Eosinophil viability is increased by acidic pH in a cAMP- and GPR65-dependent manner.
The microenvironment of the lung in asthma is acidic, yet the effect of acidity on inflammatory cells has not been well established. We now demonstrate that acidity inhibits eosinophil apoptosis and increases cellular viability in a dose-dependent manner between pH 7.5 and 6.0. Notably, acidity induced eosinophil cyclic adenosine 5'-monophosphate (cAMP) production and enhanced cellular viability in an adenylate cyclase-dependent manner. Furthermore, we identify G protein-coupled receptor 65 (GPR65) as the chief acid-sensing receptor expressed by eosinophils, as GPR65-deficient eosinophils were resistant to acid-induced eosinophil cAMP production and enhanced viability. Notably, GPR65(-/-) mice had attenuated airway eosinophilia and increased apoptosis in 2 distinct models of allergic airway disease. We conclude that eosinophil viability is increased in acidic microenvironments in a cAMP- and GPR65-dependent manner.
Kottyan
Leah C
LC
Cincinnati Children's Hospital Medical Center, OH, USA.
Collier
Ann R
AR
Cao
Khanh H
KH
Niese
Kathryn A
KA
Hedgebeth
Megan
M
Radu
Caius G
CG
Witte
Owen N
ON
Khurana Hershey
Gurjit K
GK
Rothenberg
Marc E
ME
Zimmermann
Nives
N
D000143:Acids / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001249:Asthma / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005260:Female; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011014:Pneumonia / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011522:Protons; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000143:Acids; C513337:GPR65 protein, mouse; D011522:Protons; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP