Bone marrow plasma cells require P2RX4 to sense extracellular ATP

Masaki Ishikawa (), Zainul S. Hasanali, Yongge Zhao, Arundhoti Das, Marieke Lavaert, Carly J. Roman, Jennifer Londregan, David Allman () and Avinash Bhandoola ()
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Masaki Ishikawa: Center for Cancer Research, National Cancer Institute, National Institutes of Health
Zainul S. Hasanali: Abramson Cancer Center at the University of Pennsylvania
Yongge Zhao: Center for Cancer Research, National Cancer Institute, National Institutes of Health
Arundhoti Das: Center for Cancer Research, National Cancer Institute, National Institutes of Health
Marieke Lavaert: Center for Cancer Research, National Cancer Institute, National Institutes of Health
Carly J. Roman: Perelman School of Medicine at the University of Pennsylvania
Jennifer Londregan: Perelman School of Medicine at the University of Pennsylvania
David Allman: Perelman School of Medicine at the University of Pennsylvania
Avinash Bhandoola: Center for Cancer Research, National Cancer Institute, National Institutes of Health

Nature, 2024, vol. 626, issue 8001, 1102-1107

Abstract: Abstract Plasma cells produce large quantities of antibodies and so play essential roles in immune protection1. Plasma cells, including a long-lived subset, reside in the bone marrow where they depend on poorly defined microenvironment-linked survival signals1. We show that bone marrow plasma cells use the ligand-gated purinergic ion channel P2RX4 to sense extracellular ATP released by bone marrow osteoblasts through the gap-junction protein pannexin 3 (PANX3). Mutation of Panx3 or P2rx4 each caused decreased serum antibodies and selective loss of bone marrow plasma cells. Compared to their wild-type counterparts, PANX3-null osteoblasts secreted less extracellular ATP and failed to support plasma cells in vitro. The P2RX4-specific inhibitor 5-BDBD abrogated the impact of extracellular ATP on bone marrow plasma cells in vitro, depleted bone marrow plasma cells in vivo and reduced pre-induced antigen-specific serum antibody titre with little posttreatment rebound. P2RX4 blockade also reduced autoantibody titre and kidney disease in two mouse models of humoral autoimmunity. P2RX4 promotes plasma cell survival by regulating endoplasmic reticulum homeostasis, as short-term P2RX4 blockade caused accumulation of endoplasmic reticulum stress-associated regulatory proteins including ATF4 and B-lineage mutation of the pro-apoptotic ATF4 target Chop prevented bone marrow plasma cell demise on P2RX4 inhibition. Thus, generating mature protective and pathogenic plasma cells requires P2RX4 signalling controlled by PANX3-regulated extracellular ATP release from bone marrow niche cells.

Date: 2024
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DOI: 10.1038/s41586-024-07047-2

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