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BAFF-driven NLRP3 inflammasome activation in B cells.

Ken-Hong Lim1,2,3, Lih-Chyang Chen2, Kate Hsu4,5

  • 1Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan.

Cell Death & Disease
|October 2, 2020
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B-cell survival factor BAFF activates NLRP3 inflammasomes in B cells, leading to pyroptosis. B-cell receptor signaling can inhibit this BAFF-induced inflammasome activation, revealing a new link between B-cell homeostasis and immune responses.

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • B-cell Activating Factor (BAFF) is crucial for B-cell survival and homeostasis, primarily through the NF-κB pathway.
  • The NLRP3 inflammasome, involved in innate immunity, is primed by NF-κB, but BAFF's role in its regulation remains unclear.

Purpose of the Study:

  • To investigate the role of BAFF in the regulation of NLRP3 inflammasomes in B cells.
  • To elucidate the molecular mechanisms underlying BAFF-mediated NLRP3 inflammasome activation and its interplay with B-cell receptor (BCR) signaling.

Main Methods:

  • Primary B cells and B lymphoma cell lines were utilized to study BAFF receptor engagement.
  • Techniques included assessing NLRP3 and IL-1β expression, caspase-1 activation, IL-1β secretion, pyroptosis, and analyzing protein-protein interactions and signaling pathways (Src, Lyn).

Main Results:

  • BAFF binding to its receptor initiated both priming and activation signals for NLRP3 inflammasomes.
  • BAFF induced increased NLRP3 and IL-1β expression, caspase-1 activation, IL-1β secretion, and pyroptosis in B cells.
  • Mechanistically, BAFF promoted cIAP-TRAF2 association, Src activity-dependent reactive oxygen species (ROS) production, and potassium ion efflux.
  • B-cell receptor stimulation, via Lyn signaling, inhibited BAFF-induced Src activity and attenuated NLRP3 inflammasome activation.

Conclusions:

  • BAFF plays a novel role in activating NLRP3 inflammasomes and inducing pyroptosis in B cells.
  • BAFF-mediated NLRP3 inflammasome activation is mechanistically linked to Src activity, ROS production, and ion flux.
  • BCR signaling acts as a negative regulator of BAFF-induced NLRP3 inflammasome activation, highlighting a connection between BAFF and BCR pathways in B-cell homeostasis.