HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by van der Putten, C. Articles by Bajramovic, J. J. PubMed PubMed Citation Articles by van der Putten, C. Articles by Bajramovic, J. J.

Differential Expression of Adenosine A₃ Receptors Controls Adenosine A_2A Receptor-Mediated Inhibition of TLR Responses in Microglia

Céline van der Putten^*, Ella A. Zuiderwijk-Sick^*, Linda van Straalen^*, Eveline D. de Geus, Leonie A. Boven, Ivanela Kondova, Ad P. IJzerman and Jeffrey J. Bajramovic^1,*

^* Alternatives Unit and Animal Science Department, Biomedical Primate Research Centre, Rijswijk, The Netherlands; Department of Immunology, Erasmus MC, Rotterdam, The Netherlands; and Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands

Microglia activation is a prominent feature in many neuroinflammatory disorders. Unrestrained activation can generate a chronic inflammatory environment that might lead to neurodegeneration and autoimmunity. Extracellular adenosine modulates cellular activation through adenosine receptor (ADORA)-mediated signaling. There are four ADORA subtypes that can either increase (A_2A and A_2B receptors) or decrease (A₁ and A₃ receptors) intracellular cyclic AMP levels. The expression pattern of the subtypes thus orchestrates the cellular response to extracellular adenosine. We have investigated the expression of ADORA subtypes in unstimulated and TLR-activated primary rhesus monkey microglia. Activation induced an up-regulation of A_2A and a down-regulation of A₃ receptor (A₃R) levels. The altered ADORA-expression pattern sensitized microglia to A_2A receptor (A_2AR)-mediated inhibition of subsequent TLR-induced cytokine responses. By using combinations of subtype-specific agonists and antagonists, we revealed that in unstimulated microglia, A_2AR-mediated inhibitory signaling was effectively counteracted by A₃R-mediated signaling. In activated microglia, the decrease in A₃R-mediated signaling sensitized them to A_2AR-mediated inhibitory signaling. We report a differential, activation state-specific expression of ADORA in microglia and uncover a role for A₃R as dynamically regulated suppressors of A_2AR-mediated inhibition of TLR-induced responses. This would suggest exploration of combinations of A_2AR agonists and A₃R antagonists to dampen microglial activation during chronic neuroinflammatory conditions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Jeffrey J. Bajramovic, Alternatives Unit, Biomedical Primate Research Centre, Lange Kleiweg 139, 2280 GH Rijswijk, The Netherlands. E-mail address: bajramovic{at}bprc.nl

² Abbreviations used in this paper: ADORA, adenosine receptor; A₁R, A₁ receptor; A₃R, A₃ receptor; A_2AR, A_2A receptor; A_2BR, A_2B receptor; CGS21680, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; IB, inhibitor of NF-B proteins; NECA, 5'-(N-ethylcarboxamido)adenosine; SCH58261, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine; VUF5574, N-(2-methoxyphenyl)-N'-[2-(3-pyridinyl)-4-quinazolinyl]-urea.

³ The online version of this article contains supplemental material.