bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2021‒11‒07
nineteen papers selected by
Dylan Ryan
University of Cambridge
  1. Immune and non-immune functions of adipose tissue leukocytes.
  2. IRAK4 inhibitor mitigates joint inflammation by rebalancing metabolism malfunction in RA macrophages and fibroblasts.
  3. Does Altered Cellular Metabolism Underpin the Normal Changes to the Maternal Immune System during Pregnancy?
  4. Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function.
  5. Role of GM-CSF in regulating metabolism and mitochondrial functions critical to macrophage proliferation.
  6. Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease.
  7. Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors.
  8. Macrophages as Emerging Key Players in Mitochondrial Transfers.
  9. Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells.
  10. β-Glucan Induces Distinct and Protective Innate Immune Memory in Differentiated Macrophages.
  11. The glycolysis inhibitor 2-deoxyglucose ameliorates adjuvant-induced arthritis by regulating macrophage polarization in an AMPK-dependent manner.
  12. δPKC-Mediated Drp1 Phosphorylation Impacts Macrophage Mitochondrial Function and Inflammatory Response to Endotoxin.
  13. Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.
  14. Plasmacytoid dendritic cell activation is dependent on coordinated expression of distinct amino acid transporters.
  15. An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus.
  16. d-mannose attenuates lipopolysaccharide-induced osteolysis via CPT1A-Mediated lipid metabolic regulation in macrophages.
  17. B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity.
  18. HIF-1α Regulation of Cytokine Production following TLR3 Engagement in Murine Bone Marrow-Derived Macrophages Is Dependent on Viral Nucleic Acid Length and Glucose Availability.
  19. Gasdermin D mediates host cell death but not interleukin-1β secretion in Mycobacterium tuberculosis-infected macrophages.
  1. Nat Rev Immunol. 2021 Nov 05.
    Immune and non-immune functions of adipose tissue leukocytes.
    W V Trim, L Lynch.
      Adipose tissue is a complex dynamic organ with whole-body immunometabolic influence. Much of the work into understanding the role of immune cells in adipose tissue has been in the context of obesity. These investigations have also uncovered a range of typical (immune) and non-typical functions exerted by adipose tissue leukocytes. Here we provide an overview of the adipose tissue immune system, including its role as an immune reservoir in the whole-body response to infection and as a site of parasitic and viral infections. We also describe the functional roles of specialized immunological structures found within adipose tissue. However, our main focus is on the recently discovered 'non-immune' functions of adipose tissue immune cells, which include the regulation of adipocyte homeostasis, as well as responses to changing nutrient status and body temperature. In doing so, we outline the therapeutic potential of the adipose tissue immune system in health and disease.
    DOI:  https://doi.org/10.1038/s41577-021-00635-7
  2. Life Sci. 2021 Oct 31. pii: S0024-3205(21)01101-2. [Epub ahead of print] 120114
    IRAK4 inhibitor mitigates joint inflammation by rebalancing metabolism malfunction in RA macrophages and fibroblasts.
    Sadiq Umar, Karol Palasiewicz, Michael V Volin, Brian Zanotti, Mina Al-Awqati, Nadera Sweiss, Shiva Shahrara.
