bims-imicid 2023-01-15 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒01‒15
nineteen papers selected by
Dylan Ryan
University of Cambridge

Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus.
GOT1 regulates CD8+ effector and memory T cell generation.
Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.
Tryptophan-dependent and -independent secretions of tryptophanyl- tRNA synthetase mediate innate inflammatory responses.
The Polyamine Putrescine Is a Positive Regulator of Group 3 Innate Lymphocyte Activation.
Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation.
Manipulating T-cell metabolism to enhance immunotherapy in solid tumor.
Microenvironment-driven metabolic adaptations guiding CD8+ T cell anti-tumor immunity.
HIF-1α-Dependent Metabolic Reprogramming, Oxidative Stress, and Bioenergetic Dysfunction in SARS-CoV-2-Infected Hamsters.
Lower Metabolic Potential and Impaired Metabolic Flexibility in Human Lymph Node Stromal Cells from Patients with Rheumatoid Arthritis.
An untargeted metabolomic approach to investigate antiviral defence mechanisms in memory leukocytes secreting anti-SARS-CoV-2 IgG in vitro.
High-throughput in situ perturbation of metabolite levels in the tumor micro-environment reveals favorable metabolic condition for increased fitness of infiltrated T-cells.
microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis.
Metabolites as signalling molecules.
Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.
A metabolite attenuates neuroinflammation, synaptic loss and cognitive deficits induced by chronic infection of Toxoplasma gondii.
Ascophyllum nodosum polysaccharide regulates gut microbiota metabolites to protect against colonic inflammation in mice.
A microbial metabolite to master inflammation.
Metabolic Regulation of T cell Activity: Implications for Metabolic-Based T-cell Therapies for Cancer.

Sci Immunol. 2023 Jan 13. 8(79): eabq0178

Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus.

Kelsey Voss, Allison E Sewell, Evan S Krystofiak, Katherine N Gibson-Corley, Arissa C Young, Jacob H Basham, Ayaka Sugiura, Emily N Arner, William N Beavers, Dillon E Kunkle, Megan E Dickson, Gabriel A Needle, Eric P Skaar, W Kimryn Rathmell, Michelle J Ormseth, Amy S Major, Jeffrey C Rathmell.

T cells in systemic lupus erythematosus (SLE) exhibit multiple metabolic abnormalities. Excess iron can impair mitochondria and may contribute to SLE. To gain insights into this potential role of iron in SLE, we performed a CRISPR screen of iron handling genes on T cells. Transferrin receptor (CD71) was identified as differentially critical for TH1 and inhibitory for induced regulatory T cells (iTregs). Activated T cells induced CD71 and iron uptake, which was exaggerated in SLE-prone T cells. Cell surface CD71 was enhanced in SLE-prone T cells by increased endosomal recycling. Blocking CD71 reduced intracellular iron and mTORC1 signaling, which inhibited TH1 and TH17 cells yet enhanced iTregs. In vivo treatment reduced kidney pathology and increased CD4 T cell production of IL-10 in SLE-prone mice. Disease severity correlated with CD71 expression on TH17 cells from patients with SLE, and blocking CD71 in vitro enhanced IL-10 secretion. T cell iron uptake via CD71 thus contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology.

DOI: https://doi.org/10.1126/sciimmunol.abq0178
Cell Rep. 2023 Jan 12. pii: S2211-1247(22)01891-5. [Epub ahead of print]42(1): 111987

GOT1 regulates CD8+ effector and memory T cell generation.

Wei Xu, Chirag H Patel, Liang Zhao, Im-Hong Sun, Min-Hee Oh, Im-Meng Sun, Rachel S Helms, Jiayu Wen, Jonathan D Powell.

