Eosinophils Respond to Acidic Environments with cAMP Production, Decreased Apoptosis, and a Decrease in the Expression of Pro-apoptotic Bcl-2 Family Members

Kottyan, Leah C.; Hedgebeth, Megan; Niese, Kathryn A.; Cao, Khanh H.; Hildeman, David; Montrose, Marshall H.; Rothenberg, Marc E.; Zimmermann, Nives

doi:10.1016/j.jaci.2008.12.971

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Section: Discussionmentioning

confidence: 99%

“…Our preliminary analysis demonstrates that the airway pH is indeed acidic in the OVA model of allergic airway inflammation. 48 Future studies will focus on the in vivo effect of acidic pH on eosinophil viability, effect of acidic pH on other eosinophil functions (respiratory burst, degranulation), as well as any consequences on asthma outcomes.Previous studies have shown expression of GPR65 in multiple hematopoietic cells. Similarly, we compare the expression of GPR65 (inferred from GFP expression in GPR65 Ϫ/Ϫ mice) in eosinophils, neutrophils, and T and B lymphocytes.…”

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Eosinophil viability is increased by acidic pH in a cAMP- and GPR65-dependent manner

Kottyan

Collier

Cao

et al. 2009

Blood

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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 cyclasedependent 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. IntroductionAsthma is a chronic lung disease characterized by episodes of inflammation and narrowing of the airways in response to diverse stimuli. 1 Over the past 2 decades, the incidence of asthma has increased worldwide and is now one of the chief diagnoses responsible for pediatric hospitalization. Extracellular acidosis is commonly observed in inflammatory diseases such as asthma. Several studies have shown that the pH of exhaled breath condensate (EBC) in patients with acute asthma is significantly lower than that of normal subjects. The pH of EBC is mildly alkaline in control persons (7.65 Ϯ 0.20), reaching 5.23 plus or minus 0.21 during asthma exacerbations. 2 Furthermore, the EBC pH of pediatric and adult patients with chronic asthma is also significantly decreased compared with healthy people and correlates with asthma severity. 3,4 Whereas EBC is not a direct measurement of airway lining fluid, airway acidification in asthma is supported by alternative approaches, including direct measurements of bronchial secretions. 2 Although EBC pH is not an asthma-specific biomarker, early clinical studies have suggested that acidification contributes to the disease process as inhalation of buffers that increase airway pH alleviates asthma symptoms. 5 G protein-coupled receptor 65 (GPR65), also known as T-cell death-associated gene 8, belongs to a group of acid-sensing receptors in the G2A G protein-coupled receptor (GPCR) family. [6][7][8] This group includes G2A, GPR65, ovarian cancer GPCR1 (OGR1), and GPR4. Some members of the G2A family, including GPR65, have been shown to be proton sensors in lymphocytes. Acid-sensing capacity is mediated by proton transfer to histidines in the first extracellular loop of GPR65, presumably causing a conformational change in GPR65 that activates G␣ s . This acid-sensing activity has been demonstrated by measuring intracellular cyclic adenosine 5Ј-monophosphate (cAMP) in GPR65-deficient lymphocytes incubated at several proton concentrations. 7 To better understand the functional implications of acidic microenvironments on eosinophils, hallmark cells of asthmatic inflam...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%