Abstract
Neutrophils are the first line of cellular defense in response to infections and inflammatory injuries. However, neutrophil activation and accumulation into tissues trigger tissue damage due to release of a plethora of toxic oxidants and proteases, a cause of acute lung injury (ALI). Despite its clinical importance, the molecular regulation of neutrophil migration is poorly understood. The small GTPase Rap1b is generally viewed as a positive regulator of immune cell functions by controlling bidirectional integrin signaling. However, we found that Rap1b-deficient mice exhibited enhanced neutrophil recruitment to inflamed lungs and enhanced susceptibility to endotoxin shock. Unexpectedly, Rap1b deficiency promoted the transcellular route of diapedesis through endothelial cell. Increased transcellular migration of Rap1b-deficient neutrophils in vitro was selectively mediated by enhanced PI3K-Akt activation and invadopodia-like protrusions. Akt inhibition in vivo suppressed excessive Rap1b-deficient neutrophil migration and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by activation of phosphatase SHP-1. Thus, this study reveals an unexpected role for Rap1b as a key suppressor of neutrophil migration and lung inflammation.
© 2014 Kumar et al.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Actins / metabolism
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Animals
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CD11b Antigen / metabolism
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Chemotaxis, Leukocyte / immunology
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Chemotaxis, Leukocyte / physiology*
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Heterocyclic Compounds, 3-Ring / pharmacology
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Human Umbilical Vein Endothelial Cells
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Humans
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Immune System Diseases / immunology
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Immune System Diseases / physiopathology
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Leukocyte Disorders / immunology
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Leukocyte Disorders / physiopathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophil Infiltration / immunology
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Neutrophil Infiltration / physiology*
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Neutrophils / drug effects
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Neutrophils / immunology
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Neutrophils / physiology*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphatidylinositol Phosphates / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction
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Transendothelial and Transepithelial Migration / immunology
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Transendothelial and Transepithelial Migration / physiology
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rap GTP-Binding Proteins / deficiency
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rap GTP-Binding Proteins / genetics
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rap GTP-Binding Proteins / physiology*
Substances
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Actins
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CD11b Antigen
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Heterocyclic Compounds, 3-Ring
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MK 2206
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Phosphatidylinositol Phosphates
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phosphatidylinositol 3,4,5-triphosphate
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Ptpn6 protein, mouse
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Rap1b protein, mouse
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rap GTP-Binding Proteins
Supplementary concepts
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Neutrophil Chemotactic Response, Abnormal