  T cell activation, proliferation, function, and differentiation are tightly linked to proper metabolic reprogramming and regulation. By using [U-13C]glucose tracing, we reveal a critical role for GOT1 in promoting CD8+ T cell effector differentiation and function. Mechanistically, GOT1 enhances proliferation by maintaining intracellular redox balance and serine-mediated purine nucleotide biosynthesis. Further, GOT1 promotes the glycolytic programming and cytotoxic function of cytotoxic T lymphocytes via posttranslational regulation of HIF protein, potentially by regulating the levels of α-ketoglutarate. Conversely, genetic deletion of GOT1 promotes the generation of memory CD8+ T cells.

Keywords:  CP: Metabolism; GOT1; HIF; NADH/NAD; effector and memory CD8(+) T cell; glucose; glutamate; serine

DOI:  https://doi.org/10.1016/j.celrep.2022.111987
Cell Rep. 2023 Jan 09. pii: S2211-1247(22)01842-3. [Epub ahead of print]42(1): 111941

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.

Allison K Meyers, Zhan Wang, Wenzheng Han, Qingxia Zhao, Manal Zabalawi, Likun Duan, Juan Liu, Qianyi Zhang, Rajesh K Manne, Felipe Lorenzo, Matthew A Quinn, Qianqian Song, Daping Fan, Hui-Kuan Lin, Cristina M Furdui, Jason W Locasale, Charles E McCall, Xuewei Zhu.

  Activating the macrophage NLRP3 inflammasome can promote excessive inflammation with severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages and septic mice by lowering caspase-1 cleavage and interleukin-1β (IL-1β) secretion. Inhibiting PDHK reverses NLRP3 inflammasome-induced metabolic reprogramming, enhances autophagy, promotes mitochondrial fusion over fission, preserves crista ultrastructure, and attenuates mitochondrial reactive oxygen species (ROS) production. The suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of its canonical role as a pyruvate dehydrogenase regulator. Our study suggestsa non-canonical role of mitochondrial PDHK in promoting mitochondrial stress and supporting NLRP3 inflammasome activation during acute inflammation.

Keywords:  CP: Immunology; NLRP3 inflammasome; autophagy; cristae; immunometabolism; macrophages; metabolic flux; mitochondria; mitochondrial fission and fusion; pyruvate dehydrogenase kinase; sepsis

DOI:  https://doi.org/10.1016/j.celrep.2022.111941
Cell Rep. 2022 Dec 30. pii: S2211-1247(22)01804-6. [Epub ahead of print]42(1): 111905

Tryptophan-dependent and -independent secretions of tryptophanyl- tRNA synthetase mediate innate inflammatory responses.

Tram Thuy Thuy Nguyen, Yun Hui Choi, Won-Kyu Lee, Yeounjung Ji, Eunho Chun, Yi Hyo Kim, Joo-Eun Lee, Hyun Suk Jung, Ji Hun Suh, Sunghoon Kim, Mirim Jin.

  While cytoplasmic tryptophanyl-tRNA synthetase (WARS1) ligates tryptophan (Trp) to its cognate tRNAs for protein synthesis, it also plays a role as an innate immune activator in extracellular space. However, its secretion mechanism remains elusive. Here, we report that in response to stimuli, WARS1 can be secreted via two distinct pathways: via Trp-dependent secretion of naked protein and via Trp-independent plasma-membrane-derived vesicles (PMVs). In the direct pathway, Trp binding to WARS1 induces a "closed" conformation, generating a hydrophobic surface and basic pocket. The Trp-bound WARS1 then binds stable phosphatidylinositol (4,5)-biphosphate and inner plasma membrane leaflet, passing across the membrane. In the PMV-mediated secretion, WARS1 recruits calpain 2, which is activated by calcium. WARS1 released from PMVs induces inflammatory responses in vivo. These results provide insights into the secretion mechanisms of WARS1 and improve our understanding of how WARS1 is involved in the control of local and systemic inflammation upon infection.

