Regulation of eosinophil trafficking by SWAP-70 and its role in allergic airway inflammation.
Eosinophils are the predominant inflammatory cells recruited to allergic airways. In this article, we show that human and murine eosinophils express SWAP-70, an intracellular RAC-binding signaling protein, and examine its role in mediating eosinophil trafficking and pulmonary recruitment in a murine model of allergic airway inflammation. Compared with wild-type eosinophils, SWAP-70-deficient (Swap-70(-/-)) eosinophils revealed altered adhesive interactions within inflamed postcapillary venules under conditions of blood flow by intravital microscopy, exhibiting enhanced slow rolling but decreased firm adhesion. In static adhesion assays, Swap-70(-/-) eosinophils adhered poorly to VCAM-1 and ICAM-1 and exhibited inefficient leading edge and uropod formation. Adherent Swap-70(-/-) eosinophils failed to translocate RAC1 to leading edges and displayed aberrant cell surface localization/distribution of α4 and Mac-1. Chemokine-induced migration of Swap-70(-/-) eosinophils was significantly decreased, correlating with reduced intracellular calcium levels, defective actin polymerization/depolymerization, and altered cytoskeletal rearrangement. In vivo, recruitment of eosinophils to the lungs of allergen-challenged Swap-70(-/-) mice, compared with wild-type mice, was significantly reduced, along with considerable attenuation of airway inflammation, indicated by diminished IL-5, IL-13, and TNF-α levels; reduced mucus secretion; and improved airway function. These findings suggest that regulation of eosinophil trafficking and migration by SWAP-70 is important for the development of eosinophilic inflammation after allergen exposure.
Laboratory of Allergic Diseases and Inflammation, Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
Nooshin S
NS
Bahaie
M Reza
MR
Hosseinkhani
Xiao Na
XN
Ge
Bit Na
BN
Kang
Sung Gil
SG
Ha
Malcolm S
MS
Blumenthal
Rolf
R
Jessberger
Savita P
SP
Rao
P
P
Sriramarao
D000485:Allergens; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D004268:DNA-Binding Proteins; D004804:Eosinophils / Q000473:pathology*; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D007249:Inflammation; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D012130:Respiratory Hypersensitivity / Q000209:etiology* / Q000473:pathology; D014699:Venules / Q000473:pathology
D000485:Allergens; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; C491873:SWAP70 protein, human; C113365:Swap70 protein, mouse