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

Autor: D Lempicki M; Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, United States., Paul S; Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, United States., Serbulea V; Department of Pharmacology, University of Virginia, VA 22908, United States., Upchurch CM; Department of Pharmacology, University of Virginia, VA 22908, United States., Sahu S; Department of Pharmacology, University of Virginia, VA 22908, United States., Gray JA; Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, United States., Ailawadi G; Department of Surgery, University of Virginia, VA 22908, United States., Garcia BL; Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, United States., McNamara CA; Robert M. Berne Cardiovascular Research Center, University of Virginia, VA 22908, United States., Leitinger N; Department of Pharmacology, University of Virginia, VA 22908, United States., Meher AK; Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, United States; Department of Pharmacology, University of Virginia, VA 22908, United States. Electronic address: mehera19@ecu.edu.
Jazyk: angličtina
Zdroj: Cellular immunology [Cell Immunol] 2022 Sep 09; Vol. 381, pp. 104603. Date of Electronic Publication: 2022 Sep 09.
DOI: 10.1016/j.cellimm.2022.104603
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Published by Elsevier Inc.)
Databáze: MEDLINE
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