The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation. J Exp Med 2014 Aug 25;211(9):1741-58
Date
08/06/2014Pubmed ID
25092872Pubmed Central ID
PMC4144729DOI
10.1084/jem.20131706Scopus ID
2-s2.0-84906544640 (requires institutional sign-in at Scopus site) 51 CitationsAbstract
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.
Author List
Kumar S, Xu J, Kumar RS, Lakshmikanthan S, Kapur R, Kofron M, Chrzanowska-Wodnicka M, Filippi MDAuthor
Magdalena Chrzanowska PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ActinsAnimals
CD11b Antigen
Chemotaxis, Leukocyte
Heterocyclic Compounds, 3-Ring
Human Umbilical Vein Endothelial Cells
Humans
Immune System Diseases
Leukocyte Disorders
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophil Infiltration
Neutrophils
Phosphatidylinositol 3-Kinases
Phosphatidylinositol Phosphates
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Proto-Oncogene Proteins c-akt
Signal Transduction
Transendothelial and Transepithelial Migration
rap GTP-Binding Proteins