      Recent studies show a connection between glycolysis and inflammatory response in rheumatoid arthritis (RA) macrophages (MΦs) and fibroblasts (FLS). Yet, it is unclear which pathways could be targeted to rebalance RA MΦs and FLS metabolic reprogramming. To identify novel targets that could normalize RA metabolic reprogramming, TLR7-mediated immunometabolism was characterized in RA MΦs, FLS and experimental arthritis. We uncovered that GLUT1, HIF1α, cMYC, LDHA and lactate were responsible for the TLR7-potentiated metabolic rewiring in RA MΦs and FLS, which was negated by IRAKi. While in RA FLS, HK2 was uniquely expanded by TLR7 and negated by IRAK4i. Conversely, TLR7-driven hypermetabolism, non-oxidative PPP (CARKL) and oxidative phosphorylation (PPARγ) were narrowly dysregulated in TLR7-activated RA MΦs and FLS and was reversed by IRAK4i. Consistently, IRAK4i therapy disrupted arthritis mediated by miR-Let7b/TLR7 along with impairing a broad-range of glycolytic intermediates, GLUT1, HIF1α, cMYC, HK2, PFKFB3, PKM2, PDK1 and RAPTOR. Notably, inhibition of the mutually upregulated glycolytic metabolites, HIF1α and cMYC, was capable of mitigating TLR7-induced inflammatory imprint in RA MΦs and FLS. In keeping with IRAK4i, treatment with HIF1i and cMYCi intercepted TLR7-enhanced IRF5 and IRF7 in RA MΦs, distinct from RA FLS. Interestingly, in RA MΦs and FLS, IRAKi counteracted TLR7-induced CARKL reduction in line with HIF1i. Whereas, cMYCi in concordance with IRAK4i, overturned oxidative phosphorylation via PPARγ in TLR7-activated RA MΦs and FLS. The blockade of IRAK4 and its interconnected intermediates can rebalance the metabolic malfunction by obstructing glycolytic and inflammatory phenotypes in RA MΦs and FLS.
    Keywords:  HIF1α; IRAK4; RA FLS; RA macrophages; TLR7-induced arthritis; cMYC
    DOI:  https://doi.org/10.1016/j.lfs.2021.120114
  3. Immunometabolism. 2021 Oct 04. 3(4): e210031
    Does Altered Cellular Metabolism Underpin the Normal Changes to the Maternal Immune System during Pregnancy?
    Benjamin J Jenkins, April Rees, Nicholas Jones, Catherine A Thornton.
      Pregnancy is characterised by metabolic changes that occur to support the growth and development of the fetus over the course of gestation. These metabolic changes can be classified into two distinct phases: an initial anabolic phase to prepare an adequate store of substrates and energy which are then broken down and used during a catabolic phase to meet the energetic demands of the mother, placenta and fetus. Dynamic readjustment of immune homeostasis is also a feature of pregnancy and is likely linked to the changes in energy substrate utilisation at this time. As cellular metabolism is increasingly recognised as a key determinant of immune cell phenotype and function, we consider how changes in maternal metabolism might contribute to T cell plasticity during pregnancy.
    Keywords:  Th2; Treg; immunometabolism; maternal metabolism; pregnancy
    DOI:  https://doi.org/10.20900/immunometab20210031
  4. Front Physiol. 2021 ;12 688485
    Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function.
    Heather L Caslin, Daniel Abebayehu, Julia A Pinette, John J Ryan.
      Lactate and the associated H+ ions are still introduced in many biochemistry and general biology textbooks and courses as a metabolic by-product within fast or oxygen-independent glycolysis. However, the role of lactate as a fuel source has been well-appreciated in the field of physiology, and the role of lactate as a metabolic feedback regulator and distinct signaling molecule is beginning to gain traction in the field of immunology. We now know that while lactate and the associated H+ ions are generally immunosuppressive negative regulators, there are cell, receptor, mediator, and microenvironment-specific effects that augment T helper (Th)17, macrophage (M)2, tumor-associated macrophage, and neutrophil functions. Moreover, we are beginning to uncover how lactate and H+ utilize different transporters and signaling cascades in various immune cell types. These immunomodulatory effects may have a substantial impact in cancer, sepsis, autoimmunity, wound healing, and other immunomodulatory conditions with elevated lactate levels. In this article, we summarize the known effects of lactate and H+ on immune cells to hypothesize potential explanations for the divergent inflammatory vs. anti-inflammatory effects.
    Keywords:  M2; Th17; immune; immunometabolism; immunosuppression; inflammation; lactate; lactic acid
    DOI:  https://doi.org/10.3389/fphys.2021.688485
  5. Mitochondrion. 2021 Nov 02. pii: S1567-7249(21)00149-5. [Epub ahead of print]
    Role of GM-CSF in regulating metabolism and mitochondrial functions critical to macrophage proliferation.
