Search

Staphylococcus aureus is a common cause of bacterial infections in respiratory diseases. It secretes molecules to dampen host immunity, and the recently identified adenosine is one of these molecules. The type IIA secretory phospholipase A2 (sPLA2-IIA) is a host protein endowed with antibacterial properties, especially against Gram-positive bacteria such as S. aureus. However, the role of adenosine in sPLA2-IIA–mediated S. aureus killing by host is still unknown. The present studies showed that the S. aureus mutant lacking adenosine production (∆adsA strain) increased sPLA2-IIA expression in guinea pig airways and was cleared more efficiently, compared with the wild-type strain. S. aureus ∆adsA strain induced sPLA2-IIA expression by alveolar macrophages after phagocytic process via NOD2–NF-κB–dependent mechanism. However, S. aureus adenosine (wild-type and adsA-complemented strains) and exogenous adenosine downregulated S. aureus phagocytosis by alveolar macrophages, leading to inhibition of sPLA2-IIA expression. This occurred through inhibition of p38 phosphorylation via adenosine receptors A2a-, A2b-, and protein kinase A–dependent pathways. Taken together, our studies suggest that, in the airway, S. aureus escapes sPLA2-IIA–mediated killing through adenosine-mediated inhibition of phagocytosis and sPLA2-IIA expression.

International audience; Duffy Antigen Receptor for Chemokines (DARC) is an unusual transmembrane chemokine receptor which (i) binds the two main chemokine families and (ii) does not transduct any signal as it lacks the DRY consensus sequence. It is considered as silent chemokine receptor, a tank useful for chemiotactism. DARC had been particularly studied as a major actor of malaria infection by Plasmodium vivax. It is also implicated in multiple chemokine inflammation, inflammatory diseases, in cancer and might play a role in HIV infection and AIDS. In this review, we focus on the interest to build structural model of DARC to understand more precisely its abilities to bind its physiological ligand CXCL8 and its malaria ligand. We also present innovative development on VHHs able to bind DARC protein. We underline difficulties and limitations of such bioinformatics approaches and highlight the crucial importance of biological data to conduct these kinds of researches.

International audience; We have shown previously that mice lacking the adenosine A2A receptor (A2AR) generated on a CD1 background self-administer more ethanol and exhibit hyposensitivity to acute ethanol. We aimed to investigate if the increased propensity of A2A(-/-) mice to consume ethanol is associated with an altered sensitivity in the motivational properties of ethanol in the conditioned place preference (CPP) and conditioned taste aversion (CTA) paradigms and with an altered development of sensitization to the locomotor effects of ethanol. We also tested their sensitivity to the anxiolytic effects of ethanol. Our results show that A2A(-/-) mice produced on a CD1 background displayed a reduced ethanol-induced CPP and an increased sensitivity to the anxiolytic and locomotorstimulant effects of ethanol, but they did not show alteration in ethanol-induced CTA and locomotor sensitization. Ethanol-induced CPP, ethanol consumption and the locomotor effects of ethanol were also tested in A2A(-/-) mice produced on a C57BL/6J background. Our results emphasized the importance of the genetic background because alteration in ethanol consumption and preference, ethanol-induced CPP and locomotor-stimulant effects were not found in knockout mice produced on the alcohol-preferring C57BL/6J genetic background. Finally, the A2AR agonist, 2-p-(2-carboxyethyl)-phenylethylamino-50-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680), reduced ethanol consumption and preference in C57BL/6J mice. In conclusion, A2AR deficiency in mice generated on a CD1 background leads to high ethanol consumption that is associated with an increased sensitivity to the locomotor-stimulant/anxiolytic effects of ethanol and a decrease in ethanol-induced CPP.

BACKGROUND: Adenosine may play a role in the triggering of neurocardiogenic syncope, but no information on adenosine receptors is available at the present time. OBJECTIVE: The purpose of this study was to investigate whether adenosine A2A receptors expression is altered in patients with neurocardiogenic syncope. METHODS: Adenosine plasma levels (APLs), the expression of A2A receptors, were measured (mean +/- standard error of the mean) during tilt testing. Expression of receptors was assessed on mononuclear cells using a selective receptor ligand. RESULTS: At baseline, the APLs of 16 patients with a positive test were higher than those of 17 patients with a negative test and of those of a control group (2.10 +/- 0.30 vs. 0.40 +/- 0.05 and 0.41 +/- 0.06 muM, respectively; P

