bims-imicid 2022-02-20 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–02–20
24 papers selected by
Dylan Ryan, University of Cambridge

Blockage of citrate export prevents TCA cycle fragmentation via Irg1 inactivation.
An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment.
Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF-PI3K pathway.
Themis is indispensable for IL-2 and IL-15 signaling in T cells.
Modulation of Macrophage Immunometabolism: A New Approach to Fight Infections.
Impaired phosphocreatine metabolism in white adipocytes promotes inflammation.
Zinc Levels Affect the Metabolic Switch of T Cells by Modulating Glucose Uptake and Insulin Receptor Signaling.
Circadian Control of REDOX Reactions in the Macrophage Inflammatory Response.
IL-6-induced FOXO1 activity determines the dynamics of metabolism in CD8 T cells cross-primed by liver sinusoidal endothelial cells.
TFAM-Dependent Mitochondrial Metabolism Is Required for Alveolar Macrophage Maintenance and Homeostasis.
Lactobacillus paracasei KW3110 Prevents Inflammatory-Stress-Induced Mitochondrial Dysfunction in Mouse Macrophages.
Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux.
Metabolic modulation of immune checkpoints and novel therapeutic strategies in cancer.
Influence of the Metabolism on Myeloid Cell Functions in Cancers: Clinical Perspectives.
Dimethyl fumarate ameliorates graft-versus-host disease by inhibiting T-cell metabolism and immune responses through a reactive oxygen species-dependent mechanism.
High-Fat Diet Rapidly Modifies Trafficking, Phenotype, and Function of Plasmacytoid Dendritic Cells in Adipose Tissue.
PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma.
Multistability in Macrophage Activation Pathways and Metabolic Implications.
Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives.
Adipose mitochondrial complex I deficiency modulates inflammation and glucose homeostasis in a sex-dependent manner.
Nano-ultrasonic Contrast Agent for Chemoimmunotherapy of Breast Cancer by Immune Metabolism Reprogramming and Tumor Autophagy.
Silencing of IGF2BP1 restrains ox-LDL-induced lipid accumulation and inflammation by reducing RUNX1 expression and promoting autophagy in macrophages.
Mitochondrial and Glycolytic Capacity of Peripheral Blood Mononuclear Cells Isolated From Diverse Poultry Genetic Lines: Optimization and Assessment.
The role of Cl- and K+ efflux in NLRP3 inflammasome and innate immune response activation.

Cell Rep. 2022 02 15. pii: S2211-1247(22)00112-7. [Epub ahead of print]38(7): 110391

Blockage of citrate export prevents TCA cycle fragmentation via Irg1 inactivation.

Yi Li, Yu-Chen Li, Xiao-Tian Liu, Lu Zhang, Yi-Hua Chen, Qiong Zhao, Wen Gao, Baolin Liu, Hua Yang, Ping Li.

  The metabolism of activated macrophages relies on aerobic glycolysis, while mitochondrial oxidation is disrupted. In lipopolysaccharide-activated macrophages, the citrate carrier (CIC) exports citrate from mitochondria to enhance glycolytic genes through histone acetylation. CIC inhibition or Slc25a1 knockdown reduces the occupancy of H3K9ac to hypoxia-inducible factor-1α (HIF-1α) binding sites in promoters of glycolytic genes to restrain glycolysis. HIF-1α also transcriptionally upregulates immune-responsive gene 1 for itaconate production, which is inhibited by CIC blocking. Isotopic tracing of [U-13C6] glucose shows that CIC blockage prevents citrate accumulation and itaconate production by reducing glycolytic flux and facilitating metabolic flux in the TCA cycle. Isotopic tracing of [U-13C5] glutamine reveals that CIC inhibition reduces succinate accumulation from glutaminolysis and the gamma-aminobutyric acid shunt by enhancing mitochondrial oxidation. By restraining glycolysis, CIC inhibition increases NAD+ content to ensure mitochondrial biogenesis for oxidative phosphorylation. Furthermore, blockage of citrate export reduces cerebral thrombosis by inactivation of peripheral macrophages.

Keywords:  HIF-1α; Irg1; citrate carrier; itaconate; succinate

DOI:  https://doi.org/10.1016/j.celrep.2022.110391
Sci Immunol. 2022 Feb 18. 7(68): eabi9768

An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment.

Yongyao Fu, Jocelyn Wang, Baohua Zhou, Abigail Pajulas, Hongyu Gao, Baskar Ramdas, Byunghee Koh, Benjamin J Ulrich, Shuangshuang Yang, Reuben Kapur, Jean-Christophe Renauld, Sophie Paczesny, Yunlong Liu, Robert M Tighe, Paula Licona-Limón, Richard A Flavell, Shogo Takatsuka, Daisuke Kitamura, Robert S Tepper, Jie Sun, Mark H Kaplan.

Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9-responsive cell repertoire is still not well defined. Here, we found that IL-9 mediates proallergic activities in the lungs by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c+ and CD11c- interstitial macrophage populations. Interstitial macrophages were required for IL-9-dependent allergic responses. Mechanistically, IL-9 affected the function of lung macrophages by inducing Arg1 activity. Compared with Arg1-deficient lung macrophages, Arg1-expressing macrophages expressed greater amounts of CCL5. Adoptive transfer of Arg1+ lung macrophages but not Arg1- lung macrophages promoted allergic inflammation that Il9r-/- mice were protected against. In parallel, the elevated expression of IL-9, IL-9R, Arg1, and CCL5 was correlated with disease in patients with asthma. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation.