    Matthew Wessendarp, Miki Watanabe-Chailland, Serena Liu, Traci Stankiewicz, Yan Ma, Rajesh K Kasam, Kenjiro Shima, Claudia Chalk, Brenna Carey, Lindsey-Romick Rosendale, Marie Dominique Filippi, Paritha Arumugam.
      Granulocyte-macrophage colony-stimulating factor (GM-CSF) exerts pleiotropic effects on macrophages and is required for self-renewal but the mechanisms responsible are unknown. Using mouse models with disrupted GM-CSF signaling, we show GM-CSF is critical for mitochondrial turnover, functions, and integrity. GM-CSF signaling is essential for fatty acid β-oxidation and markedly increased tricarboxylic acid cycle activity, oxidative phosphorylation, and ATP production. GM-CSF also regulated cytosolic pathways including glycolysis, pentose phosphate pathway, and amino acid synthesis. We conclude that GM-CSF regulates macrophages in part through a critical role in maintaining mitochondria, which are necessary for cellular metabolism as well as proliferation and self-renewal.
    Keywords:  GM-CSF; apoptosis; fatty acid oxidation; macrophage metabolism; mitochondrial functions; self-renewal
    DOI:  https://doi.org/10.1016/j.mito.2021.10.009
  6. Cell Metab. 2021 Nov 02. pii: S1550-4131(21)00488-5. [Epub ahead of print]33(11): 2260-2276.e7
    Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease.
    Daniel Erny, Nikolaos Dokalis, Charlotte Mezö, Angela Castoldi, Omar Mossad, Ori Staszewski, Maximilian Frosch, Matteo Villa, Vidmante Fuchs, Arun Mayer, Jana Neuber, Janika Sosat, Stefan Tholen, Oliver Schilling, Andreas Vlachos, Thomas Blank, Mercedes Gomez de Agüero, Andrew J Macpherson, Edward J Pearce, Marco Prinz.
      As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia maturation and function by the production of short-chain fatty acids (SCFAs). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation.
    Keywords:  Alzheimer’s disease; SCFA; acetate; germ-free; metabolism; microbiota; microglia; mitochondria; respiratory chain
    DOI:  https://doi.org/10.1016/j.cmet.2021.10.010
  7. Cell Rep. 2021 Nov 02. pii: S2211-1247(21)01432-7. [Epub ahead of print]37(5): 109955
    Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors.
    Lizhi He, Jhih-Hua Jhong, Qi Chen, Kai-Yao Huang, Karin Strittmatter, Johannes Kreuzer, Michael DeRan, Xu Wu, Tzong-Yi Lee, Nikolai Slavov, Wilhelm Haas, Alexander G Marneros.
      Macrophages undergoing M1- versus M2-type polarization differ significantly in their cell metabolism and cellular functions. Here, global quantitative time-course proteomics and phosphoproteomics paired with transcriptomics provide a comprehensive characterization of temporal changes in cell metabolism, cellular functions, and signaling pathways that occur during the induction phase of M1- versus M2-type polarization. Significant differences in, especially, metabolic pathways are observed, including changes in glucose metabolism, glycosaminoglycan metabolism, and retinoic acid signaling. Kinase-enrichment analysis shows activation patterns of specific kinases that are distinct in M1- versus M2-type polarization. M2-type polarization inhibitor drug screens identify drugs that selectively block M2- but not M1-type polarization, including mitogen-activated protein kinase kinase (MEK) and histone deacetylase (HDAC) inhibitors. These datasets provide a comprehensive resource to identify specific signaling and metabolic pathways that are critical for macrophage polarization. In a proof-of-principle approach, we use these datasets to show that MEK signaling is required for M2-type polarization by promoting peroxisome proliferator-activated receptor-γ (PPARγ)-induced retinoic acid signaling.
    Keywords:  HDAC inhibitors; M1-type polarization; M2-type polarization; MEK signaling; age-related macular degeneration; kinase enrichment analysis; macrophage metabolism; macrophage polarization; phosphoproteomics; retinoic acid signaling
    DOI:  https://doi.org/10.1016/j.celrep.2021.109955
  8. Front Cell Dev Biol. 2021 ;9 747377
    Macrophages as Emerging Key Players in Mitochondrial Transfers.