Keywords:  CP: Immunology; CP: Molecular biology; calpain 2; innate immune response; phosphatidylinositol (4,5)-biphosphate; plasma membrane-derived vesicles; tryptophan; tryptophanyl-tRNA synthetase

DOI:  https://doi.org/10.1016/j.celrep.2022.111905
Immunohorizons. 2023 Jan 01. 7(1): 41-48

The Polyamine Putrescine Is a Positive Regulator of Group 3 Innate Lymphocyte Activation.

Prakash Sah, Lauren A Zenewicz.

Group 3 innate lymphocytes (ILC3s) rapidly respond to invading pathogens or inflammatory signals, which requires shifting cellular metabolic demands. Metabolic adaptations regulating ILC3 function are not completely understood. Polyamines are polycationic metabolites that have diverse roles in cellular functions and in immunity regulate immune cell biology, including Th17 cells. Whether polyamines play a role in ILC3 activation is unknown. In this article, we report that the polyamine synthesis pathway is important for ILC3 activation. IL-23-activated mouse ILC3s upregulate ornithine decarboxylase, the enzyme catalyzing the rate-limiting step of the conversion of ornithine to putrescine in polyamine synthesis, with a subsequent increase in putrescine levels. Inhibition of ornithine decarboxylase via a specific inhibitor, α-difluoromethylornithine, reduced levels of IL-22 produced by steady-state or IL-23-activated ILC3s in a putrescine-dependent manner. Thus, the polyamine putrescine is a positive regulator of ILC3 activation. Our results suggest that polyamines represent a potential target for therapeutic modulation of ILC3 activation during infection or inflammatory disorders.

DOI: https://doi.org/10.4049/immunohorizons.2200097
Nat Commun. 2023 Jan 06. 14(1): 108

Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation.

Andrea Irazoki, Isabel Gordaliza-Alaguero, Emma Frank, Nikolaos Nikiforos Giakoumakis, Jordi Seco, Manuel Palacín, Anna Gumà, Lykke Sylow, David Sebastián, Antonio Zorzano.

Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics in mitigating such processes and their impact on muscle fitness remain unaddressed. Here we report that opposite mitochondrial morphologies induce distinct inflammatory signatures, caused by differential activation of DNA sensors TLR9 or cGAS. In the context of mitochondrial fragmentation, we demonstrate that mitochondria-endosome contacts mediated by the endosomal protein Rab5C are required in TLR9 activation in cells. Skeletal muscle mitochondrial fragmentation promotes TLR9-dependent inflammation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which improved upon chronic anti-inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in preventing sterile inflammatory responses, which precede the development of muscle atrophy and impaired physical performance. Thus, we propose the targeting of mitochondrial dynamics as an approach to treating disorders characterized by chronic inflammation and mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-022-35732-1
Front Immunol. 2022 ;13 1090429

Manipulating T-cell metabolism to enhance immunotherapy in solid tumor.

Chen Chen, Zehua Wang, Yi Ding, Yanru Qin.

  Cellular metabolism is not only essential for tumor cells to sustain their rapid growth and proliferation, but also crucial to maintain T cell fitness and robust immunity. Dysregulated metabolism has been recognized as a hallmark of cancer, which provides survival advantages for tumor cells under stress conditions. Also, emerging evidence suggests that metabolic reprogramming impacts the activation, differentiation, function, and exhaustion of T cells. Normal stimulation of resting T cells promotes the conversion of catabolic and oxidative metabolism to aerobic glycolysis in effector T cells, and subsequently back to oxidative metabolism in memory T cells. These metabolic transitions profoundly affect the trajectories of T-cell differentiation and fate. However, these metabolic events of T cells could be dysregulated by their interplays with tumor or the tumor microenvironment (TME). Importantly, metabolic competition in the tumor ecosystem is a new mechanism resulting in strong suppression of effector T cells. It is appreciated that targeting metabolic reprogramming is a promising way to disrupt the hypermetabolic state of tumor cells and enhance the capacity of immune cells to obtain nutrients. Furthermore, immunotherapies, such as immune checkpoint inhibitor (ICI), adoptive cell therapy (ACT), and oncolytic virus (OV) therapy, have significantly refashioned the clinical management of solid tumors, they are not sufficiently effective for all patients. Understanding how immunotherapy affects T cell metabolism provides a bright avenue to better modulate T cell anti-tumor response. In this review, we provide an overview of the cellular metabolism of tumor and T cells, provide evidence on their dynamic interaction, highlight how metabolic reprogramming of tumor and T cells regulate the anti-tumor responses, describe T cell metabolic patterns in the context of ICI, ACT, and OV, and propose hypothetical combination strategies to favor potent T cell functionality.

Keywords:  T cell; adoptive cell therapy; immune checkpoint inhibitor; metabolism reprogramming; oncolytic virus therapy; solid tumor

DOI:  https://doi.org/10.3389/fimmu.2022.1090429
Immunity. 2023 Jan 10. pii: S1074-7613(22)00644-6. [Epub ahead of print]56(1): 32-42

Microenvironment-driven metabolic adaptations guiding CD8+ T cell anti-tumor immunity.

Jaeoh Park, Pei-Chun Hsueh, Zhiyu Li, Ping-Chih Ho.

The metabolic stress occurring in the tumor microenvironment (TME) hampers T cell anti-tumor immunity by disturbing T cell metabolic and epigenetic programs. Recent studies are making headway toward identifying strategies to unleash T cell activities by targeting T cell metabolism. Furthermore, efforts have been made to improve the efficacy of immune checkpoint blockade and adoptive cell transfer therapies. However, distinct treatment outcomes across different cancers raise the question of whether our understanding of the features of CD8+ T cells within the TME are universal, regardless of their tissue of origin. Here, we review the common and distinct environmental factors affecting CD8+ T cells across tumors. Moreover, we discuss how distinct tissue-specific niches are interpreted by CD8+ T cells based on studies on tissue-resident memory T (Trm) cells and how these insights can pave the way for a better understanding of the metabolic regulation of CD8+ T cell differentiation and anti-tumor immunity.

DOI: https://doi.org/10.1016/j.immuni.2022.12.008
Int J Mol Sci. 2022 Dec 29. pii: 558. [Epub ahead of print]24(1):

HIF-1α-Dependent Metabolic Reprogramming, Oxidative Stress, and Bioenergetic Dysfunction in SARS-CoV-2-Infected Hamsters.

Sirsendu Jana, Michael R Heaven, Charles B Stauft, Tony T Wang, Matthew C Williams, Felice D'Agnillo, Abdu I Alayash.

  The mechanistic interplay between SARS-CoV-2 infection, inflammation, and oxygen homeostasis is not well defined. Here, we show that the hypoxia-inducible factor (HIF-1α) transcriptional pathway is activated, perhaps due to a lack of oxygen or an accumulation of mitochondrial reactive oxygen species (ROS) in the lungs of adult Syrian hamsters infected with SARS-CoV-2. Prominent nuclear localization of HIF-1α and increased expression of HIF-1α target proteins, including glucose transporter 1 (Glut1), lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase-1 (PDK1), were observed in areas of lung consolidation filled with infiltrating monocytes/macrophages. Upregulation of these HIF-1α target proteins was accompanied by a rise in glycolysis as measured by extracellular acidification rate (ECAR) in lung homogenates. A concomitant reduction in mitochondrial respiration was also observed as indicated by a partial loss of oxygen consumption rates (OCR) in isolated mitochondrial fractions of SARS-CoV-2-infected hamster lungs. Proteomic analysis further revealed specific deficits in the mitochondrial ATP synthase (Atp5a1) within complex V and in the ATP/ADP translocase (Slc25a4). The activation of HIF-1α in inflammatory macrophages may also drive proinflammatory cytokine production and complement activation and oxidative stress in infected lungs. Together, these findings support a role for HIF-1α as a central mediator of the metabolic reprogramming, inflammation, and bioenergetic dysfunction associated with SARS-CoV-2 infection.

