BAFF antagonism via the BAFF receptor 3 binding site attenuates BAFF 60-mer-induced classical NF-κB signaling and metabolic reprogramming of B cells

Cell Immunol. 2022 Sep 9:381:104603. doi: 10.1016/j.cellimm.2022.104603. Online ahead of print.

Abstract

Human recombinant B cell activating factor (BAFF) is secreted as 3-mers, which can associate to form 60-mers in culture supernatants. However, the presence of BAFF multimers in humans is still debated and it is incompletely understood how BAFF multimers activate the B cells. Here, we demonstrate that BAFF can exist as 60-mers or higher order multimers in human plasma. In vitro, BAFF 60-mer strongly induced the transcriptome of B cells which was partly attenuated by antagonism using a soluble fragment of BAFF receptor 3. Furthermore, compared to BAFF 3-mer, BAFF 60-mer strongly induced a transient classical and prolonged alternate NF-κB signaling, glucose oxidation by both aerobic glycolysis and oxidative phosphorylation, and succinate utilization by mitochondria. BAFF antagonism selectively attenuated classical NF-κB signaling and glucose oxidation. Altogether, our results suggest critical roles of BAFF 60-mer and its BAFF receptor 3 binding site in hyperactivation of B cells.

Keywords: B cell activation; BAFF multimers; Metabolic reprogramming; NF-κB signaling; Transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Cell Activating Factor* / genetics
  • B-Cell Activation Factor Receptor / metabolism
  • Binding Sites
  • Glucose
  • Humans
  • Metabolic Reprogramming
  • NF-kappa B* / metabolism

Substances

  • NF-kappa B
  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • Glucose