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Adenosine A2A Receptor Mediates Inhibition of Synovitis and Osteoclastogenesis after Electroacupuncture in Rats with Collagen-Induced Arthritis.

ABSTRACT: Background:This study was to investigate the role of adenosine A2A receptors (A2AR) in inhibiting the effect of electroacupuncture (EA) on osteoclastogenesis in collagen-induced arthritis (CIA). Methods:Wistar rats were divided into four groups: sham-control group, CIA-control group, CIA-EA group, and CIA-EA-SCH58261 (A2AR antagonist) group. We detected tumor necrosis factor-? (TNF-?), nuclear transcription factor-?B (NF-?B), receptor activator of NF-?B ligand (RANKL), protein kinase A (PKA), and extracellular regulatory protein kinase 1/2 (ERK1/2) in peripheral blood by ELISA. PKA, ERK1/2, and NF-?B in ankle joints were determined by western blotting. We evaluated the arthritis damage by histological examination and determined the number of osteoclasts by tartrate-resistant acid phosphatase (TRAP) staining. Results:EA treatment downregulated the expression of TNF-?, RANKL, PKA, ERK1/2, and NF-?B in peripheral blood but increased the levels of PKA and ERK1/2 in ankle joints. Importantly, EA treatment reduced bone erosion as evidenced by the histological findings and inhibited osteoclastogenesis as revealed by TRAP staining. All these effects of the EA treatment were reversed by combining EA treatment with the A2AR antagonist SCH58261. Conclusion:Our data suggest that EA treatment activated A2AR. The effects of the A2AR antagonist SCH58261 suggest that the inhibition of osteoclast formation, the inhibition of TNF-?, RANKL, and NF-?B expression, and the increase of ERK1/2 are all dependent on this EA-induced A2AR activation. It is therefore likely that these pathways with clearly defined roles in inflammation and bone erosion are at least partially involved in the mediation of the inhibition of synovitis and osteoclast formation induced by EA.

SUBMITTER: Du ZH

PROVIDER: S-EPMC6431381 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Adenosine A2A Receptor Mediates Inhibition of Synovitis and Osteoclastogenesis after Electroacupuncture in Rats with Collagen-Induced Arthritis.

Du Zhong-Heng ZH Zhang Chun-Wu CW Xie Wen-Xia WX Chen Yong Y Cong Wen-Jie WJ Wang Ze-Dong ZD Wang En-Pei EP Wu Guang-Yu GY Ye Tian-Shen TS

Evidence-based complementary and alternative medicine : eCAM 20190306

<h4>Background</h4>This study was to investigate the role of adenosine A2A receptors (A2AR) in inhibiting the effect of electroacupuncture (EA) on osteoclastogenesis in collagen-induced arthritis (CIA).<h4>Methods</h4>Wistar rats were divided into four groups: sham-control group, CIA-control group, CIA-EA group, and CIA-EA-SCH58261 (A2AR antagonist) group. We detected tumor necrosis factor-<i>α</i> (TNF-<i>α</i>), nuclear transcription factor-<i>κ</i>B (NF-<i>κ</i>B), receptor activator of NF-<i ...[more]

PMID: 30956681

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Project description:Strategies are needed to reverse the immune cell hyporesponsiveness and prevent bacterial overgrowth associated with high mortality rates in septic patients. Adenosine signaling may be mediating immunosuppressive signals within the inflammatory microenvironment that are safeguarding bacteria by rendering immune cells hyporesponsive. We examined A2A adenosine receptor (A2AR)-mediated immune responses in a chronic model of cecal ligation and puncture (CLP)-induced sepsis using both wild-type (WT) and A2AR knockout (KO) mice. In this model, chronic bacterial peritonitis was established that results in the first death on day 4. A2A adenosine receptors promoted bacterial overgrowth that was associated with a high 28-day sepsis mortality (WT 87% vs. A2AR KO 13%; P < 0.0001). Chronic bacteremia persisted in both WT and A2AR KO mice over the 28-day study period. Bacteremia was significantly decreased in A2AR KO mice 2 days after antibiotic therapy cessation (day 6 after CLP; P < 0.005). Local and disseminated bacteria levels were compared at the end of the 28-day study period or from moribund mice. A2A adenosine receptor deficiency dramatically decreased peritoneal (P < 0.05), splenic (P < 0.05), and blood (P < 0.01) bacterial levels. A2A adenosine receptor deficiency caused an early reduction in inflammatory mediators IL-6, macrophage inflammatory protein 2, TNF-srI, and TNF-srII (P < 0.05), but not in TNF-α, IL-1β, IL-10, or monocyte chemotactic protein 1 within 24 h after CLP. In response to an intravenous lipopolysaccharide (day 5 after CLP) challenge, A2AR KO mice showed enhanced secretion of TNF-α (2 h), IFN-γ, IL-6, monocyte chemotactic protein 1, IL-10, and macrophage inflammatory protein 2 (9 h) (P < 0.05), suggesting that A2ARs attenuate inflammatory responses to repeat infectious insults. These data demonstrate that A2AR blockade may be an effective immunotherapy treatment to prevent bacterial overgrowth and reduce mortality secondary to immunosuppression in septic patients.

Project description:Background and purposeBoth cannabinoid CB1 and adenosine A2A receptors (CB1 receptors and A2A receptors) control synaptic transmission at corticostriatal synapses, with great therapeutic importance for neurological and psychiatric disorders. A postsynaptic CB1 -A2A receptor interaction has already been elucidated, but the presynaptic A2A receptor-mediated control of presynaptic neuromodulation by CB1 receptors remains to be defined. Because the corticostriatal terminals provide the major input to the basal ganglia, understanding the interactive nature of converging neuromodulation on them will provide us with novel powerful tools to understand the physiology of corticostriatal synaptic transmission and interpret changes associated with pathological conditions.Experimental approachPharmacological manipulation of CB1 and A2A receptors was carried out in brain nerve terminals isolated from rats and mice, using flow synaptometry, immunoprecipitation, radioligand binding, ATP and glutamate release measurement. Whole-cell patch-clamp recordings were made in horizontal corticostriatal slices.Key resultsFlow synaptometry showed that A2A receptors were extensively co-localized with CB1 receptor-immunopositive corticostriatal terminals and A2A receptors co-immunoprecipitated CB1 receptors in these purified terminals. A2A receptor activation decreased CB1 receptor radioligand binding and decreased the CB1 receptor-mediated inhibition of high-K(+) -evoked glutamate release in corticostriatal terminals. Accordingly, A2A receptor activation prevented CB1 receptor-mediated paired-pulse facilitation and attenuated the CB1 receptor-mediated inhibition of synaptic transmission in glutamatergic synapses of corticostriatal slices.Conclusions and implicationsActivation of presynaptic A2A receptors dampened CB1 receptor-mediated inhibition of corticostriatal terminals. This constitutes a thus far unrecognized mechanism to modulate the potent CB1 receptor-mediated presynaptic inhibition, allowing frequency-dependent enhancement of synaptic efficacy at corticostriatal synapses.

Dataset Information

Adenosine A2A Receptor Mediates Inhibition of Synovitis and Osteoclastogenesis after Electroacupuncture in Rats with Collagen-Induced Arthritis.

Publications

Adenosine A2A Receptor Mediates Inhibition of Synovitis and Osteoclastogenesis after Electroacupuncture in Rats with Collagen-Induced Arthritis.

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