Adenosine A<sub>1</sub> receptor promotion of multinucleated giant cell formation by human monocytes. A mechanism for methotrexate‐induced nodulosis in rheumatoid arthritis

Merrill, Joan T.; Shen, Charles; Schreibman, David; Coffey, Dan; Zakharenko, Olga; Fisher, Robert C.; Lahita, Robert G.; Salmon, Jane E.; Cronstein, Bruce N.

doi:10.1002/art.1780400716

Cited by 47 publications

(46 citation statements)

References 28 publications

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“…Previous studies have demonstrated a role for adenosine and adenosine A 1 R in regulating formation of multinucleated giant cells from peripheral blood monocytes [45][46][47], a finding consistent with the observations here. Similarly, in preliminary studies, we have observed that both DPCPX and rolofylline block osteoclast formation from human bone marrow-derived precursors (He, Mazumder and Cronstein, unpublished observations).…”

Section: Discussionsupporting

confidence: 92%

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

Cronstein

2012

Purinergic Signalling

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Adenosine is an endogenous nucleoside that modulates many physiological processes through four receptor subtypes (A 1 , A 2a , A 2b , A 3 ). Previous work from our laboratory has uncovered a critical role for adenosine A 1 receptor (A 1 R) in osteoclastogenesis both in vivo and in vitro. Our current work focuses on understanding the details of how A 1 R modulates the receptor activator of NF-κB ligand (RANKL)-induced signaling in osteoclastogenesis. Osteoclasts were generated from mouse bone marrow precursors in the presence of RANKL and macrophage-colony stimulating factor. A pharmacological antagonist of A 1 R (DPCPX) inhibited RANKL-induced osteoclast differentiation, including osteoclast-specific genes (Acp5, MMP9, β 3 Integrin, α v Integrin, and CTSK) and osteoclast-specific transcription factors such as c-fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) expression in a dose-dependent manner. DPCPX also inhibited RANKL-induced activation of NF-κB and JNK/ c-Jun but had little effect on other mitogen-activated protein kinases (p38 and Erk). Finally, immunoprecipitation analysis showed that blockade of A 1 R resulted in disruption of the association of tumor necrosis factor receptor-associated factor 6 (TRAF6) and transforming growth factor-β-activated kinase 1 (TAK1), a signaling event that is important for activation of NF-κB and JNK, suggesting the participation of adenosine/ A 1 R in early signaling of RANKL. Collectively, these data demonstrated an important role of adenosine, through A 1 R in RANKL-induced osteoclastogenesis.

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Section: Discussionsupporting

confidence: 92%

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

Cronstein

2012

Purinergic Signalling

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“…Altogether, these findings suggest that GM-CSF promotion of multinucleated MA requires P2X 7 purinergic signaling carried out through the release of ATP and its conversion into adenosine, which mediates MA fusion. In support of this, adenosine has been reported to promote the formation of multinucleated giant cell by human monocytes (68). In addition, lung inflammation resulting from elevated adenosine in adenosine deaminase-deficient mice is characterized by accumulation of multinucleated giant MA (69).…”

Section: Discussionmentioning

confidence: 90%

The P2X7 Receptor and Pannexin-1 Are Both Required for the Promotion of Multinucleated Macrophages by the Inflammatory Cytokine GM-CSF

