Human airway eosinophils respond to chemoattractants with greater eosinophil-derived neurotoxin release, adherence to fibronectin, and activation of the Ras-ERK pathway when compared with blood eosinophils.
Human blood eosinophils exposed ex vivo to hematopoietic cytokines (e.g., IL-5 or GM-CSF) subsequently display enhanced responsiveness to numerous chemoattractants, such as chemokines, platelet-activating factor, or FMLP, through a process known as priming. Airway eosinophils, obtained by bronchoalveolar lavage after segmental Ag challenge, also exhibit enhanced responsiveness to selected chemoattractants, suggesting that they are primed during cell trafficking from the blood to the airway. Earlier work has shown that chemoattractants stimulate greater activation of ERK1 and ERK2 following IL-5 priming in vitro, thus revealing that ERK1/ERK2 activity can be a molecular readout of priming under these circumstances. Because few studies have examined the intracellular mechanisms regulating priming as it relates to human airway eosinophils, we evaluated the responsiveness of blood and airway eosinophils to chemoattractants (FMLP, platelet-activating factor, CCL11, CCL5, CXCL8) with respect to degranulation, adherence to fibronectin, or Ras-ERK signaling cascade activation. When compared with blood eosinophils, airway eosinophils exhibited greater FMLP-stimulated eosinophil-derived neurotoxin release as well as augmented FMLP- and CCL11-stimulated adherence to fibronectin. In airway eosinophils, FMLP, CCL11, and CCL5 stimulated greater activation of Ras or ERK1/ERK2 when compared with baseline. Ras activation by FMLP in blood eosinophils was also enhanced following IL-5 priming. These studies are consistent with a model of in vivo priming of eosinophils by IL-5 or related cytokines following allergen challenge, and further demonstrate the key role of priming in the chemoattractant-stimulated responses of eosinophils. These data also demonstrate the importance of the Ras-ERK signaling pathway in the regulation of eosinophil responses to chemoattractants in the airway. Human airway eosinophils respond to several chemoattractants with increased activation of the Ras-ERK cascade, eosinophil-derived neurotoxin release, and adherence to fibronectin relative to blood eosinophils.
Bates
Mary Ellen
ME
Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53706, USA.
Sedgwick
Julie B
JB
Zhu
Yiming
Y
Liu
Lin Ying
LY
Heuser
Rose G
RG
Jarjour
Nizar N
NN
Kita
Hirohito
H
Bertics
Paul J
PJ
D000293:Adolescent; D000328:Adult; D002448:Cell Adhesion / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology; D002630:Chemotactic Factors / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology*; D047208:Eosinophil-Derived Neurotoxin / Q000096:biosynthesis* / Q000276:immunology; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005353:Fibronectins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008168:Lung / Q000166:cytology / Q000276:immunology*; D008875:Middle Aged; D015398:Signal Transduction / Q000276:immunology*; D055815:Young Adult; D018631:ras Proteins / Q000276:immunology / Q000378:metabolism
D002630:Chemotactic Factors; D005353:Fibronectins; D048049:Extracellular Signal-Regulated MAP Kinases; D047208:Eosinophil-Derived Neurotoxin; D018631:ras Proteins