Immunol Cell Biol 2015 Jan, 93(1):77-85.

Activation of the P2X7 receptor induces the rapid shedding of CD23 from human and murine B cells.

Pupovac A, Geraghty NJ, Watson D, Sluyter R.

School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia, Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.

 

Abstract

Activation of the P2X7 receptor by the extracellular damage-associated molecular pattern, adenosine 5’-triphosphate (ATP), induces the shedding of cell-surface molecules including the low-affinity IgE receptor, CD23, from human leukocytes. A disintegrin and metalloprotease (ADAM) 10 mediates P2X7-induced shedding of CD23 from multiple myeloma RPMI 8226 B cells, but whether this process occurs in primary B cells is unknown. The aim of the current study was to determine if P2X7 activation induces the rapid shedding of CD23 from primary human and murine B cells. Flow cytometric and ELISA measurements of ATP-induced loss of cell-surface CD23 showed that ATP treatment of human and murine B cells induced the rapid shedding of CD23. Treatment of cells with the specific P2X7 antagonist, AZ10606120, near-completely impaired ATP-induced CD23 shedding from both human and murine B cells. ATP-induced CD23 shedding was also impaired in B cells from P2X7 knockout mice. The absence of full-length, functional P2X7 in the P2X7 knockout mice was confirmed by immunoblotting of splenic cells, and by flow cytometric measurements of ATP-induced YO-PRO-12+ uptake into splenic B and T cells. The broad-spectrum metalloprotease antagonist, BB-94, and the ADAM10 antagonist, GI254023X, impaired P2X7-induced CD23 shedding from both human and murine B cells. This data indicates that P2X7 activation induces the rapid shedding of CD23 from primary human and murine B cells and that this process may be mediated by ADAM10.

PMID: 25155463

 

Supplementary

CD23 is a transmembrane receptor for immunoglobulin E. CD23 can also be shed from the surface of immune cells to form soluble CD23. Soluble CD23 can activate B and T cells, and monocytes to promote inflammation and immunity. Soluble CD23 is elevated in patients with disorders such as rheumatoid arthritis and Sjogren’s syndrome, suggesting a role for this molecule in these disorders. Other studies suggest roles for the damage associated molecular pattern receptor, P2X7, and for B cells in rheumatoid arthritis and Sjogren’s syndrome. The role of P2X7 in these disorders has largely been attributed to the release of pro-inflammatory cytokines. This article shows that P2X7 activation induces the shedding of CD23 from human and mouse B cells, and that this process is mediated by the membrane metalloprotease ADAM10. Thus, the possibility remains that P2X7-induced shedding of pro-inflammatory soluble CD23 from B cells may be important in rheumatoid arthritis and Sjogren’s syndrome. Further, P2X7 or pathways downstream of this receptor may provide novel therapeutic targets in these disorders.

Pupovac Figure1

 

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