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IMPAIRMENT OF ADENOSINE A3 RECEPTOR ACTIVITY DISRUPTS NEUTROPHIL MIGRATORY CAPACITY AND IMPACTS INNATE IMMUNE FUNCTION IN VIVO

Butler, Matt and Sanmugalingam, Devika and Burton, Victoria and Wilson, Tammy and Pearson, Ruth and Watson, Robert and 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
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7379

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