Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle

Urbanczyk, Sophia; Baris, Olivier; Hofmann, Jörg; Taudte, Regina Verena; Guegen, Naïg; Golombek, Florian; Castiglione, Kathrin; Meng, Xianjun; Bözec, Aline; Thomas, Jana; Weckwerth, Leonie; Mougiakakos, Dimitrios; Schulz, Sebastian; Schuh, Wolfgang; Schlötzer‐Schrehardt, Ursula; Steinmetz, Tobit; Brodesser, Susanne; Wiesner, Rudolf J.; Mielenz, Dirk

doi:10.1016/j.celrep.2022.110912

Cited by 38 publications

(30 citation statements)

References 85 publications

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“…Together, these notions prompted us to address whether TFG indeed contributes to lipid homeostasis in B cells. To this end, we performed shotgun lipidomic analyses of glycerophospholipids (GPL) (Kumar et al, 2015; Urbanczyk et al, 2022) from untreated CH12tfgWT and KO B cells. Figure 3A depicts a representative neutral loss mass spectrum showing phosphatidylglycerol (PG) from CH12 tfg WT and KO B cells.…”

Section: Resultsmentioning

confidence: 99%

“…JK6L cells were cultured in R10 medium supplemented with supernatants of IL-6-producing J558 cells (Meister et al, 2007). Primary mouse B cells were prepared form spleen and activated with lipopolysaccharide (LPS) for 24h as described (Urbanczyk et al, 2022).…”

Section: Methodsmentioning

confidence: 99%

“…Liposome production was based as recently described (S. T. Poschenrieder, 2016; Urbanczyk et al, 2022). Here, 11.4 mL of vesicle buffer (10 mM Tris-HCl, 150 mM NaCl, pH 8.0) were poured into unbaffled miniaturized stirred tank reactors (BioREACTOR48, 2mag, Munich, Germany) and stirred at 4000 rpm at 25°C using an S-type stirrer.…”

Section: Methodsmentioning

confidence: 99%

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Quantitative proteomics and lipidomics of TFG-deficient B cells provide insights into mechanisms of autophagic flux and plasma cell biology

Steinmetz

Reimann

Schulz

et al. 2022

Preprint

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The autophagy-flux-promoting protein TFG (Trk-fused gene) is up-regulated during B cell differentiation into plasma cells and supports survival of CH12 B cells. We hypothesized that quantitative proteomics analysis of CH12tfgKO B cells with intact or blocked autophagy-lysosome flux (via NH4Cl) will identify mechanisms of TFG-dependent autophagy, plasma cell biology and B cell survival. Analysis of CH12WT B cells in the presence of NH4Cl will identify proteins whose presence is continuously regulated by lysosomes independent of TFG. We determined hundreds of proteins to be controlled by TFG and/or NH4Cl. Notably, NH4Cl treatment alone increased the abundance of a cluster of cytosolic and mitochondrial translational proteins while it also reduced a number of proteins. Within the B cell relevant protein pool, BCL10 was reduced, while JCHAIN was increased in CH12tfgKO B cells. Furthermore, TFG regulated the abundance of transcription factors, such as JUNB, metabolic enzymes, such as the short-chain fatty acid activating enzyme ACOT9 or the glycolytic enzyme ALDOC. Gene ontology enrichment analysis revealed that TFG-regulated proteins localized to mitochondria and membrane-bounded organelles. Due to these findings we performed shotgun lipidomics of glycerophospholipids, uncovering that a particular phosphatidylethanolamine (PE) species, 32:0 PE, which lipidates LC3 most efficiently, was less abundant while phosphatidylglycerol (PG) was more abundant in CH12tfgKO B cells. In line with the role of PG as precursor for Cardiolipin (CL), the CL content was higher in CH12tfgKO B cells and addition of PG liposomes to B cells increased the amount of CL. We propose a role for TFG in B cell activation and plasma cell biology via regulation of proteins involved in germinal center and plasma cell development, such as BCL10 or JCHAIN, as well as in lipid homeostasis, mitochondria and metabolism.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Quantitative proteomics and lipidomics of TFG-deficient B cells provide insights into mechanisms of autophagic flux and plasma cell biology

