Butler, Matt, Sanmugalingam, Devika, Burton, Victoria, Wilson, Tammy, Pearson, Ruth, Watson, Robert, Smith, Philip and Parkinson, Scott James (2012) IMPAIRMENT OF ADENOSINE A3 RECEPTOR ACTIVITY DISRUPTS NEUTROPHIL MIGRATORY CAPACITY AND IMPACTS INNATE IMMUNE FUNCTION IN VIVO. European Journal of Immunology. ISSN 0014-2980

Abstract

Adenosine possesses potent anti-inflammatory properties which are partly mediated by Gi-coupled adenosine A3 receptors (A3R). A3R agonists have shown clinical benefit in a number of inflammatory conditions but some studies in A3R-deficient mice still suggest a pro-inflammatory role. We investigated the possibility that, in addition to cell signalling effects, A3R compounds inhibit neutrophil chemotaxis by disrupting a purinergic feedback loop controlling leukocyte migration. Activation of human neutrophils induced a rapid upregulation of cell surface A3R expression which was disrupted by pre-treatment with either A3R agonist or antagonist. Both compounds reduced migration velocity and neutrophil transmigration capacity without impacting the response to chemokines per se. Bone marrow-derived neutrophils from A3R-deficient mice displayed a similarly impaired migratory phenotype confirming a key role for A3R in leukocyte migration. In a dextran-sodium sulphate (DSS)-induced model of colitis, 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 colon tissue-associated bacteria by day 21. Our data indicate that A3Rs regulate the neutrophil migratory response and that disturbing their function can adversely affect the innate immune response.

Item Type:	Article
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Date Deposited:	13 Oct 2015 13:14
Last Modified:	13 Oct 2015 13:14
URI:	https://oak.novartis.com/id/eprint/7379