Document Detail


Slit2 regulates attractive eosinophil and repulsive neutrophil chemotaxis through differential srGAP1 expression during lung inflammation.
MedLine Citation:
PMID:  20944010     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Directional migration of leukocytes is an essential step in leukocyte trafficking during inflammatory responses. However, the molecular mechanisms governing directional chemotaxis of leukocytes remain poorly understood. The Slit family of guidance cues has been implicated for inhibition of leuocyte migration. We report that Clara cells in the bronchial epithelium secreted Slit2, whereas eosinophils and neutrophils expressed its cell-surface receptor, Robo1. Compared to neutrophils, eosinophils exhibited a significantly lower level of Slit-Robo GTPase-activating protein 1 (srGAP1), leading to activation of Cdc42, recruitment of PI3K to Robo1, enhancment of eotaxin-induced eosinophil chemotaxis, and exaggeration of allergic airway inflammation. Notably, OVA sensitization elicited a Slit2 gradient at so-called bronchus-alveoli axis, with a higher level of Slit2 in the bronchial epithelium and a lower level in the alveolar tissue. Aerosol administration of rSlit2 accelerated eosinophil infiltration, whereas i.v. administered Slit2 reduced eosinophil deposition. In contrast, Slit2 inactivated Cdc42 and suppressed stromal cell-derived factor-1α-induced chemotaxis of neutrophils for inhibiting endotoxin-induced lung inflammation, which were reversed by blockade of srGAP1 binding to Robo1. These results indicate that the newly identified Slit2 gradient at the bronchus-alveoli axis induces attractive PI3K signaling in eosinophils and repulsive srGAP1 signaling in neutrophils through differential srGAP1 expression during lung inflammation.
Authors:
Bu-Qing Ye; Zhen H Geng; Li Ma; Jian-Guo Geng
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-10-13
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  185     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-04     Completed Date:  2010-12-02     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6294-305     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bronchi / immunology,  metabolism
Chemotaxis, Leukocyte / physiology*
Eosinophils / immunology,  metabolism*
Fluorescent Antibody Technique
GTPase-Activating Proteins / biosynthesis*,  immunology
Humans
Immunoblotting
Immunoprecipitation
Intercellular Signaling Peptides and Proteins / immunology,  secretion*
Mice
Mice, Inbred C57BL
Nerve Tissue Proteins / biosynthesis,  immunology,  secretion*
Neutrophils / immunology,  metabolism*
Pneumonia / immunology,  metabolism*
Pulmonary Alveoli / immunology,  metabolism
Receptors, Immunologic / biosynthesis,  immunology
Respiratory Hypersensitivity / immunology,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / immunology
Grant Support
ID/Acronym/Agency:
R01 CA126897/CA/NCI NIH HHS; R01AI064743/AI/NIAID NIH HHS; R01CA126897/CA/NCI NIH HHS; R56 AI064743/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/GTPase-Activating Proteins; 0/Intercellular Signaling Peptides and Proteins; 0/Nerve Tissue Proteins; 0/Receptors, Immunologic; 0/Slit homolog 2 protein; 0/roundabout protein

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