DOI: https://doi.org/10.1126/sciimmunol.abi9768
Elife. 2022 02 14. pii: e73796. [Epub ahead of print]11

Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF-PI3K pathway.

Seth Boyer, Ho-Joon Lee, Nina Steele, Li Zhang, Peter Sajjakulnukit, Anthony Andren, Matthew H Ward, Rima Singh, Venkatesha Basrur, Yaqing Zhang, Alexey I Nesvizhskii, Marina Pasca di Magliano, Christopher J Halbrook, Costas A Lyssiotis.

  The pancreatic ductal adenocarcinoma microenvironment is composed of a variety of cell types and marked by extensive fibrosis and inflammation. Tumor-associated macrophages (TAMs) are abundant, and they are important mediators of disease progression and invasion. TAMs are polarized in situ to a tumor promoting and immunosuppressive phenotype via cytokine signaling and metabolic crosstalk from malignant epithelial cells and other components of the tumor microenvironment. However, the specific distinguishing features and functions of TAMs remain poorly defined. Here, we generated tumor-educated macrophages (TEMs) in vitro and performed detailed, multiomic characterization (i.e., transcriptomics, proteomics, metabolomics). Our results reveal unique genetic and metabolic signatures of TEMs, the veracity of which were queried against our in-house single-cell RNA sequencing dataset of human pancreatic tumors. This analysis identified expression of novel, metabolic TEM markers in human pancreatic TAMs, including ARG1, ACLY, and TXNIP. We then utilized our TEM model system to study the role of mutant Kras signaling in cancer cells on TEM polarization. This revealed an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) and lactate on TEM polarization, molecules released from cancer cells in a mutant Kras-dependent manner. Lastly, we demonstrate that GM-CSF dysregulates TEM gene expression and metabolism through PI3K-AKT pathway signaling. Collectively, our results define new markers and programs to classify pancreatic TAMs, how these are engaged by cancer cells, and the precise signaling pathways mediating polarization.

Keywords:  cancer biology; human; immunology; inflammation; metabolomics; mouse; pancreatic cancer; proteomics; tumor-associated macrophages

DOI:  https://doi.org/10.7554/eLife.73796
Sci Signal. 2022 Feb 15. 15(721): eabi9983

Themis is indispensable for IL-2 and IL-15 signaling in T cells.

Yongchao Liu, Yu Cong, Yujia Niu, Yin Yuan, Fancheng Tan, Qian Lai, Yanyan Hu, Bowen Hou, Jian Li, Chunjie Lin, Haiping Zheng, Junchen Dong, Jian Tang, Qinwei Chen, Joanna Brzostek, Xueqin Zhang, Xiao Lei Chen, Hong-Rui Wang, Nicholas R J Gascoigne, Bing Xu, Shu-Hai Lin, Guo Fu.

To perform their antiviral and antitumor functions, T cells must integrate signals both from the T cell receptor (TCR), which instruct the cell to remain quiescent or become activated, and from cytokines that guide cellular proliferation and differentiation. In mature CD8+ T cells, Themis has been implicated in integrating TCR and cytokine signals. We investigated whether Themis plays a direct role in cytokine signaling in mature T cells. Themis was required for IL-2- and IL-15-driven CD8+ T cell proliferation both in mice and in vitro. Mechanistically, we found that Themis promoted the activation of the transcription factor Stat and mechanistic target of rapamycin signaling downstream of cytokine receptors. Metabolomics and stable isotope tracing analyses revealed that Themis deficiency reduced glycolysis and serine and nucleotide biosynthesis, demonstrating a receptor-proximal requirement for Themis in triggering the metabolic changes that enable T cell proliferation. The cellular, metabolic, and biochemical defects caused by Themis deficiency were corrected in mice lacking both Themis and the phosphatase Shp1, suggesting that Themis mediates IL-2 and IL-15 receptor-proximal signaling by restraining the activity of Shp1. Together, these results not only shed light on the mechanisms of cytokine signaling but also provide new clues on manipulating T cells for clinical applications.

DOI: https://doi.org/10.1126/scisignal.abi9983
Front Immunol. 2022 ;13 780839

Modulation of Macrophage Immunometabolism: A New Approach to Fight Infections.

Thierry Gauthier, Wanjun Chen.

  Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection.

Keywords:  SARS – CoV – 2; immunometabolism; infections; macrophage; therapeutics

DOI:  https://doi.org/10.3389/fimmu.2022.780839
Nat Metab. 2022 Feb 14.

Impaired phosphocreatine metabolism in white adipocytes promotes inflammation.

Salwan Maqdasy, Simon Lecoutre, Gianluca Renzi, Scott Frendo-Cumbo, David Rizo-Roca, Thomas Moritz, Marta Juvany, Ondrej Hodek, Hui Gao, Morgane Couchet, Michael Witting, Alastair Kerr, Martin O Bergo, Robin P Choudhury, Myriam Aouadi, Juleen R Zierath, Anna Krook, Niklas Mejhert, Mikael Rydén.