Keywords:  COVID-19 disease; bioenergetics; hamster; hypoxia; proteomics

DOI:  https://doi.org/10.3390/ijms24010558
Cells. 2022 Dec 20. pii: 1. [Epub ahead of print]12(1):

Lower Metabolic Potential and Impaired Metabolic Flexibility in Human Lymph Node Stromal Cells from Patients with Rheumatoid Arthritis.

Tineke A de Jong, Johanna F Semmelink, Simone W Denis, Janne W Bolt, Mario Maas, Marleen G H van de Sande, Riekelt H L Houtkooper, Lisa G M van Baarsen.

  Cellular metabolism is important for determining cell function and shaping immune responses. Studies have shown a crucial role for stromal cells in steering proper immune responses in the lymph node microenvironment. These lymph node stromal cells (LNSCs) tightly regulate immune tolerance. We hypothesize that malfunctioning LNSCs create a microenvironment in which normal immune responses are not properly controlled, possibly leading to the development of autoimmune diseases such as rheumatoid arthritis (RA). Therefore, we set out to determine their metabolic profile during health and systemic autoimmunity. We included autoantibody positive individuals at risk of developing RA (RA-risk individuals), RA patients and healthy volunteers. All study subjects underwent lymph node biopsy sampling. Mitochondrial function in cultured LNSCs was assessed by quantitative PCR, flow cytometry, Seahorse and oleate oxidation assays. Overall, mitochondrial respiration was lower in RA(-risk) LNSCs compared with healthy LNSCs, while metabolic potential was only lower in RA LNSCs. To maintain basal mitochondrial respiration, all LNSCs were mostly dependent on fatty acid oxidation. However, RA(-risk) LNSCs were also dependent on glutamine oxidation. Finally, we showed that RA LNSCs have impaired metabolic flexibility. Our results show that the metabolic landscape of LNSCs is not only altered during established disease, but partly already in individuals at risk of developing RA. Future studies are needed to investigate the impact of restoring metabolic capacity in LNSC-mediated immunomodulation and disease progression.

Keywords:  RA-risk individuals; autoimmunity; lymph node stromal cells (LNSCs); mitochondrial respiration

DOI:  https://doi.org/10.3390/cells12010001
Sci Rep. 2023 Jan 12. 13(1): 629

An untargeted metabolomic approach to investigate antiviral defence mechanisms in memory leukocytes secreting anti-SARS-CoV-2 IgG in vitro.

Gevi Federica, Fanelli Giuseppina, Lelli Veronica, Zarletti Gianpaolo, Tiberi Massimo, De Molfetta Veronica, Scapigliati Giuseppe, Timperio Anna Maria.

Evidence shows that individuals infected by SARS-CoV-2 experience an altered metabolic state in multiple organs. Metabolic activities are directly involved in modulating immune responses against infectious diseases, yet our understanding of how host metabolism relates to inflammatory responses remains limited. To better elucidate the underlying biochemistry of the leukocyte response, we focused our analysis on possible relationships between SARS-CoV-2 post-infection stages and distinct metabolic pathways. Indeed, we observed a significant altered metabolism of tryptophan and urea cycle pathways in cultures of peripheral blood mononuclear cells obtained 60-90 days after infection and showing in vitro IgG antibody memory for spike-S1 antigen (n = 17). This work, for the first time, identifies metabolic routes in cell metabolism possibly related to later stages of immune defence against SARS-CoV-2 infection, namely, when circulating antibodies may be absent but an antibody memory is present. The results suggest reprogramming of leukocyte metabolism after viral pathogenesis through activation of specific amino acid pathways possibly related to protective immunity against SARS-CoV-2.

DOI: https://doi.org/10.1038/s41598-022-26156-4
Front Cell Dev Biol. 2022 ;10 1032360

High-throughput in situ perturbation of metabolite levels in the tumor micro-environment reveals favorable metabolic condition for increased fitness of infiltrated T-cells.