    Yidan Pang, Changqing Zhang, Junjie Gao.
      Macrophages are a group of heterogeneous cells widely present throughout the body. Under the influence of their specific environments, via both contact and noncontact signals, macrophages integrate into host tissues and contribute to their development and the functions of their constituent cells. Mitochondria are essential organelles that perform intercellular transfers to regulate cell homeostasis. Our review focuses on newly discovered roles of mitochondrial transfers between macrophages and surrounding cells and summarizes emerging functions of macrophages in transmitophagy, metabolic regulation, and immune defense. We also discuss the negative influence of mitochondrial transfers on macrophages, as well as current therapies targeting mitochondria in macrophages. Regulation of macrophages through mitochondrial transfers between macrophages and their surrounding cells is a promising therapy for various diseases, including cardiovascular diseases, inflammatory diseases, obesity, and cancer.
    Keywords:  adipocyte; cardiomyocyte; macrophage; mitochondrial transfer; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2021.747377
  9. Elife. 2021 Nov 02. pii: e65109. [Epub ahead of print]10
    Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells.
    Michael C Kiritsy, Katelyn McCann, Daniel Mott, Stephen M Holland, Samuel M Behar, Christopher M Sassetti, Andrew J Olive.
      The immunological synapse allows antigen presenting cells (APC) to convey a wide array of functionally distinct signals to T cells, which ultimately shape the immune response. The relative effect of stimulatory and inhibitory signals is influenced by the activation state of the APC, which is determined by an interplay between signal transduction and metabolic pathways. While pathways downstream of toll-like receptors rely on glycolytic metabolism for the proper expression of inflammatory mediators, little is known about the metabolic dependencies of other critical signals such as interferon gamma (IFNg). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in murine macrophages to identify the regulators of IFNg-inducible T cell stimulatory or inhibitory proteins MHCII, CD40, and PD-L1. Our multi-screen approach enabled us to identify novel pathways that control these functionally distinct markers. Further integration of these screening data implicated complex I of the mitochondrial respiratory chain in the expression of all three markers, and by extension the IFNg signaling pathway. We report that the IFNg response requires mitochondrial respiration, and APCs are unable to activate T cells upon genetic or chemical inhibition of complex I. These findings suggest a dichotomous metabolic dependency between IFNg and toll-like receptor signaling, implicating mitochondrial function as a fulcrum of innate immunity.
    Keywords:  human; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.65109
  10. J Immunol. 2021 Nov 05. pii: ji2100107. [Epub ahead of print]
    β-Glucan Induces Distinct and Protective Innate Immune Memory in Differentiated Macrophages.
    Cody L Stothers, Katherine R Burelbach, Allison M Owen, Naeem K Patil, Margaret A McBride, Julia K Bohannon, Liming Luan, Antonio Hernandez, Tazeen K Patil, David L Williams, Edward R Sherwood.
      Bacterial infections are a common and deadly threat to vulnerable patients. Alternative strategies to fight infection are needed. β-Glucan, an immunomodulator derived from the fungal cell wall, provokes resistance to infection by inducing trained immunity, a phenomenon that persists for weeks to months. Given the durability of trained immunity, it is unclear which leukocyte populations sustain this effect. Macrophages have a life span that surpasses the duration of trained immunity. Thus, we sought to define the contribution of differentiated macrophages to trained immunity. Our results show that β-glucan protects mice from Pseudomonas aeruginosa infection by augmenting recruitment of innate leukocytes to the site of infection and facilitating local clearance of bacteria, an effect that persists for more than 7 d. Adoptive transfer of macrophages, trained using β-glucan, into naive mice conferred a comparable level of protection. Trained mouse bone marrow-derived macrophages assumed an antimicrobial phenotype characterized by enhanced phagocytosis and reactive oxygen species production in parallel with sustained enhancements in glycolytic and oxidative metabolism, increased mitochondrial mass, and membrane potential. β-Glucan induced broad transcriptomic changes in macrophages consistent with early activation of the inflammatory response, followed by sustained alterations in transcripts associated with metabolism, cellular differentiation, and antimicrobial function. Trained macrophages constitutively secreted CCL chemokines and robustly produced proinflammatory cytokines and chemokines in response to LPS challenge. Induction of the trained phenotype was independent of the classic β-glucan receptors Dectin-1 and TLR-2. These findings provide evidence that β-glucan induces enhanced protection from infection by driving trained immunity in macrophages.