The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters adenosine monophosphate-activated protein kinase activity via effects on adenosine triphosphate/adenosine diphosphate levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased chemokine (C-C motif) ligand 2 (CCL2) production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction.

DOI: https://doi.org/10.1038/s42255-022-00525-9
Mol Nutr Food Res. 2022 Feb 19. e2100944

Zinc Levels Affect the Metabolic Switch of T Cells by Modulating Glucose Uptake and Insulin Receptor Signaling.

Yiming Peng-Winkler, Inga Wessels, Lothar Rink, Henrike Josephine Fischer.

   SCOPE: T cell activation requires a metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis to rapidly provide substrates for biosynthesis. An individual's zinc status plays an important role in balancing the activation of T cells and is required for a proper function of immune cells. Furthermore, zinc plays an important role during effector T cell polarization to T helper cell subsets or regulatory T cells, with effector T cells relying on glycolysis and regulatory T cells on oxidative phosphorylation. Therefore, we aimed to analyze if zinc also impacts on T cell activation on the level of intracellular metabolism.
METHODS AND RESULTS: We used mixed lymphocyte culture and anti-CD3/CD28 stimulation as in vitro models for T cell activation to investigate the effect of zinc supplementation and deprivation on metabolic switching. We observed promoted glucose uptake, insulin receptor expression and signaling in both zinc conditions, whereas key metabolic enzymes were stimulated mainly by zinc deprivation. Alterations in cytokine production suggest an immune-activating effect of zinc deprivation and a balancing effect of zinc supplementation.
CONCLUSION: Our results suggest a supportive effect of both zinc supplementation and deprivation on the metabolic switch during T cell activation, adding another level of immune regulation by zinc. This article is protected by copyright. All rights reserved.

Keywords:  T cell; zinc ; glycolytic switch; immunology; metabolism

DOI:  https://doi.org/10.1002/mnfr.202100944
Antioxid Redox Signal. 2022 Feb 15.

Circadian Control of REDOX Reactions in the Macrophage Inflammatory Response.

James Rian O'Siorain, Annie Curtis.

SIGNIFICANCE: Macrophages are immune sentinels located throughout the body that function in both the amplification and resolution of the inflammatory response. The circadian clock has emerged as a central regulator of macrophage inflammation. Reduction-oxidation (REDOX) reactions are central to both circadian clock and macrophage function. Recent Advances: Circadian regulation of metabolism controls the macrophage inflammatory response, whereby disruption of the clock causes dysfunctional inflammation. Altering metabolism and reactive oxygen/nitrogen species (RONS) production rescues the inflammatory phenotype of clock-disrupted macrophages.
CRITICAL ISSUES: The circadian clock possesses many layers of regulation. Understanding how REDOX reactions coordinate clock function is critical to uncover the full extent of circadian regulation of macrophage inflammation. We provide insights into how circadian regulation of REDOX affects macrophage pattern recognition receptor signaling, immunometabolism, phagocytosis, and inflammasome activation.
FUTURE DIRECTIONS: Many diseases associated with aberrant macrophage derived inflammation exhibit time of day rhythms in disease symptoms and severity and are sensitive to circadian disruption. Macrophage function is highly dependent on REDOX reactions that signal through RONS. Future studies are needed to evaluate the extent of circadian control of macrophage inflammation, specifically in the context of REDOX signaling.

DOI: https://doi.org/10.1089/ars.2022.0014
Cell Rep. 2022 02 15. pii: S2211-1247(22)00110-3. [Epub ahead of print]38(7): 110389

IL-6-induced FOXO1 activity determines the dynamics of metabolism in CD8 T cells cross-primed by liver sinusoidal endothelial cells.

Michael Dudek, Kerstin Lohr, Sainitin Donakonda, Tobias Baumann, Max Lüdemann, Silke Hegenbarth, Lena Dübbel, Carola Eberhagen, Savvoula Michailidou, Abdallah Yassin, Marco Prinz, Bastian Popper, Stefan Rose-John, Hans Zischka, Percy A Knolle.

  Liver sinusoidal endothelial cells (LSECs) are liver-resident antigen (cross)-presenting cells that generate memory CD8 T cells, but metabolic properties of LSECs and LSEC-primed CD8 T cells remain understudied. Here, we report that high-level mitochondrial respiration and constitutive low-level glycolysis support LSEC scavenger and sentinel functions. LSECs fail to increase glycolysis and co-stimulation after TLR4 activation, indicating absence of metabolic and functional maturation compared with immunogenic dendritic cells. LSEC-primed CD8 T cells show a transient burst of oxidative phosphorylation and glycolysis. Mechanistically, co-stimulatory IL-6 signaling ensures high FOXO1 expression in LSEC-primed CD8 T cells, curtails metabolic activity associated with T cell activation, and is indispensable for T cell functionality after re-activation. Thus, distinct immunometabolic features characterize non-immunogenic LSECs compared with immunogenic dendritic cells and LSEC-primed CD8 T cells with memory features compared with effector CD8 T cells. This reveals local features of metabolism and function of T cells in the liver.

