title: Impairment of adenosine A3 receptor activity disrupts neutrophil migratory capacity and impacts innate immune function in vivo.
abstract: 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 hypothesised that, in addition to cell signalling effects, A3R compounds might inhibit neutrophil chemotaxis by disrupting the purinergic feedback loop controlling 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 desensitisation and genetic ablation had the same functional outcome. In a dextran sodium sulphate-induced colitis model, A3R-deficient mice exhibited reduced colon pathology and decreased tissue myeloperoxidase levels at day 8 - consistent with reduced neutrophil recruitment. However, A3R-deficient mice were unable to resolve the dextran sodium sulphate-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.
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland. matt.butler@novartis.com
authors.forename: Matt
authors.initials: M
authors.lastname: Butler
authors.forename: Devika
authors.initials: D
authors.lastname: Sanmugalingam
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Burton
authors.forename: Tammy
authors.initials: T
authors.lastname: Wilson
authors.forename: Ruth
authors.initials: R
authors.lastname: Pearson
authors.forename: Robert P
authors.initials: RP
authors.lastname: Watson
authors.forename: Philip
authors.initials: P
authors.lastname: Smith
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Parkinson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology; D043684:Receptor, Adenosine A3 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
chemical_list: C110041:9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D011799:Quinazolines; D043684:Receptor, Adenosine A3; D014230:Triazoles; D016264:Dextran Sulfate; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide