Document Detail

Impairment of adenosine a3 receptor activity disrupts neutrophil migratory capacity and impacts innate immune function in vivo.
MedLine Citation:
PMID:  23027555     Owner:  NLM     Status:  Publisher    
Adenosine possesses potent anti-inflammatory properties which are partly mediated by G(i) -coupled adenosine A3 receptors (A3Rs). A3R agonists have shown clinical benefit in a number of inflammatory conditions although some studies in A3R-deficient mice suggest a pro-inflammatory role. We hypothesized that, in addition to cell signaling effects, A3R compounds might inhibit neutrophil chemotaxis by disrupting the purinergic feedback loop controling leukocyte migration. Human neutrophil activation triggered rapid upregulation of surface A3R expression which was disrupted by pre-treatment with either agonist (Cl-IB-MECA) or antagonist (MRS1220). Both compounds reduced migration velocity and neutrophil transmigration capacity without impacting the response to chemokines per se. Similar effects were observed in murine neutrophils, while cells from A3R-deficient mice displayed a constitutively impaired migratory phenotype indicating compound-induced desensitization and genetic ablation had the same functional outcome. In a dextran-sodium sulphate (DSS)-induced colitis model, A3R-deficient mice exhibited reduced colon pathology and decreased tissue MPO levels at day 8 - consistent with reduced neutrophil recruitment. However, A3R-deficient mice were unable to resolve the DSS-induced inflammation and had elevated numbers of tissue-associated bacteria by day 21. Our data indicate that A3Rs play a role in neutrophil migration and disrupting this function has the potential to adversely affect innate immune responses.
Matt Butler; Devika Sanmugalingam; Victoria J Burton; Tammy Wilson; Ruth Pearson; Robert P Watson; Philip Smith; Scott J Parkinson
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-2
Journal Detail:
Title:  European journal of immunology     Volume:  -     ISSN:  1521-4141     ISO Abbreviation:  Eur. J. Immunol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1273201     Medline TA:  Eur J Immunol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Novartis Institutes for Biomedical Research, Basel, Switzerland.
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