ATP release mediated by pannexin-3 is required for plasma cell survival via P2X4 receptors in bone marrow

Extracellular adenosine-5′-triphosphate (ATP) is an important extracellular messenger that influences cellular processes, such as proliferation, apoptosis, and differentiation. Once ATP is released into the extracellular space, it can bind purinergic receptors in the cells that released the nucleotide or in neighboring cells. In a recent publication in Nature, Ishikawa et al. [1] showed that extracellular ATP released by osteoblasts via pannexin-3 channels in gap junctions in the bone marrow niche cells acts in a paracrine fashion, binding P2X4 receptors in plasma cells. The expression of both channels is required for appropriate antibody production and plasma cell survival. In contrast, genetic deletion of either Panx3 in osteoblastic cells or P2X4 receptors in plasma cells caused plasma cell depletion and reduced their ability to produce antibodies in vitro. In addition, treatment with a selective P2X4 receptor antagonist, 5-BDBD, in vitro and in vivo reduced serum antibody titer and plasma cell survival. The authors also illustrate the potential implication of this mechanism in an autoimmune disease, such as systemic lupus erythematosus, as P2X4 receptor activity in bone marrow plasma cells is shown to inhibit endoplasmic reticulum-induced apoptosis.