Keywords:  glycolysis; immune cell metabolism; liver immune tolerance; memory T cells; mitochondrial respiration; non-professional antigen-presenting cells

DOI:  https://doi.org/10.1016/j.celrep.2022.110389
J Immunol. 2022 Feb 14. pii: ji2100741. [Epub ahead of print]

TFAM-Dependent Mitochondrial Metabolism Is Required for Alveolar Macrophage Maintenance and Homeostasis.

Xiaochen Gao, Bibo Zhu, Yue Wu, Chaofan Li, Xian Zhou, Jinyi Tang, Jie Sun.

Alveolar macrophages (AMs) are major lung tissue-resident macrophages capable of proliferating and self-renewal in situ. AMs are vital in pulmonary antimicrobial immunity and surfactant clearance. The mechanisms regulating AM compartment formation and maintenance remain to be fully elucidated currently. In this study, we have explored the roles of mitochondrial transcription factor A (TFAM)-mediated mitochondrial fitness and metabolism in regulating AM formation and function. We found that TFAM deficiency in mice resulted in significantly reduced AM numbers and impaired AM maturation in vivo. TFAM deficiency was not required for the generation of AM precursors nor the differentiation of AM precursors into AMs, but was critical for the maintenance of AM compartment. Mechanistically, TFAM deficiency diminished gene programs associated with AM proliferation and self-renewal and promoted the expression of inflammatory genes in AMs. We further showed that TFAM-mediated AM compartment impairment resulted in defective clearance of cellular debris and surfactant in the lung and increased the host susceptibility to severe influenza virus infection. Finally, we found that influenza virus infection in AMs led to impaired TFAM expression and diminished mitochondrial fitness and metabolism. Thus, our data have established the critical function of TFAM-mediated mitochondrial metabolism in AM maintenance and function.

DOI: https://doi.org/10.4049/jimmunol.2100741
Int J Mol Sci. 2022 Jan 27. pii: 1443. [Epub ahead of print]23(3):

Lactobacillus paracasei KW3110 Prevents Inflammatory-Stress-Induced Mitochondrial Dysfunction in Mouse Macrophages.

Takahiro Yamazaki, Sayuri Yamada, Konomi Ohshio, Miho Sugamata, Yuji Morita.

  Lactobacillus paracasei KW3110 (KW3110) has anti-inflammatory effects, including the prevention of blue light exposure induced retinal inflammation and ageing-related chronic inflammation in mice. The mechanism involves the promotion of anti-inflammatory cytokine interleukin (IL)-10 production by KW3110, leading to reduced pro-inflammatory cytokine IL-1β production. Although various stress-induced mitochondrial damages are associated with excessive inflammatory responses, the effect of KW3110 on inflammatory-stress-induced mitochondrial damage remains unknown. In this study, we investigated the effect of KW3110 on inflammatory stress-induced mitochondrial damage using the murine macrophage-like cell line J774A.1. KW3110 treatment suppressed lipopolysaccharide (LPS)-induced mitochondrial dysfunction, including downregulation of membrane potential, induction of reactive oxygen species, and respiratory dysfunction. In addition, KW3110 prevented LPS-induced disruption of mitochondrial morphology including cristae structures. IL-10 treatment also ameliorated LPS-induced mitochondrial dysfunction and morphology disruption. These results suggest that KW3110 prevents LPS-induced mitochondrial dysfunction, potentially via promoting IL-10 production in mouse macrophages. We are the first to reveal a suppressive effect of lactic acid bacteria on mitochondrial morphology disruption in inflammatory-stressed macrophages. Our findings contribute to understanding inflammatory-stress-induced mitochondrial damage and developing food ingredients with preventive effects on mitochondrial-damage-derived inflammatory conditions.

Keywords:  inflammation; interleukin-10; lactic acid bacteria; macrophage; mitochondria; probiotics

DOI:  https://doi.org/10.3390/ijms23031443
Commun Biol. 2022 Feb 15. 5(1): 132

Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux.

Idit Dotan, Jiaqi Yang, Jiro Ikeda, Ziv Roth, Evan Pollock-Tahiri, Harsh Desai, Tharini Sivasubramaniyam, Sonia Rehal, Josh Rapps, Yu Zhe Li, Helen Le, Gedaliah Farber, Edouard Alchami, Changting Xiao, Saraf Karim, Marcela Gronda, Michael F Saikali, Amit Tirosh, Kay-Uwe Wagner, Jacques Genest, Aaron D Schimmer, Vikas Gupta, Mark D Minden, Carolyn L Cummins, Gary F Lewis, Clinton Robbins, Jenny Jongstra-Bilen, Myron Cybulsky, Minna Woo.

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2V617F activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2V617F mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.

DOI: https://doi.org/10.1038/s42003-022-03078-5
Semin Cancer Biol. 2022 Feb 10. pii: S1044-579X(22)00031-1. [Epub ahead of print]

Metabolic modulation of immune checkpoints and novel therapeutic strategies in cancer.

Yi Wang, Yuya Wang, Yifei Ren, Qi Zhang, Ping Yi, Chunming Cheng.

  Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) have led to significant improvements in the overall survival of patients with certain cancers and are expected to benefit patients by achieving complete, long-lasting remissions and cure. However, some patients who receive ICIs either fail treatment or eventually develop immunotherapy resistance. The existence of such patients necessitates a deeper understanding of cancer progression, specifically nutrient regulation in the tumor microenvironment (TME), which includes both metabolic cross-talk between metabolites and tumor cells, and intracellular metabolism in immune and cancer cells. Here we review the features and behaviors of the TME and discuss the recently identified major immune checkpoints. We comprehensively and systematically summarize the metabolic modulation of tumor immunity and immune checkpoints in the TME, including glycolysis, amino acid metabolism, lipid metabolism, and other metabolic pathways, and further discuss the potential metabolism-based therapeutic strategies tested in preclinical and clinical settings. These findings will help to determine the existence of a link or crosstalk between tumor metabolism and immunotherapy, which will provide an important insight into cancer treatment and cancer research.

Keywords:  Amine acid metabolism; Fatty acid synthesis; Glycolysis; Immune checkpoint; Immunotherapy; Lipid metabolism; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2022.02.010
Cells. 2022 Feb 05. pii: 554. [Epub ahead of print]11(3):

Influence of the Metabolism on Myeloid Cell Functions in Cancers: Clinical Perspectives.

Thomas Boyer, Céline Blaye, Nicolas Larmonier, Charlotte Domblides.

  Tumor metabolism plays a crucial role in sustaining tumorigenesis. There have been increasing reports regarding the role of tumor metabolism in the control of immune cell functions, generating a potent immunosuppressive contexture that can lead to immune escape. The metabolic reprogramming of tumor cells and the immune escape are two major hallmarks of cancer, with several instances of crosstalk between them. In this paper, we review the effects of tumor metabolism on immune cells, focusing on myeloid cells due to their important role in tumorigenesis and immunosuppression from the early stages of the disease. We also discuss ways to target this specific crosstalk in cancer patients.

Keywords:  cancer; immunomodulation; immunotherapy; macrophages; metabolism; myeloid cells; myeloid-derived suppressive cells; therapeutic strategies

DOI:  https://doi.org/10.3390/cells11030554
Br J Haematol. 2022 Feb 15.

Dimethyl fumarate ameliorates graft-versus-host disease by inhibiting T-cell metabolism and immune responses through a reactive oxygen species-dependent mechanism.

Kiyomi Mashima, Kazuya Sato, Takashi Ikeda, Junko Izawa, Norihito Takayama, Hiroko Hayakawa, Shin-Ichiro Kawaguchi, Hirofumi Nakano, Takashi Nagayama, Kento Umino, Kaoru Morita, Kaoru Tominaga, Hitoshi Endo, Yoshinobu Kanda.

DOI: https://doi.org/10.1111/bjh.18082
J Immunol. 2022 Feb 18. pii: ji2100022. [Epub ahead of print]

High-Fat Diet Rapidly Modifies Trafficking, Phenotype, and Function of Plasmacytoid Dendritic Cells in Adipose Tissue.

Susanne Stutte, Hellen Ishikawa-Ankerhold, Lydia Lynch, Sarah Eickhoff, Simona Nasiscionyte, Chenglong Guo, Dominic van den Heuvel, Daniel Setzensack, Marco Colonna, Daniela Maier-Begandt, Ludwig Weckbach, Thomas Brocker, Christian Schulz, Barbara Walzog, Ulrich von Andrian.

Plasmacytoid dendritic cells (pDCs) display an increased abundance in visceral adipose tissue (VAT) of humans with obesity. In the current study, we set out to decipher the molecular mechanisms of their recruitment to VAT and the functional relevance of this process. We observed increased pDC numbers in murine blood, liver, spleen, and VAT after feeding a high-fat diet (HFD) for 3 wk when compared with a standard diet. pDCs were enriched in fat-associated lymphoid clusters representing highly specific lymphoid regions within VAT. HFD led to an enlargement of fat-associated lymphoid clusters with an increased density and migratory speed of pDCs as shown by intravital multiphoton microscopy. For their recruitment into VAT, pDCs employed P-selectin with E-selectin and L-selectin being only critical in response to HFD, indicating that the molecular cues underlying pDC trafficking were dependent on the nutritional state. Subsequent recruitment steps required α4β1 and α4β7 integrins and engagement of CCR7. Application of fingolimod (FTY720) abrogated egress of pDCs from VAT, indicating the involvement of sphingosine-1-phosphate in this process. Furthermore, HFD altered pDC functions by promoting their activation and type 1 IFN expression. Blocking pDC infiltration into VAT prevented weight gain and improved glucose tolerance during HFD. In summary, a HFD fundamentally alters pDC biology by promoting their trafficking, retention, and activation in VAT, which in turn seems to regulate metabolism.

DOI: https://doi.org/10.4049/jimmunol.2100022
Gut. 2022 Feb 16. pii: gutjnl-2021-326350. [Epub ahead of print]

PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma.

Li-Gong Lu, Zhi-Ling Zhou, Xu-Yan Wang, Bo-Yuan Liu, Jin-Ying Lu, Shuai Liu, Guang-Bo Zhang, Mei-Xiao Zhan, Yun Chen.