    DOI:  https://doi.org/10.4049/jimmunol.2100107
  11. Mol Immunol. 2021 Oct 28. pii: S0161-5890(21)00297-2. [Epub ahead of print]140 186-195
    The glycolysis inhibitor 2-deoxyglucose ameliorates adjuvant-induced arthritis by regulating macrophage polarization in an AMPK-dependent manner.
    Weiwei Cai, Jingwen Cheng, Shiye Zong, Yun Yu, Ying Wang, Yining Song, Rui He, Siqi Yuan, Tao Chen, Mengru Hu, Yousheng Pan, Ran Ma, Hao Liu, Fang Wei.
      Macrophages are highly plastic cells critical for the development of rheumatoid arthritis (RA). Macrophages exhibit a high degree of pro-inflammatory plasticity in RA, accompanied by a metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis. 2-deoxyglucose (2-DG), a glycolysis inhibitor, has previously been shown to exhibit anti-inflammatory and anti-arthritic properties. However, the specific mechanisms of inflammatory modulation by 2-DG remain unclear. This study used 2-DG to treat rats with adjuvant arthritis (AA) and investigated its specific anti-arthritic mechanisms in the murine-derived macrophage cell line RAW264.7 in vitro. 2-DG reduced the arthritis index as well as alleviated cellular infiltration, synovial hyperplasia, and bone erosion in AA rats. Moreover, 2-DG treatment modulated peritoneal macrophage polarization, increasing levels of the arginase1 (Arg1) and decreasing expression of the inducible nitric oxide synthase (iNOS). 2-DG activated AMP-activated protein kinase (AMPK) via phosphorylation and reduced activation of the nuclear factor κB (NF-κB) in peritoneal macrophages of AA rats. In vitro, we verified that 2-DG promoted macrophage transition from M1 to M2-type by upregulating the expression of p-AMPKα and suppressing NF-κB activation in LPS-stimulated RAW264.7 cells. LPS-induced macrophages exhibited a metabolic shift from glycolysis to OXPHOS following 2-DG treatment, as observed by reduced extracellular acidification rate (ECAR), lactate export, glucose consumption, as well as an elevated oxygen consumption rate (OCR) and intracellular ATP concentration. Importantly, changes in polarization and metabolism in response to 2-DG were dampened after AMPKα knockdown. These findings indicate that the anti-arthritic 2-DG effect is mediated by a modulation of macrophage polarization in an AMPK-dependent manner.
    Keywords:  2-Deoxyglucose; AMP-activated protein kinase; Adjuvant induced arthritis; Macrophage polarization; Nuclear factor κB
    DOI:  https://doi.org/10.1016/j.molimm.2021.10.007
  12. Shock. 2021 Nov 03.
    δPKC-Mediated Drp1 Phosphorylation Impacts Macrophage Mitochondrial Function and Inflammatory Response to Endotoxin.
    Amanda J Lin, Amit U Joshi, Riddhita Mukherjee, Carly A Tompkins, Vijith Vijayan, Daria Mochly-Rosen, Bereketeab Haileselassie.
      BACKGROUND: Recent studies have demonstrated that alterations in mitochondrial dynamics can impact innate immune function. However, the upstream mechanisms which link mitochondrial dynamics to innate immune phenotypes have not been completely elucidated. This study asks if δPKC-mediated phosphorylation of Drp1, a key driver of mitochondrial fission, impacts macrophage pro-inflammatory response following bacterial-derived lipopolysaccharide (LPS) stimulation.METHODS: Using RAW 264.7 cells, bone marrow-derived macrophages from C57BL/6J mice, as well as human monocyte-derived macrophages, we first characterized changes in δPKC-mediated phosphorylation of Drp1 following LPS stimulation. Next, using rationally-designed peptides that inhibit δPKC activation (δV1-1) and δPKC-Drp1 interaction (ψDrp1), we determined whether δPKC-mediated phosphorylation of Drp1 impacts LPS-induced changes in mitochondrial morphology, mitochondrial function, and inflammatory response.