Veronica Valvo, Elena Parietti, Kyle Deans, Sebastian W Ahn, Noel Ruth Park, Benjamin Ferland, Devon Thompson, Christine Dominas, Sharath K Bhagavatula, Shawn Davidson, Oliver Jonas.

  Tumor-infiltrating immune cells experience significant metabolic reprogramming in the tumor microenvironment (TME), and they share similar metabolic pathways and nutrient needs with malignant cells. This positions these cell types in direct nutrient competition in the TME. We currently lack a complete understanding of the similarities, differences, and functional consequences of the metabolic pathways utilized by activated immune cells from different lineages versus neoplastic cells. This study applies a novel in situ approach using implantable microdevices to expose the tumor to 27 controlled and localized metabolic perturbations in order to perform a systematic investigation into the metabolic regulation of the cellular fitness and persistence between immune and tumor cells directly within the native TME. Our findings identify the most potent metabolites, notably glutamine and arginine, that induce a favorable metabolic immune response in a mammary carcinoma model, and reveal novel insights on less characterized pathways, such as cysteine and glutathione. We then examine clinical samples from cancer patients to confirm the elevation of these pathways in tumor regions that are enriched in activated T cells. Overall, this work provides the first instance of a highly multiplexed in situ competition assay between malignant and immune cells within tumors using a range of localized microdose metabolic perturbations. The approach and findings may be used to potentiate the effects of T cell stimulating immunotherapies on a tumor-specific or personalized basis through targeted enrichment or depletion of specific metabolites.

Keywords:  T-cells infiltration; cancer metabolism; immunometabolism; immunotherapy; in situ perturbation; tumor micro-environment

DOI:  https://doi.org/10.3389/fcell.2022.1032360
JCI Insight. 2023 Jan 10. pii: e158100. [Epub ahead of print]

microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis.

Farida Ahangari, Nathan L Price, Shipra Malik, Maurizio Chioccioli, Thomas Bärnthaler, Taylor S Adams, Jooyoung Kim, Sai Pallavi Pradeep, Shuizi Ding, Carlos Cosme, Kadi-Ann S Rose, John E McDonough, Nachelle R Aurelien, Gabriel Ibarra, Norihito Omote, Jonas C Schupp, Giuseppe DeIuliis, Julian A Villalba Nunez, Lokesh Sharma, Changwan Ryu, Charles S Dela Cruz, Xinran Liu, Antje Prasse, Ivan Rosas, Raman Bahal, Carlos Fernandez-Hernando, Naftali Kaminski.

  Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of SREBP (sterol regulatory element binding protein) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immuno-metabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in Broncho Alveolar Lavage (BAL) cells isolated from IPF patients compared to healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 Peptide Nucleic Acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. Together, these studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a novel therapeutic approach to treat this disease.

Keywords:  Autophagy; Fatty acid oxidation; Fibrosis; Metabolism; Pulmonology

DOI:  https://doi.org/10.1172/jci.insight.158100
Nat Rev Mol Cell Biol. 2023 Jan 12.

Metabolites as signalling molecules.

Steven Andrew Baker, Jared Rutter.

Traditional views of cellular metabolism imply that it is passively adapted to meet the demands of the cell. It is becoming increasingly clear, however, that metabolites do more than simply supply the substrates for biological processes; they also provide critical signals, either through effects on metabolic pathways or via modulation of other regulatory proteins. Recent investigation has also uncovered novel roles for several metabolites that expand their signalling influence to processes outside metabolism, including nutrient sensing and storage, embryonic development, cell survival and differentiation, and immune activation and cytokine secretion. Together, these studies suggest that, in contrast to the prevailing notion, the biochemistry of a cell is frequently governed by its underlying metabolism rather than vice versa. This important shift in perspective places common metabolites as key regulators of cell phenotype and behaviour. Yet the signalling metabolites, and the cognate targets and transducers through which they signal, are only beginning to be uncovered. In this Review, we discuss the emerging links between metabolism and cellular behaviour. We hope this will inspire further dissection of the mechanisms through which metabolic pathways and intermediates modulate cell function and will suggest possible drug targets for diseases linked to metabolic deregulation.

