An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus

Abstract

Objective To evaluate the dysfunction of B cell metabolism and its involvement in SLE pathology. Methods We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation. Results The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19+ cells and with SLEDAI, a disease activity score. Stimulation of CD19+ cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-α enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, ATP production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-α-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation. Conclusions Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE.

The Role of Immunometabolism in the Pathogenesis of Systemic Lupus Erythematosus

“…Furthermore, the degree of hyperpolarization correlated with SLEDAI-2K. The authors also noted that glutaminolysis, which generates essential metabolites for OXPHOS, played a key role in the differentiation into plasmablasts ( 31 ).…”

Association of Viral Infection With the Development and Pathogenesis of Systemic Lupus Erythematosus

“…The glutaminase inhibitor BPTES, which is a limited inhibitor of glutamine degradation, decreased DiOc6 expression, oxidative phosphorylation, ROS production, and ATP production, as well as suppressed plasmablast differentiation and antibody production. Metformin inhibited CpG-and IFNαinduced glutamine uptake, as well as suppressed plasmablast differentiation and antibody production (Figure 1) (109). In SLE patients, B-cells are activated and differentiated by viral and autoantigen-derived nucleic acids and IFN-α stimulation through the uptake of amino acids such as methionine and glutamine, which are related to the pathogenesis of SLE.…”

Altered Germinal-Center Metabolism in B Cells in Autoimmunity

“…Liu et al showed that BAFF is critical for the survival of anergic B cells, as well as rescuing autoreactive B cells from checkpoint deletion [78][79][80]. Several clinical studies have shown that lupus patients have much higher serum BAFF than healthy individuals, which allows the autoreactive B cells in lupus patients to escape metabolic restriction [81][82][83][84].…”

“…In lupus patients, T cells show mitochondrial synthesis and poor mitophagy [80]. Similarity B cells in SLE have larger mitochondria [81]. A study by Sumikawa et al showed that mitochondrial dysfunction in B cells was linked to plasmablast differentiation and disease activity in SLE.…”

“…A study by Sumikawa et al showed that mitochondrial dysfunction in B cells was linked to plasmablast differentiation and disease activity in SLE. They showed that enhanced mitochondrial capabilities mediated by glutamine metabolism are required for plasmablast development, which might be a therapeutic target for SLE [81].…”