    RESULTS: Our results demonstrated that δPKC-dependent Drp1 activation is associated with increased mitochondrial fission, impaired cellular respiration, and increased mitochondrial reactive oxygen species in LPS-treated macrophages. This is reversed using a rationally-designed peptide which selectively inhibits δPKC phosphorylation of Drp1 (ψDrp1). Interestingly, limiting excessive mitochondrial fission using ψDrp1 reduced LPS-triggered pro-inflammatory response, including a decrease in NF-κB nuclear localization, decreased iNOS induction, and a reduction in pro-inflammatory cytokines (IL-1β, TNFα, IL-6).
    CONCLUSION: These data suggest that inhibiting Drp1 phosphorylation by δPKC abates the excessive mitochondrial fragmentation and mitochondrial dysfunction that is seen following LPS treatment. Furthermore, these data suggest that limiting δPKC-dependent Drp1 activation decreases the pro-inflammatory response following LPS treatment. Altogether, δPKC-dependent Drp1 phosphorylation might be an upstream mechanistic link between alterations in mitochondrial dynamics and innate immune phenotypes, and may have therapeutic potential.
    DOI:  https://doi.org/10.1097/SHK.0000000000001885
  13. Cell Rep. 2021 Nov 02. pii: S2211-1247(21)01384-X. [Epub ahead of print]37(5): 109911
    Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.
    Maria I Matias, Carmen S Yong, Amir Foroushani, Chloe Goldsmith, Cédric Mongellaz, Erdinc Sezgin, Kandice R Levental, Ali Talebi, Julie Perrault, Anais Rivière, Jonas Dehairs, Océane Delos, Justine Bertand-Michel, Jean-Charles Portais, Madeline Wong, Julien C Marie, Ameeta Kelekar, Sandrina Kinet, Valérie S Zimmermann, Ilya Levental, Laurent Yvan-Charvet, Johannes V Swinnen, Stefan A Muljo, Hector Hernandez-Vargas, Saverio Tardito, Naomi Taylor, Valérie Dardalhon.
      Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.
    Keywords:  CAR T cells; DNA methylation; T cell differentiation; TCA cycle; Th1; Treg; lipidome; mitochondrial metabolism; triacylglyceride synthesis; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.celrep.2021.109911
  14. Immunity. 2021 Oct 23. pii: S1074-7613(21)00446-5. [Epub ahead of print]
    Plasmacytoid dendritic cell activation is dependent on coordinated expression of distinct amino acid transporters.
    Katarzyna M Grzes, David E Sanin, Agnieszka M Kabat, Michal A Stanczak, Joy Edwards-Hicks, Mai Matsushita, Alexandra Hackl, Fabian Hässler, Kristin Knoke, Sophie Zahalka, Matteo Villa, David M Kofler, Reinhard E Voll, Paola Zigrino, Mario Fabri, Erika L Pearce, Edward J Pearce.
      Human plasmacytoid dendritic cells (pDCs) are interleukin-3 (IL-3)-dependent cells implicated in autoimmunity, but the role of IL-3 in pDC biology is poorly understood. We found that IL-3-induced Janus kinase 2-dependent expression of SLC7A5 and SLC3A2, which comprise the large neutral amino acid transporter, was required for mammalian target of rapamycin complex 1 (mTORC1) nutrient sensor activation in response to toll-like receptor agonists. mTORC1 facilitated increased anabolic activity resulting in type I interferon, tumor necrosis factor, and chemokine production and the expression of the cystine transporter SLC7A11. Loss of function of these amino acid transporters synergistically blocked cytokine production by pDCs. Comparison of in vitro-activated pDCs with those from lupus nephritis lesions identified not only SLC7A5, SLC3A2, and SLC7A11 but also ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) as components of a shared transcriptional signature, and ENPP2 inhibition also blocked cytokine production. Our data identify additional therapeutic targets for autoimmune diseases in which pDCs are implicated.
