Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 on Dendritic Cells Is Required for Airway Responses in a Murine Asthma Model

Abstract

Ovarian cancer G protein-coupled receptor 1 (OGR1) stimulation by extracellular protons causes the activation of G proteins and subsequent cellular functions. However, the physiological and pathophysiological roles of OGR1 in airway responses remain largely unknown. In the present study, we show that OGR1-deficient mice are resistant to the cardinal features of asthma, including airway eosinophilia, airway hyperresponsiveness (AHR), and goblet cell metaplasia, in association with a remarkable inhibition of Th2 cytokine and IgE production, in an ovalbumin (OVA)-induced asthma model. Intratracheal transfer to wild-type mice of OVA-primed bone marrow-derived dendritic cells (DCs) from OGR1-deficient mice developed lower AHR and eosinophilia after OVA inhalation compared with the transfer of those from wild-type mice. Migration of OVA-pulsed DCs to peribronchial lymph nodes was also inhibited by OGR1 deficiency in the adoption experiments. The presence of functional OGR1 in DCs was confirmed by the expression of OGR1 mRNA and the OGR1-sensitive Ca2+ response. OVA-induced expression of CCR7, a mature DC chemokine receptor, and migration response to CCR7 ligands in an in vitro Transwell assay were attenuated by OGR1 deficiency. We conclude that OGR1 on DCs is critical for migration to draining lymph nodes, which, in turn, stimulates Th2 phenotype change and subsequent induction of airway inflammation and AHR.

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

“…67 Aoki et al demonstrated that GPR68-deficient mice were resistant to asthma along with inhibiting Th2 cytokine and immunoglobulin E production. 68 This study concludes that GPR68 in dendritic cells is crucial for the onset of asthmatic responses. 68 Moreover, GPR65 has been implicated as having a role in respiratory disorders as it is highly expressed in eosinophils, hallmark cells for asthmatic inflammation.…”

“…68 This study concludes that GPR68 in dendritic cells is crucial for the onset of asthmatic responses. 68 Moreover, GPR65 has been implicated as having a role in respiratory disorders as it is highly expressed in eosinophils, hallmark cells for asthmatic inflammation. 69 Kottyan et al showed that GPR65 increased the viability of eosinophils within an acidic environment through the cAMP pathway in murine asthma models.…”

“…[64][65][66][67] GPR68-null mice are resistant to asthma. 68 Skeletal inhibits osteoclastic bone resorption; relative bone density is reduced in GPR65-null mice. 81 N/A Regulates gene expression in response to acidosis in bone cells.…”

Extracellular acidification activates ovarian cancer G-protein-coupled receptor 1 and GPR4 homologs of zebra fish

“…The change in intracellular Ca 2þ concentration ([Ca 2þ ] i ) was measured using a fura-2 method as described previously [22,23]. The changes in the intensities of 540 nm fluorescence obtained by 340 nm and 380 nm excitations were monitored by an FP-8200 spectrofluorometer (JASCO, Tokyo, Japan).…”

Acidic environment augments FcεRI-mediated production of IL-6 and IL-13 in mast cells

“…Specifically, acidic pH attenuates proinflammatory cytokine production from mouse peritoneal macrophages through TDAG8 [7] and stimulates interleukin (IL)-6 and connective tissue growth factor production in human airway smooth muscle cells (ASMCs) through OGR1 [8,9]. Additionally, in an ovalbumin-induced asthma model, we found that OGR1-deficient mice are resistant to AHR and airway inflammation; this was associated with the remarkable inhibition of Th2 cytokine production via a change in DCs migration activity [10]. The actions of extracellular pH, mediated by OGR1 family G protein-coupled receptors (GPCRs), have also been reported by other research groups investigating ASMCs [11] and eosinophils [12].…”