Bone marrow plasma cells require P2RX4 to sense extracellular ATP

Area of Science:

• Immunology
• Cell Biology
• Bone Biology

Background:

• Plasma cells are vital for immune protection, producing antibodies and residing in the bone marrow.
• Long-lived plasma cells depend on poorly understood bone marrow microenvironment survival signals.

Purpose of the Study:

• To elucidate the molecular mechanisms by which bone marrow plasma cells receive survival signals.
• To investigate the role of extracellular ATP and purinergic signaling in plasma cell maintenance.

Main Methods:

• Utilized genetic mutations in Panx3 and P2rx4 in mice.
• Assessed serum antibody levels and bone marrow plasma cell populations.
• Employed P2RX4-specific inhibitor (5-BDBD) in vitro and in vivo.
• Analyzed endoplasmic reticulum stress markers and apoptosis pathways.

Main Results:

• Mutation of Panx3 or P2rx4 led to reduced serum antibodies and bone marrow plasma cell loss.
• PANX3-null osteoblasts secreted less extracellular ATP, impairing plasma cell support.
• P2RX4 inhibition depleted bone marrow plasma cells, reduced antibody titers, and ameliorated autoimmunity in mouse models.
• P2RX4 signaling regulates endoplasmic reticulum homeostasis, with Chop mediating P2RX4 inhibition-induced plasma cell death.

Conclusions:

• Bone marrow plasma cell survival is critically dependent on P2RX4-mediated sensing of extracellular ATP.
• PANX3 on osteoblasts regulates extracellular ATP release, controlling P2RX4 signaling and plasma cell homeostasis.
• Targeting P2RX4 offers a potential therapeutic strategy for antibody-mediated autoimmune diseases.