paul
P
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase