The purinergic receptor P2Y2 receptor mediates chemotaxis of dendritic cells and eosinophils in allergic lung inflammation.
BACKGROUND
Extracellular ATP contributes to the pathogenesis of asthma via signalling at purinergic receptors. However, the precise purinergic receptors subtypes mediating the pro-asthmatic effects of ATP have not been identified, yet.


METHODS
In vivo studies were performed using the OVA-alum model. Functional expression of the P2Y(2) purinergic receptor subtype on human monocyte-derived dendritic cells and eosinophils was investigated using real-time PCR, migration assays, and production of reactive oxygen species.


RESULTS
Compared to wild-type animals P2Y(2) -/- mice showed reduced allergic airway inflammation which can be explained by defective migration of blood myeloid DCs towards ATP in vitro and in vivo, whereas the influence of ATP on maturation and cytokine production was not changed. Additionally, ATP failed to induce migration of bone marrow-derived eosinophils from P2Y(2) R-deficient animals. The relevance of our findings for humans was confirmed in functional studies with human monocyte-derived DCs and eosinophils. Interestingly, stimulation of human DCs derived from allergic individuals with house dust mite allergen induced functional up-regulation of the P2Y(2) R subtype. Furthermore, eosinophils isolated from asthmatic individuals expressed higher levels of P2Y(2) R compared to healthy controls. This was of functional relevance as these eosinophils were more sensitive to ATP-induced migration and production of reactive oxygen metabolites.


CONCLUSIONS
In summary, P2Y(2) R appears to be involved in asthmatic airway inflammation by mediating ATP-triggered migration of mDCs and eosinophils, as well as reactive oxygen species production. Together our data suggest that targeting P2Y(2) R might be a therapeutic option for the treatment of asthma.
Müller
T
T
Department of Pneumology, University Medical Centre Freiburg, Freiburg, Germany.
Robaye
B
B
Vieira
R P
RP
Ferrari
D
D
Grimm
M
M
Jakob
T
T
Martin
S F
SF
Di Virgilio
F
F
Boeynaems
J-M
JM
Virchow
J C
JC
Idzko
M
M
D000255:Adenosine Triphosphate / Q000276:immunology; D000818:Animals; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology*; D017382:Reactive Oxygen Species; D058473:Receptors, Purinergic P2Y2 / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017382:Reactive Oxygen Species; D058473:Receptors, Purinergic P2Y2; D000255:Adenosine Triphosphate