DOI: https://doi.org/10.1038/s41580-022-00572-w
Cancer Cell. 2023 Jan 03. pii: S1535-6108(22)00594-3. [Epub ahead of print]

Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.

Gaopeng Li, Jae Eun Choi, Ilona Kryczek, Yilun Sun, Peng Liao, Shasha Li, Shuang Wei, Sara Grove, Linda Vatan, Reagan Nelson, Grace Schaefer, Steven G Allen, Kamya Sankar, Leslie A Fecher, Mishal Mendiratta-Lala, Timothy L Frankel, Angel Qin, Jessica J Waninger, Alangoya Tezel, Ajjai Alva, Christopher D Lao, Nithya Ramnath, Marcin Cieslik, Paul W Harms, Michael D Green, Arul M Chinnaiyan, Weiping Zou.

  Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintuitively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor-infiltrating CD8+ T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and β-catenin signaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD+, resulting in reduction of SIRT1-mediated β-catenin deacetylation and enhanced β-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-β-catenin axis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNγ-PKM2-β-catenin cascade underlies ICB-associated HPD.

Keywords:  FGF2; IFNγ; PD-L1/PD-1 pathway; T cell immunity; complete response; glycolytic metabolism; hyperprogressive disease; immune checkpoint blockade; oncogenesis; β-catenin

DOI:  https://doi.org/10.1016/j.ccell.2022.12.008
Front Immunol. 2022 ;13 1043572

A metabolite attenuates neuroinflammation, synaptic loss and cognitive deficits induced by chronic infection of Toxoplasma gondii.

Yan He, Daxiang Xu, Ziyi Yan, Yongshuai Wu, Yongsheng Zhang, Xiaokang Tian, Jinhang Zhu, Zhuanzhuan Liu, Wanpeng Cheng, Kuiyang Zheng, Xiaoying Yang, Yinghua Yu, Wei Pan.

  Background: Neurodegenerative diseases including AD is currently one of intractable problems globally due to the insufficiency of intervention strategies. Long-term infection of Toxoplasma gondii (T. gondii) can induce cognitive impairment in hosts, which is closely implicated in the pathogenesis of neurodegenerative diseases. Aconitate decarboxylase 1 (Acod1) and its produced metabolite itaconate (termed Acod1/itaconate axis), have recently attracted extensive interests due to its anti-inflammatory role in macrophages. However, whether the axis can influence cognitive function remains unknown.Methods: A chronic T. gondii-infected mice (C57BL/6J) model was established via administration of cysts by gavage. Novel location (NL), novel object recognition (NOR), Y-maze spatial memory and nest building tests were used to evaluate the behavior performance. Transmission electron microscopy, immunofluorescence, RT-PCR, western-blotting and RNA sequencing were utilized to determine the pathological changes, neuroinflammation and transcription profile in hippocampus tissues post infection, respectively. Moreover, the protective effect of Acod1/itaconate axis in T. gondii-induced cognitive deficits was evaluated.
Results: We found that the latent infection of the parasite impaired the cognitive function, which was assessed behaviorally by novel location (NL), novel object recognition (NOR), Y-maze spatial memory and nest building tests. RNA sequencing of hippocampus showed that the infection downregulated the expression of genes related to synaptic plasticity, transmission and cognitive behavior. To our attention, the infection robustly upregulated the expression of genes associated with pro-inflammatory responses, which was characterized by microglia activation and disorder of Acod1/itaconate axis. Interestingly, administration of dimethyl itaconate (DI, an itaconate derivative with cell membrane permeability) could significantly ameliorate the cognitive deficits induced by T. gondii, which was proved by improvement of behavior performance and synaptic ultrastructure impairment, and lower accumulation of pro-inflammatory microglia. Notably, DI administration had a potential therapeutic effect on the cognitive deficits and synaptic impairment induced by the parasitic infection.
Conclusions: Overall, these findings provide a novel insight for the pathogenesis of T. gondii-related cognitive deficits in hosts, and also provide a novel clue for the potential therapeutic strategies.