Steinmetz

Reimann

Schulz

et al. 2022

Preprint

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“…Activated B cells exposed to high levels of BAFF increased glucose uptake and mitochondrial mass, resulting in increased glycolysis and oxidative phosphorylation 40,41 . Although the mitochondrial dynamics in PCs have not been studied in detail, it is likely that IgG secretion in these cells is linked to increased metabolic rates and induces cellular stress responses 40,[42][43][44] . The observed Ca 2+ influx in response to LPI stimulation may play an important role in the regulation of cellular responses in PCs, including mitochondrial physiology and Ig production 45 .…”

Section: Discussionmentioning

confidence: 99%

GPR55 in B cells limits atherosclerosis development and regulates plasma cell maturation

Guillamat-Prats¹,

Hering²,

Derle³

et al. 2022

Nat Cardiovasc Res

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Dissecting the pathways regulating the adaptive immune response in atherosclerosis is of particular therapeutic interest. Here we report that the lipid G-protein-coupled receptor GPR55 is highly expressed by splenic plasma cells (PCs), upregulated in mouse spleens during atherogenesis and human unstable or ruptured compared to stable plaques. Gpr55-deficient mice developed larger atherosclerotic plaques with increased necrotic core size compared to their corresponding controls. Lack of GPR55 hyperactivated B cells, disturbed PC maturation and resulted in IgG overproduction. B-cell-specific Gpr55 depletion or adoptive transfer of Gpr55-deficient B cells was sufficient to promote plaque development and elevated IgG titers. In vitro, the endogenous GPR55 ligand lysophsophatidylinositol (LPI) enhanced PC proliferation, whereas GPR55 antagonism blocked PC maturation and increased their mitochondrial content. Collectively, these discoveries provide previously undefined evidence for GPR55 in B cells as a key modulator of the adaptive immune response in atherosclerosis.

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“…Thus, mTORC1 serves as a (positive) metabolic sensor potentially integrating glucose, amino acid, and/or oxygen availability to prepare B cells for PC differentiation (15,26). Notably, the function of mTORC1 in PC differentiation is further dependent on adequate mitochondrial function, particularly oxidative phosphorylation (39).…”

Section: B Cell Activation and Plasma Cell Differentiationmentioning

confidence: 99%

Influence of nutrients and metabolites on the differentiation of plasma cells and implications for autoimmunity

et al. 2022

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The modulation of inflammatory (auto)immune reactions by nutrients and gut bacterial metabolites is of great interest for potential preventive and therapeutic strategies. B cell-derived plasma cells are major players in inflammatory (auto)immune responses and can exhibit pro- or anti-inflammatory effects through (auto)antibody-dependent and -independent functions. Emerging evidence indicates a key role of nutrients and microbial metabolites in regulating the differentiation of plasma cells as well as their differentiation to pro- or anti-inflammatory phenotypes. These effects might be mediated indirectly by influencing other immune cells or directly through B cell-intrinsic mechanisms. Here, we provide an overview of nutrients and metabolites that influence B cell-intrinsic signaling pathways regulating B cell activation, plasma cell differentiation, and effector functions. Furthermore, we outline important inflammatory plasma cell phenotypes whose differentiation could be targeted by nutrients and microbial metabolites. Finally, we discuss possible implications for inflammatory (auto)immune conditions.

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Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle

Cited by 38 publications

References 85 publications

Quantitative proteomics and lipidomics of TFG-deficient B cells provide insights into mechanisms of autophagic flux and plasma cell biology

Quantitative proteomics and lipidomics of TFG-deficient B cells provide insights into mechanisms of autophagic flux and plasma cell biology

GPR55 in B cells limits atherosclerosis development and regulates plasma cell maturation

Influence of nutrients and metabolites on the differentiation of plasma cells and implications for autoimmunity

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