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.
Highlights
B cell-activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, maintains B cell homeostasis[1]
BAFF-induced NLRP3 inflammasome activities We first investigated whether BAFF could modulate the expression of NLRP3 and pro-IL-1β in B cells
In contrast to NLRP3 and pro-IL-1β whose expression levels were significantly up-regulated by BAFF in the three types of B cells tested, the levels of NLRP1 or NLRC4 did not increase by BAFF (Figs. 1a, b and S1)
Summary
B cell-activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, maintains B cell homeostasis[1]. This homeostasis of mature B lymphocytes is known to mediate survival through BAFF receptor 3 (BR3, known as BAFFR)[2,3] or through coordinated B-cell receptor (BCR) signaling[4,5]. Stimulation of BAFFR recruits TNF receptorassociated factor 3 (TRAF3), resulting in further release of NF-κB-inducing kinase (NIK). This strongly activates the alternative nuclear factor-B2 (NF-κB2) pathway and weakly activates the classical NF-κB1 pathway in B cells[1]. Mice treated with reagents that block BAFF binding to BAFFR resulted in loss of most follicular cells, while mice with transgenically induced elevation of BAFF expression
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