Keywords:  Acod1/itaconate axis; Toxoplasma gondii; cognition; hippocampus; metabolic reprogramming; neuroinflammation; synaptic plasticity

DOI:  https://doi.org/10.3389/fimmu.2022.1043572
Food Funct. 2023 Jan 09.

Ascophyllum nodosum polysaccharide regulates gut microbiota metabolites to protect against colonic inflammation in mice.

Lilong Wang, Chunhong Yan, Linlin Wang, Chunqing Ai, Songtao Wang, Caihong Shen, Yuqin Tong, Shuang Song.

Ascophyllum nodosum polysaccharide (ANP) can protect against colonic inflammation but the underlying mechanism is still unclear. This study has determined the metabolites of gut microbiota regulated by ANP to reveal the mechanism of the anti-inflammation effect of ANP. Using an in vitro colonic fermentation model, the results indicate that gut microbiota could utilize a proportion of ANP to increase the concentrations of short-chain fatty acids (SCFAs) and decrease ammonia content. Metabolomics revealed that 46 differential metabolites, such as betaine, L-carnitine, and aminoimidazole carboxamide ribonucleotide (AICAR), could be altered by ANP. Metabolic pathway analysis showed that ANP mainly up-regulated the phenylalanine, tyrosine, and tryptophan biosynthesis and aminoacyl-tRNA biosynthesis, which were negatively correlated with inflammation progression. Interestingly, these metabolites associated with inflammation were also up-regulated by ANP in colitis mice, including betaine, L-carnitine, AICAR, N-acetyl-glutamine, tryptophan, and valine, which were mainly associated with amino acid metabolism and aminoacyl-tRNA biosynthesis. Furthermore, the metabolites modulated by ANP were associated with the relative abundances of Akkermansia, Bacteroides, Blautia, Coprobacillus, Enterobacter, and Klebsiella. Additionally, based on VIP values, betaine is a key metabolite after the ANP supplement in vitro and in vivo. As indicated by these findings, ANP can up-regulate the production of SCFAs, betaine, L-carnitine, and AICAR and aminoacyl-tRNA biosynthesis to protect against colonic inflammation and maintain intestinal health.

DOI: https://doi.org/10.1039/d2fo02964b
Nat Rev Microbiol. 2023 Jan 12.

A microbial metabolite to master inflammation.

Agustina Taglialegna.

DOI: https://doi.org/10.1038/s41579-023-00853-x
Iran Biomed J. 2023 Dec 19. pii: A-10-5091-1. [Epub ahead of print]

Metabolic Regulation of T cell Activity: Implications for Metabolic-Based T-cell Therapies for Cancer.

Jahangir Abdesheikhi, Farnaz Sedghy, Merat Mahmoodi, Hossein Fallah, Mahdi Ranjkesh.

Immunometabolism is an emerging field in tumor immunotherapy. Understanding the metabolic competition for access to the limited nutrients between tumor cells and immune cells can reveal the complexity of the tumor microenvironment and help develop new therapeutic approaches for cancer. Recent studies have focused on modifying the function of immune cells by manipulating their metabolic pathways. Besides, identifying metabolic events affecting the function of immune cells leads to new therapeutic opportunities for the treatment of inflammatory diseases and immune-related conditions. According to the literature, metabolic pathways, such as glycolysis, TCA cycle, and fatty acid metabolism, affect significantly the survival, proliferation, activation, and function of immune cells and thus regulate immune responses. In this paper, we reviewed the role of metabolic processes and major signaling pathways in T-cell regulation and T-cell responses against tumor cells. Moreover, we summarized the new therapeutics suggested to enhance anti-tumor activity of T cells through manipulating metabolic pathways.

Keywords: cancer metabolism; immunometabolism; metabolic pathways