   OBJECTIVE: Patients with increased PD-L1+ host cells in tumours are more potent to benefit from antiprogrammed death-1/programmed death ligand-1 (PD-L1) treatment, but the underlying mechanism is still unclear. We aim to elucidate the nature, regulation and functional relevance of PD-L1+ host cells in hepatocellular carcinoma (HCC).
DESIGN: A total of untreated 184 HCC patients was enrolled randomly. C57BL/6 mice are given injection of Hepa1-6 cells to form autologous hepatoma. ELISpot, flow cytometry and real-time PCR are applied to analyse the phenotypic characteristics of PD-L1+ cells isolated directly from HCC specimens paired with blood samples or generated from ex vivo and in vitro culture systems. Immunofluorescence and immunohistochemistry are performed to detect the presence of immune cells on paraffin-embedded and formalin-fixed samples. The underlying regulatory mechanisms of metabolic switching are assessed by both in vitro and in vivo studies.
RESULTS: We demonstrate that PD-L1+ host macrophages, which constructively represent the major cellular source of PD-L1 in HCC tumours, display an HLA-DRhighCD86high glycolytic phenotype, significantly produce antitumourigenic IL-12p70 and are polarised by intrinsic glycolytic metabolism. Mechanistically, a key glycolytic enzyme PKM2 triggered by hepatoma cell derived fibronectin 1, via a HIF-1α-dependent manner, concurrently controls the antitumourigenic properties and inflammation-mediated PD-L1 expression in glycolytic macrophages. Importantly, although increased PKM2+ glycolytic macrophages predict poor prognosis of patients, blocking PD-L1 on these cells eliminates PD-L1-dominant immunosuppression and liberates intrinsic antitumourigenic properties.
CONCLUSIONS: Selectively modulating the 'context' of glycolytic macrophages in HCC tumours might restore their antitumourigenic properties and provide a precise strategy for anticancer therapy.

Keywords:  cancer immunobiology; glucose metabolism; hepatoma; immunotherapy; macrophages

DOI:  https://doi.org/10.1136/gutjnl-2021-326350
Cells. 2022 Jan 25. pii: 404. [Epub ahead of print]11(3):

Multistability in Macrophage Activation Pathways and Metabolic Implications.

Carsten Geiß, Elvira Salas, Jose Guevara-Coto, Anne Régnier-Vigouroux, Rodrigo A Mora-Rodríguez.

  Macrophages are innate immune cells with a dynamic range of reversible activation states including the classical pro-inflammatory (M1) and alternative anti-inflammatory (M2) states. Deciphering how macrophages regulate their transition from one state to the other is key for a deeper understanding of inflammatory diseases and relevant therapies. Common regulatory motifs reported for macrophage transitions, such as positive or double-negative feedback loops, exhibit a switchlike behavior, suggesting the bistability of the system. In this review, we explore the evidence for multistability (including bistability) in macrophage activation pathways at four molecular levels. First, a decision-making module in signal transduction includes mutual inhibitory interactions between M1 (STAT1, NF-KB/p50-p65) and M2 (STAT3, NF-KB/p50-p50) signaling pathways. Second, a switchlike behavior at the gene expression level includes complex network motifs of transcription factors and miRNAs. Third, these changes impact metabolic gene expression, leading to switches in energy production, NADPH and ROS production, TCA cycle functionality, biosynthesis, and nitrogen metabolism. Fourth, metabolic changes are monitored by metabolic sensors coupled to AMPK and mTOR activity to provide stability by maintaining signals promoting M1 or M2 activation. In conclusion, we identify bistability hubs as promising therapeutic targets for reverting or blocking macrophage transitions through modulation of the metabolic environment.

Keywords:  bistability; macrophage; metabolism; miRNA; multistability; systems biology

DOI:  https://doi.org/10.3390/cells11030404
Front Immunol. 2022 ;13 807271

Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives.

Florent Peyraud, Jean-Philippe Guegan, Dominique Bodet, Sophie Cousin, Alban Bessede, Antoine Italiano.

  Metabolism of tryptophan (Trp), an essential amino acid, represent a major metabolic pathway that both promotes tumor cell intrinsic malignant properties as well as restricts antitumour immunity, thus emerging as a drug development target for cancer immunotherapy. Three cytosolic enzymes, namely indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO2), catalyzes the first-rate limiting step of the degradation of Trp to kynurenine (Kyn) and modulates immunity toward immunosuppression mainly through the aryl hydrocarbon receptor (AhR) activation in numerous types of cancer. By restoring antitumor immune responses and synergizing with other immunotherapies, the encouraging preclinical data of IDO1 inhibitors has dramatically failed to translate into clinical success when combined with immune checkpoints inhibitors, reigniting the debate of combinatorial approach. In this review, we i) provide comprehensive evidences on immunomodulatory role of the Trp catabolism metabolites that highlight this pathway as relevant target in immuno-oncology, ii)ii) discuss underwhelming results from clinical trials investigating efficacy of IDO1 inhibitors and underlying mechanisms that might have contributed to this failure, and finally, iii) discuss the current state-of-art surrounding alternative approaches of innovative antitumor immunotherapies that target molecules of Trp catabolism as well as challenges and perspectives in the era of immunotherapy.

Keywords:  cancer; immunotherapy; indoleamine 2,3-dioxygenase; kynurenine; tryptophan metabolism

DOI:  https://doi.org/10.3389/fimmu.2022.807271
Endocrinology. 2022 Feb 16. pii: bqac018. [Epub ahead of print]

Adipose mitochondrial complex I deficiency modulates inflammation and glucose homeostasis in a sex-dependent manner.

