ATP drives eosinophil effector responses through P2 purinergic receptors.
BACKGROUND
Eosinophils recognize various stimuli, such as cytokines, chemokines, immunoglobulins, complement, and external pathogens, resulting in their accumulation in mucosal tissues and the progression of inflammation. Eosinophils are also involved in innate Th2-type immune responses mediated through endogenous danger signals, including IL-33, uric acid (UA), or ATP, in non-sensitized mice exposed to environmental allergens. However, the mechanism involved in eosinophil responses to these danger signals remains insufficiently understood.


METHODS
We examined migration, adhesion, superoxide production and degranulation of human eosinophils. Isolated eosinophils were incubated with monosodium urate (MSU) crystals and ATPγS, a non-hydrolysable ATP analogue. To determine the involvement of P2 or P2Y2 receptors in eosinophil responses to UA and ATP, eosinophils were preincubated with a pan-P2 receptor inhibitor, oxidized ATP (oATP), or anti-P2Y2 antibody before incubation with MSU crystals or ATPγS.


RESULTS
MSU crystals induced adhesion of eosinophils to recombinant human (rh)-ICAM-1 and induced production of superoxide. oATP abolished eosinophil responses to MSU crystals, suggesting involvement of endogenous ATP and its receptors. Furthermore, exogenous ATP, as ATPγS, induced migration of eosinophils through a model basement membrane, adhesion to rh-ICAM-1, superoxide generation, and degranulation of eosinophil-derived neurotoxin (EDN). oATP and anti-P2Y2 significantly reduced these eosinophil responses.


CONCLUSIONS
ATP serves as an essential mediator of functional responses in human eosinophils. Eosinophil responses to ATP may be implicated in airway inflammation in patients with asthma.
Allergy Center, Saitama Medical University, Saitama, Japan; Department of General Internal Medicine, Saitama Medical University, Saitama, Japan; Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.
Takehito
T
Kobayashi
Allergy Center, Saitama Medical University, Saitama, Japan; Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan. Electronic address: tsoma@saitama-med.ac.jp.
Tomoyuki
T
Soma
Allergy Center, Saitama Medical University, Saitama, Japan; Department of General Internal Medicine, Saitama Medical University, Saitama, Japan.
Toru
T
Noguchi
Allergy Center, Saitama Medical University, Saitama, Japan; Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.
Kazuyuki
K
Nakagome
Department of General Internal Medicine, Saitama Medical University, Saitama, Japan.
Hidetomo
H
Nakamoto
Division of Allergic Diseases, Department of Internal Medicine, Department of Immunology, Mayo Clinic, Rochester, MN, USA.
Hirohito
H
Kita
Allergy Center, Saitama Medical University, Saitama, Japan; Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.
Makoto
M
Nagata
D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D000328:Adult; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
D018048:Receptors, Purinergic P2; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; D000255:Adenosine Triphosphate
ATP; Danger signal; Eosinophils; P2Y(2) receptor; Uric acids