    Keywords:  GM-CSF; IL-3; JAK-STAT signaling; amino acid transporters; autoimmunity; cytokines; mTORC1; metabolism; plasmacytoid dendritic cells
    DOI:  https://doi.org/10.1016/j.immuni.2021.10.009
  15. Rheumatology (Oxford). 2021 Nov 03. pii: keab824. [Epub ahead of print]
    An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus.
    Maiko Hajime Sumikawa, Shigeru Iwata, Mingzeng Zhang, Hiroko Miyata, Masanobu Ueno, Yasuyuki Todoroki, Atsushi Nagayasu, Ryuichiro Kanda, Koshiro Sonomoto, Keiichi Torimoto, Seunghyun Lee, Shingo Nakayamada, Kazuo Yamamoto, Yosuke Okada, Yoshiya Tanaka.
      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.
    Keywords:  B cell; Glutamine; Glutaminolysis; Immunology; Immunometabolism; Metformin; Mitochondria; SLE; Therapy; plasmablast
    DOI:  https://doi.org/10.1093/rheumatology/keab824
  16. Biochem Biophys Res Commun. 2021 Oct 08. pii: S0006-291X(21)01418-2. [Epub ahead of print]583 135-141
    d-mannose attenuates lipopolysaccharide-induced osteolysis via CPT1A-Mediated lipid metabolic regulation in macrophages.
    Zhenzhen Zhang, Xueman Zhou, Jiaqi Liu, Yingcheng Zheng, Yange Wu, Wenke Yang, Yating Yi, Jin Liu, Jun Wang.
      Inflammatory osteolysis is usually linked to the activation of proinflammatory macrophage and the consequent excessive osteoclast formation. Emerging evidence indicates that agents or drugs targeting lipid metabolism in macrophages might be potential in the prevention and treatment of osteolysis. d-mannose, as a natural-existed metabolic regulator, exerts strong effects on attenuating osteopenia and inflammation. However, whether d-mannose is therapeutically effective on osteolysis and whether a metabolic mechanism counts for the effect remain to be addressed. Here, by using an in vivo lipopolysaccharide (LPS)-induced inflammatory osteolysis mouse model as well as an in vitro LPS-induced inflammatory macrophage culture system, we show that d-mannose attenuates inflammatory osteolysis and inhibits excessive osteoclastogenesis by reversing the LPS-induced activation of proinflammatory macrophage. Mechanically, d-mannose recovers LPS-suppressed Cpt1a transcription and promotes lipid metabolism of macrophage. Treatment with etomoxir, an inhibitor of CPT1A, abolishes the effects of d-mannose on LPS-treated macrophage in vitro and eliminates its protection against osteolysis in vivo. Collectively, our results imply that d-mannose attenuates LPS-induced osteolysis by manipulating CPT1A-mediated lipid metabolism in macrophages. Our results disclose the unrecognized utilization of d-mannose as an effective intervention against inflammatory osteolysis and provide evidence to manage inflammatory scenarios by therapeutically targeting lipid metabolism in macrophage.
    Keywords:  Carnitine palmitoyl transferase 1A; Lipid metabolism; Macrophage; Osteolysis; d-mannose
    DOI:  https://doi.org/10.1016/j.bbrc.2021.10.020
  17. Nature. 2021 Nov 03.
    B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity.
    Baihao Zhang, Alexis Vogelzang, Michio Miyajima, Yuki Sugiura, Yibo Wu, Kenji Chamoto, Rei Nakano, Ryusuke Hatae, Rosemary J Menzies, Kazuhiro Sonomura, Nozomi Hojo, Taisaku Ogawa, Wakana Kobayashi, Yumi Tsutsui, Sachiko Yamamoto, Mikako Maruya, Seiko Narushima, Keiichiro Suzuki, Hiroshi Sugiya, Kosaku Murakami, Motomu Hashimoto, Hideki Ueno, Takashi Kobayashi, Katsuhiro Ito, Tomoko Hirano, Katsuyuki Shiroguchi, Fumihiko Matsuda, Makoto Suematsu, Tasuku Honjo, Sidonia Fagarasan.
      Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1-3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.
    DOI:  https://doi.org/10.1038/s41586-021-04082-1
  18. J Immunol. 2021 Nov 05. pii: ji2001282. [Epub ahead of print]
    HIF-1α Regulation of Cytokine Production following TLR3 Engagement in Murine Bone Marrow-Derived Macrophages Is Dependent on Viral Nucleic Acid Length and Glucose Availability.
    Duale Ahmed, Allan Humphrey, David Roy, Mary-Elizabeth Sheridan, Zoya Versey, Allison Jaworski, Alex Edwards, James Donner, Alfonso Abizaid, William Willmore, Ashok Kumar, Ashkan Golshani, Edana Cassol.
      Hypoxia-inducible factor-1α (HIF-1α) is an important regulator of glucose metabolism and inflammatory cytokine production in innate immune responses. Viruses modulate HIF-1α to support viral replication and the survival of infected cells, but it is unclear if this transcription factor also plays an important role in regulating antiviral immune responses. In this study, we found that short and long dsRNA differentially engage TLR3, inducing distinct levels of proinflammatory cytokine production (TNF-α and IL-6) in bone marrow-derived macrophages from C57BL/6 mice. These responses are associated with differential accumulation of HIF-1α, which augments NF-κB activation. Unlike TLR4 responses, increased HIF-1α following TLR3 engagement is not associated with significant alterations in glycolytic activity and was more pronounced in low glucose conditions. We also show that the mechanisms supporting HIF-1α stabilization may differ following stimulation with short versus long dsRNA and that pyruvate kinase M2 and mitochondrial reactive oxygen species play a central role in these processes. Collectively, this work suggests that HIF-1α may fine-tune proinflammatory cytokine production during early antiviral immune responses, particularly when there is limited glucose availability or under other conditions of stress. Our findings also suggest we may be able to regulate the magnitude of proinflammatory cytokine production during antiviral responses by targeting proteins or molecules that contribute to HIF-1α stabilization.
    DOI:  https://doi.org/10.4049/jimmunol.2001282
  19. Cell Death Discov. 2021 Oct 30. 7(1): 327
    Gasdermin D mediates host cell death but not interleukin-1β secretion in Mycobacterium tuberculosis-infected macrophages.
    Sebastian J Theobald, Jessica Gräb, Melanie Fritsch, Isabelle Suárez, Hannah S Eisfeld, Sandra Winter, Maximilian Koch, Christoph Hölscher, Manolis Pasparakis, Hamid Kashkar, Jan Rybniker.
      Necrotic cell death represents a major pathogenic mechanism of Mycobacterium tuberculosis (Mtb) infection. It is increasingly evident that Mtb induces several types of regulated necrosis but how these are interconnected and linked to the release of pro-inflammatory cytokines remains unknown. Exploiting a clinical cohort of tuberculosis patients, we show here that the number and size of necrotic lesions correlates with IL-1β plasma levels as a strong indicator of inflammasome activation. Our mechanistic studies reveal that Mtb triggers mitochondrial permeability transition (mPT) and subsequently extensive macrophage necrosis, which requires activation of the NLRP3 inflammasome. NLRP3-driven mitochondrial damage is dependent on proteolytic activation of the pore-forming effector protein gasdermin D (GSDMD), which links two distinct cell death machineries. Intriguingly, GSDMD, but not the membranolytic mycobacterial ESX-1 secretion system, is dispensable for IL-1β secretion from Mtb-infected macrophages. Thus, our study dissects a novel mechanism of pathogen-induced regulated necrosis by identifying mitochondria as central regulatory hubs capable of delineating cytokine secretion and lytic cell death.
    DOI:  https://doi.org/10.1038/s41420-021-00716-5
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