Kyung-Mi Choi, Karen K Ryan, John C Yoon.

  Mitochondrial dysfunction in adipose tissue has been associated with type 2 diabetes, but it is unclear whether it is a cause or the consequence. Mitochondrial complex I is a major site of reactive oxygen species generation and a therapeutic target. Here we report that genetic deletion of the complex I subunit Ndufs4 specifically in adipose tissue results in an increased propensity to develop diet-induced weight gain, glucose intolerance, and elevated levels of fat inflammatory genes. This outcome is apparent in young males but not in young females, suggesting that females are relatively protected from the adverse consequences of adipose mitochondrial dysfunction for metabolic health. Mutant mice of both sexes exhibit defects in brown adipose tissue thermogenesis. Fibroblast growth factor 21 (FGF21) signaling in adipose tissue is selectively blunted in male mutant mice relative to wild-type littermates, consistent with sex-dependent regulation of its autocrine/paracrine action in adipocytes. Together, these findings support that adipocyte-specific mitochondrial dysfunction is sufficient to induce tissue inflammation and can cause systemic glucose abnormalities in male mice.

Keywords:  FGF21; Ndufs4; impaired glucose tolerance; inflammation; mitochondria

DOI:  https://doi.org/10.1210/endocr/bqac018
ACS Nano. 2022 Feb 14.

Nano-ultrasonic Contrast Agent for Chemoimmunotherapy of Breast Cancer by Immune Metabolism Reprogramming and Tumor Autophagy.

Xupeng Yang, Meng Zhao, Zhihua Wu, Chuanrong Chen, Yanhua Zhang, Liting Wang, Qianqian Guo, Quan Wang, Shunshun Liang, Suxian Hu, Yourong Duan, Ying Sun.

  The functional status of innate immune cells is a considerable determinant of effective antitumor immune response. However, the triple-negative breast cancer tumor microenvironment with high lactic acid metabolism and high antioxidant levels limits immune cell survival, differentiation, and function. Here, we determine that the tumor microenvironment-responsive nano-ultrasonic contrast agent Pt(IV)/CQ/PFH NPs-DPPA-1 boosts the ratio of mature dendritic cells (mDCs) and proinflammatory macrophages by reprogramming the metabolism of immature DCs (iDCs) and tumor-associated macrophages (TAMs). Specifically, platinum(IV) in cancer cells or iDCs was reduced to cisplatin, which can increase the intracellular content of ROS and therefore enhance the ratio of mDCs and apoptotic tumor cells. Meanwhile, chloroquine (CQ) released from nanoparticles (NPs) minimizes protective autophagy caused by cisplatin in tumor cells and reprograms the metabolism of TAMs to enhance the proportion of proinflammatory macrophages, achieving a superior synergistic effect of chemoimmunotherapy combined with Pt(IV) and anti-PD-L1 peptide (DPPA-1). Furthermore, perfluorohexane (PFH) in NPs realizes monitoring treatment corresponding to ultrasound. Collectively, the nano-ultrasonic contrast agent supports a candidate for monitoring treatment and augmenting antitumor chemoimmunotherapy by suppressing tumor cell autophagy and reprogramming immunocyte metabolism.

Keywords:  autophagy; chloroquine; immune metabolism reprogramming; nano-ultrasonic contrast agent; platinum(IV)

DOI:  https://doi.org/10.1021/acsnano.2c00462
J Biochem Mol Toxicol. 2022 Feb 18. e22994

Silencing of IGF2BP1 restrains ox-LDL-induced lipid accumulation and inflammation by reducing RUNX1 expression and promoting autophagy in macrophages.

Mingxin Liu, Guizhou Tao, Yiming Cao, Yu Hu, Zhe Zhang.

  Atherosclerosis (AS) is a chronic inflammatory disease with the formation and accumulation of macrophage-derived foam cells in the subendothelial space of blood vessels as one major characteristic. Insulin-like growth factor 2 messenger RNA (mRNA) binding protein 1 (IGF2BP1) is an RNA-binding factor and its elevation has been reported to be associated with macrophage infiltration into the atherosclerotic vascular wall. This study aims to investigate the roles of IGF2BP1 in AS-associated foam cell formation. Herein, ApoE-/- mice fed with high-fat diet developed atherosclerotic lesions in the aorta, where IGF2BP1 expression was upregulated and autophagy was impaired. IGF2BP1 expressed in F4/80+ macrophages and coexisted with p62. In vitro, IGF2BP1 expression was upregulated in RAW264.7 macrophages exposed to oxidized low-density lipoprotein (ox-LDL) (100 μg/ml). Interestingly, silencing of IGF2BP1 ameliorated ox-LDL-induced lipid accumulation and inflammation, and enhanced autophagic flux in macrophages. Furthermore, the expression of RUNX family transcription factor 1 (RUNX1), a gene that is able to inhibit autophagy in multiple cell types, was elevated in atherosclerotic aortas and in ox-LDL-treated macrophages. In addition, RNA immunoprecipitation results revealed that IGF2BP1 is bound to RUNX1 mRNA. Alterations induced by IGF2BP1 knockdown in ox-LDL-treated macrophages were abolished by RUNX1 overexpression. Furthermore, after autophagy inhibitor 3-methyladenine administration, silencing of IGF2BP1-reduced lipid accumulation and inflammation were recovered in RAW264.7 cells. In summary, our study demonstrated that silencing of IGF2BP1 restrained ox-LDL-induced lipid accumulation and inflammation by reducing RUNX1 expression and facilitating autophagy in macrophages. IGF2BP1/RUNX1 axis may be considered as a potential therapeutic target in AS.

