Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan.
Department of Medicine, MacKay Medical College, New Taipei City, 25245, Taiwan.
Cell Death Dis. 2020 Oct 1;11(9):820. doi: 10.1038/s41419-020-03035-2.
BAFF supports B-cell survival and homeostasis by activating the NF-κB pathway. While NF-κB is also involved in the priming signal of NLRP3 inflammasome, the role of BAFF in NLRP3 inflammasome regulation is unknown. Here we report BAFF engagement to BAFF receptor elicited both priming and activating signals for NLRP3 inflammasomes in primary B cells and B lymphoma cell lines. This induction of NLRP3 inflammasomes by BAFF led to increased NLRP3 and IL-1β expression, caspase-1 activation, IL-1β secretion, and pyroptosis. Mechanistically, BAFF activated NLRP3 inflammasomes by promoting the association of cIAP-TRAF2 with components of NLRP3 inflammasomes, and by inducing Src activity-dependent ROS production and potassium ion efflux. B-cell receptor (BCR) stimulation on the Lyn signaling pathway inhibited BAFF-induced Src activities and attenuated BAFF-induced NLRP3 inflammasome activation. These findings reveal an additional function of BAFF in B-cell homeostasis that is associated with BCR activities.
BAFF 通过激活 NF-κB 途径来支持 B 细胞的存活和稳态。虽然 NF-κB 也参与 NLRP3 炎性体的初始信号，但 BAFF 在 NLRP3 炎性体调节中的作用尚不清楚。在这里，我们报告了 BAFF 与 BAFF 受体的结合，在原代 B 细胞和 B 淋巴瘤细胞系中引发了 NLRP3 炎性体的初始和激活信号。BAFF 诱导的 NLRP3 炎性体导致 NLRP3 和 IL-1β 的表达增加、半胱天冬酶-1 的激活、IL-1β 的分泌和细胞焦亡。在机制上，BAFF 通过促进 cIAP-TRAF2 与 NLRP3 炎性体成分的结合，以及通过诱导Src 活性依赖性 ROS 产生和钾离子外流，激活 NLRP3 炎性体。B 细胞受体 (BCR) 在 Lyn 信号通路的刺激抑制了 BAFF 诱导的Src 活性，并减弱了 BAFF 诱导的 NLRP3 炎性体激活。这些发现揭示了 BAFF 在与 BCR 活性相关的 B 细胞稳态中的另一个功能。
