BAFF-driven NLRP3 inflammasome activation in B cells

Abstract 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.