Keywords:  Runt-related transcription factor 1; atherosclerosis; autophagy; insulin-like growth factor 2 mRNA binding protein 1; macrophage

DOI:  https://doi.org/10.1002/jbt.22994
Front Vet Sci. 2021 ;8 815878

Mitochondrial and Glycolytic Capacity of Peripheral Blood Mononuclear Cells Isolated From Diverse Poultry Genetic Lines: Optimization and Assessment.

Meaghan M Meyer, Susan J Lamont, Elizabeth A Bobeck.

  Cellular metabolic preference is a culmination of environment, nutrition, genetics, and individual variation in poultry. The Seahorse XFe24 analyzer was used to generate foundational immune cellular metabolic data in layer, broiler, and legacy genetic strains using fresh chicken peripheral blood mononuclear cells (PBMCs). Baseline mitochondrial respiration [oxygen consumption rate (OCR)] and glycolytic activity [extracellular acidification rate (ECAR)] were determined in modern commercial laying hen (Bovans White) and broiler (Ross 308) lines, as well as the highly inbred lines of Iowa State University (L8, Fayoumi M-15.2, Spanish, Ghs-6), partially inbred broiler line, and advanced intercrosses of broiler by Fayoumi M-15.2 and broiler by Leghorn lines. Commercial broiler vs. Bovans layer and unvaccinated vs. vaccinated Bovans layer immune cell metabolic potential were compared following an in-assay pathway inhibitor challenge. Titrations consistently showed that optimal PBMC density in laying hens and broilers was 3 million cells per well monolayer. Assay media substrate titrations identified 25 mM glucose, 1 mM glutamine, and 1 mM sodium pyruvate as the optimal concentration for layer PBMCs. Pathway inhibitor injection titrations in Bovans layers and broilers showed that 0.5 μM carbonyl cyanide-4 phenylhydrazone (FCCP) and 1 μM oligomycin were optimal. Baseline OCR and ECAR were significantly affected by genetic line of bird (p < 0.05), with the dual-purpose, L8 inbred line showing the highest OCR (mean 680 pmol/min) and the partially inbred broiler line showing the greatest ECAR (mean 74 mpH/min). ECAR metabolic potential tended to be greater in modern layers than broilers (p < 0.10), indicating increased ability to utilize the glycolytic pathway to produce energy. OCR was significantly higher in vaccinated than unvaccinated hens (p < 0.05), while baseline ECAR values were significantly lower in vaccinated Bovans laying hens, showing increased oxidative capacity in activated immune cells. These baseline data indicate that different genetic strains of birds utilized the mitochondrial respiration pathway differently and that modern commercial lines may have reduced immune cell metabolic capacity compared with legacy lines due to intense selection for production traits. Furthermore, the Seahorse assay demonstrated the ability to detect differences in cellular metabolism between genetic lines and immune status of chickens.

Keywords:  PBMC; cellular metabolism; genetic selection; glycolysis; mitochondrial respiration

DOI:  https://doi.org/10.3389/fvets.2021.815878
Am J Physiol Cell Physiol. 2022 Feb 16.

The role of Cl- and K+ efflux in NLRP3 inflammasome and innate immune response activation.

Rainelli Koumangoye.

  Inflammation is part of innate immunity and is a natural response of the body to bacteria, virus, any other pathogen infections, or to damaged tissues. However, too much inflammation or chronic inflammation contributes to a wide variety of diseases such as inflammatory bowel disease, cancer, type 2 diabetes, heart disease, or autoimmune disease such as rheumatoid arthritis. Recent studies underscored the critical role of K+ and Cl- efflux in the activation of the inflammasome. The NLRP3 inflammasome is a multiprotein complex that mediates the production of the proinflammatory cytokines IL-1β and IL-18 and initiates the inflammatory cell death or pyroptosis. The NLRP3 inflammasome can be activated by multiple stimuli such as extracellular ATP, microbial toxins, ROS, mitochondria DNA or particulate matter. Although the precise mechanisms of NLRP3 activation and regulation by these diverse agonists remain unclear, multiple reports indicate that all NLRP3 agonists ultimately lead to a drop in intracellular concentration of potassium (K+ efflux) and chloride (Cl- efflux). The WNK-SPAK/OSR1-[N]KCC pathway plays a critical role maintaining K+ and Cl- ions concentration in the cell. Recent advances indicate that the WNK-SPAK-[N]KCC pathway play a role in the activation of the innate immune response. This review highlights recent discoveries detailing how ion transport regulates innate immune cell response to inflammatory stimuli.

Keywords:  Inflammasome; Inflammation; WNK kinase; macrophages; neutrophils

DOI:  https://doi.org/10.1152/ajpcell.00421.2021