International audience; Dopamine and adenosine receptors are known to share a considerable overlap in their regional distribution, being especially rich in the basal ganglia. Dopamine and adenosine receptors have been demonstrated to exhibit a parallel distribution on certain neuronal populations, and even when not directly co-localized, relationships (both antagonistic and synergistic) have been described. This study was designed to investigate dopaminergic and purinergic systems in mice with ablations of individual dopamine or adenosine receptors. In situ hybridization histochemistry and autoradiography was used to examine the level of mRNA and protein expression of specific receptors and transporters in dopaminergic pathways. Expression of the mRNA encoding the dopamine D2 receptor was elevated in the caudate putamen of D1, D3 and A2A receptor knockout mice; this was mirrored by an increase in D2 receptor protein in D1 and D3 receptor knockout mice, but not in A2A knockout mice. Dopamine D1 receptor binding was decreased in the caudate putamen, nucleus accumbens, olfactory tubercle and ventral pallidum of D2 receptor knockout mice. In substantia nigra pars compacta, dopamine transporter mRNA expression was dramatically decreased in D3 receptor knockout mice, but elevated in A2A receptor knockout mice. All dopamine receptor knockout mice examined exhibited increased A2A receptor binding in the caudate putamen, nucleus accumbens and olfactory tubercle. These data are consistent with the existence of functional interactions between dopaminergic and purinergic systems in these reward and motor-related brain regions.

We have shown previously that the severity of handling-induced convulsions during ethanol withdrawal was reduced in A(2A)receptor knock-out (A(2A)R(−/−)) mice. In the present report, we further characterize the role of adenosine A(2A) receptors in ethanol consumption and neurobiological responses to this drug of abuse. Male A(2A)R(−/−) mice showed increased consumption of solutions containing 6 and 20% (v/v) ethanol compared with wild-type (A(2A)R(+/+)) control mice; female A(2A)R(−/−) mice showed increased consumption of solutions containing 6 and 10% ethanol. This slightly higher ethanol consumption was also related to increased ethanol preference. In contrast, A(2A)R(−/−) mice showed normal consumption of solutions containing either sucrose or quinine. Relative to A(2A)R(+/+) mice, A(2A)R(−/−) mice were found to be less sensitive to the sedative effect of 3.0 gm/kg ethanol, as measured by more rapid recovery from ethanol-induced loss of righting reflex, and to the hypothermic effects of 1.5, 3.0, and 4.0 gm/kg ethanol, although plasma ethanol levels did not differ significantly between the two genotypes. The selective adenosine A(2A) receptor antagonist ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol) (10–30 mg/kg) significantly attenuated ethanol-induced (4.0 gm/kg) hypothermia in CD1 mice. To assess whether ethanol administration would induce differential tolerance in A(2A)R(−/−) and wild-type mice, we administered ethanol (3.0 gm/kg) over 4 consecutive days and found no difference in the development of tolerance; however, female A(2A)R(−/−) mice showed a lower tolerance-acquisition rate. These data suggest that activating the A(2A) receptors may play a role in suppressing alcohol-drinking behavior and is associated with the sensitivity to the intoxicating effects of acute ethanol administration.

Adenosine can influence dopaminergic neurotransmission in the basal ganglia via postsynaptic interaction between adenosine A2A and dopamine D2 receptors. We have used a human neuroblastoma cell line (SH-SY5Y) that was found to express constitutively moderate levels of adenosine A1 and A2A receptors (approximately 100 fmol/mg of protein) to investigate the interactions of A2A/D2 receptors, at a cellular level. After transfection with human D2L receptor cDNA, SH-SY5Y cells expressed between 500 and 1,100 fmol of D2 receptors/mg of protein. In membrane preparations, stimulation of adenosine A2A receptors decreased the affinity of dopamine D2 receptors for dopamine. In intact cells, the calcium concentration elevation induced by KCI treatment was moderate, and dopamine had no effect on either resting intracellular free Ca2+ concentration ([Ca2+]i) or KCI-induced responses. In contrast, pretreatment with adenosine deaminase for 2 days dramatically increased the elevation of [Ca2+]i evoked by KCI, which then was totally reversed by dopamine. The effects induced by 48-h adenosine inactivation were mimicked by application of adenosine A1 antagonists and could not be further reversed by acute activation of either A1 or A2A receptors. Acute application of the selective A2 receptor agonist CGS-21680 counteracted the D2 receptor-induced [Ca2+]i responses. The present study shows that SH-SY5Y cells are endowed with functional adenosine A2A and A1 receptors and that A2A receptors exert an antagonistic acute effect on dopamine D2 receptor-mediated functions. In contrast, A1 receptors induce a tonic modulatory role on these dopamine functions.