Lemaire

Falzoni

Zhang

et al. 2011

The Journal of Immunology

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The P2X7 receptor (P2X7R), an ATP-gated ion channel, has been implicated in the process of cell-to-cell fusion into multinucleated macrophages (MA), but its contribution to MA fusion driven by physiological/pathological stimuli is not clearly established. Based on several lines of evidence, we demonstrate that P2X7R is critical for the induction of multinucleated MA by the inflammatory cytokine GM-CSF: 1) pharmacological inhibition of P2X7R with oxidized ATP (oATP), KN-62, and the selective antagonist A740003 abrogated GM-CSF action on rat alveolar MA and murine peritoneal MA; 2) a murine J774 P2X7 low MA clone, selected for defective P2X7R function, was unresponsive; 3) MA from mice lacking P2X7R failed to respond to GM-CSF, in contrast to wild-type. GM-CSF also stimulated ATP-induced membrane permeabilization in J774 P2X7 high MA and rat alveolar MA, an effect absent in the P2X7 low MA clone and inhibited by the P2X7 blockers oATP and KN-62. Notably, the stimulatory effects of GM-CSF on pore formation and MA fusion were both inhibited by blocking functional Pannexin-1 (Panx-1), and GM-CSF failed to stimulate MA fusion in cells from Panx-1 knockout mice. We provide further evidence that extracellular ATP release from peritoneal MA is dependent on P2X7 but not on Panx-1 expression and that its metabolism to adenosine mediates P2X7-dependent MA fusion. These data demonstrate that both P2X7 and Panx-1 are required for GM-CSF promotion of MA fusion but likely act independently through different signaling pathway(s).

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“…1). Adenosine influences monocyte maturation also by promoting the formation of multinucleated giant cells via A 1 receptor stimulation, whereas A 2 receptor activation prevents the generation of giant cells (Merrill et al, 1997; Fig. 1).…”

Section: Effect Of Adenosine On Monocyte/macrophage Maturation and Prmentioning

confidence: 99%

Shaping of monocyte and macrophage function by adenosine receptors

Haskó

Pacher

Deitch

et al. 2007

Pharmacology & Therapeutics

194

154

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Adenosine is an endogenous purine nucleoside that, following its release into the extracellular space, binds to specific adenosine receptors expressed on the cell surface. Adenosine appears in the extracellular space under metabolically stressful conditions, which are associated with ischemia, inflammation, and cell damage. There are 4 types of adenosine receptors (A 1 , A 2A , A 2B and A 3 ) and all adenosine receptors are members of the G protein-coupled family of receptors. Adenosine receptors are expressed on monocytes and macrophages and through these receptors adenosine modulates monocyte and macrophage function. Since monocytes and macrophages are activated by the same danger signals that cause accumulation of extracellular adenosine, adenosine receptors expressed on macrophages represent a sensor system that provide monocytes and macrophages with information about the stressful environment. Adenosine receptors, thus, allow monocytes and macrophages to fine-tune their responses to stressful stimuli. Here, we review the consequences of adenosine receptor activation on monocyte/macrophage function. We will detail the effect of stimulating the various adenosine receptor subtypes on macrophage differentiation/proliferation, phagocytosis, and tissue factor (TF) expression. We will also summarize our knowledge of how adenosine impacts the production of extracellular mediators secreted by monocytes and macrophages in response to toll-like receptor (TLR) ligands and other inflammatory stimuli. Specifically, we will delineate how adenosine affects the production of superoxide, nitric oxide (NO), tumor necrosis factor-α, interleukin (IL)-12, IL-10, and vascular endothelial growth factor (VEGF). A deeper insight into the regulation of monocyte and macrophage function by adenosine receptors should assist in developing new therapies for inflammatory diseases.

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Adenosine A₁ receptor promotion of multinucleated giant cell formation by human monocytes. A mechanism for methotrexate‐induced nodulosis in rheumatoid arthritis

Cited by 47 publications

References 28 publications

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

The P2X7 Receptor and Pannexin-1 Are Both Required for the Promotion of Multinucleated Macrophages by the Inflammatory Cytokine GM-CSF

Shaping of monocyte and macrophage function by adenosine receptors

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Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes. A mechanism for methotrexate‐induced nodulosis in rheumatoid arthritis

Cited by 47 publications

References 28 publications

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

The P2X7 Receptor and Pannexin-1 Are Both Required for the Promotion of Multinucleated Macrophages by the Inflammatory Cytokine GM-CSF

Shaping of monocyte and macrophage function by adenosine receptors

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Adenosine A₁ receptor promotion of multinucleated giant cell formation by human monocytes. A mechanism for methotrexate‐induced nodulosis in rheumatoid arthritis