Bone marrow plasma cells require P2RX4 to sense extracellular ATP

• Published in: Nature (London) 2024-02, Vol.626 (8001), p.1102-1107
• Main Authors: Ishikawa, Masaki, Hasanali, Zainul S., Zhao, Yongge, Das, Arundhoti, Lavaert, Marieke, Roman, Carly J., Londregan, Jennifer, Allman, David, Bhandoola, Avinash
• Format: Article
• Language: English
• Subjects: 13; 13/31; 631/250/2152/2153/1291; 631/250/38; Adenosine Triphosphate - metabolism; Animal models; Animals; Antibodies; Antigens; Apoptosis; ATP; Autoantibodies; Autoantibodies - immunology; Autoimmune diseases; Autoimmunity; Autoimmunity - immunology; Bone marrow; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Cell Lineage; Cell survival; Connexins - genetics; Connexins - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress; Homeostasis; Humanities and Social Sciences; Immunoglobulins; Ion channels; Kidney diseases; Ligands; Lymphocytes; Mice; Microenvironments; multidisciplinary; Mutagenesis; Mutation; Osteoblasts; Osteoblasts - metabolism; Plasma; Plasma cells; Plasma Cells - cytology; Plasma Cells - immunology; Plasma Cells - metabolism; Proteins; Receptors, Purinergic P2X4 - metabolism; Regulatory proteins; Science; Science (multidisciplinary); Signal Transduction; Spleen; Survival
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-024-07047-2

Plasma cells produce large quantities of antibodies and so play essential roles in immune protection 1 . Plasma cells, including a long-lived subset, reside in the bone marrow where they depend on poorly defined microenvironment-linked survival signals 1 . 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 P2r x 4 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 C hop 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. We demonstrate the role of the ligand-gated purinergic ion channel P2RX4 in maintaining mouse plasma cells in their bone marrow niche.