PDF(Pubmed)
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.
摘要：
浆细胞产生大量抗体，因此在免疫保护中起着重要作用。浆细胞,包括一个长期存在的子集，位于骨髓中，它们依赖于定义不清的微环境相关生存信号1。我们表明，骨髓浆细胞使用配体门控的嘌呤能离子通道P2RX4来感知骨髓成骨细胞通过间隙连接蛋白pannexin3（PANX3）释放的细胞外ATP。Panx3或P2rx4的突变均导致血清抗体降低和骨髓浆细胞的选择性丧失。与它们的野生型对应物相比，PANX3无效的成骨细胞分泌较少的细胞外ATP，并且无法在体外支持浆细胞。P2RX4特异性抑制剂5-BDBD在体外消除了细胞外ATP对骨髓浆细胞的影响，体内骨髓浆细胞耗尽，预诱导抗原特异性血清抗体滴度降低，治疗后反弹很少。P2RX4阻断还降低了两种体液自身免疫小鼠模型中的自身抗体滴度和肾脏疾病。P2RX4通过调节内质网稳态促进浆细胞存活，因为短期P2RX4阻断导致内质网应激相关调节蛋白的积累,包括ATF4和促凋亡ATF4靶的B系突变Chop阻止P2RX4抑制后骨髓浆细胞死亡.因此，产生成熟的保护性和致病性浆细胞需要P2RX4信号传导，该信号由PANX3调节的细胞外ATP从骨髓小生境细胞释放控制。
