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

• Published in: Cellular immunology Vol. 381; p. 104603
• Main Authors: D. Lempicki, Melissa, Paul, Saikat, Serbulea, Vlad, Upchurch, Clint M., Sahu, Srabani, Gray, Jake A., Ailawadi, Gorav, Garcia, Brandon L., McNamara, Coleen A., Leitinger, Norbert, Meher, Akshaya K.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-11-2022
• Subjects: B cell activation; B-Cell Activating Factor - genetics; B-Cell Activation Factor Receptor - metabolism; BAFF multimers; Binding Sites; Glucose; Humans; Metabolic Reprogramming; NF-kappa B - metabolism; NF-κB signaling; Transcriptomics; BAFF; BR3; BAFF multimers; OXPHOS; BCMA; IKKα; Metabolic reprogramming; IKKβ; B cell activation; FPKM; LPS; ECAR; NF-κB signaling; SEC; NF-κB; TACI; Transcriptomics; mBaffR-Fc; IPA; OCR
• ISSN: 0008-8749; 1090-2163; 1090-2163
• DOI: 10.1016/j.cellimm.2022.104603

•BAFF 3-mer, BAFF 60-mer, and higher order multimers are present in human plasma.•Compared to the BAFF 3-mer, BAFF 60-mer strongly induces the transcriptome of B cells.•BAFF 60-mer is critical for classical NF-κB signaling and glucose oxidation.•BAFF 60-mer-induced classical NF-κB signaling drives glucose oxidation.•BR3 binding site on BAFF is critical BAFF 60-mer-induced B cell hyperactivation.
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.