bims-imicid 2022-11-27 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022‒11‒27
27 papers selected by
Dylan Ryan
University of Cambridge

Macrophage acetyl-CoA carboxylase regulates acute inflammation through control of glucose and lipid metabolism.
How neutrophil metabolism affects bacterial killing.
Mitochondria as disease-relevant organelles in rheumatoid arthritis.
FABP5 Deficiency Impaired Macrophage Inflammation by Regulating AMPK/NF-κB Signaling Pathway.
The tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 regulates polycystic kidney disease progression.
Adipose tissue macrophages: Regulators of adipose tissue immunometabolism during obesity.
DOT1L regulates lipid biosynthesis and inflammatory responses in macrophages and promotes atherosclerotic plaque stability.
Alveolar macrophage metabolic programming via a C-type lectin receptor protects against lipo-toxicity and cell death.
CD36-Fatty Acid-Mediated Metastasis via the Bidirectional Interactions of Cancer Cells and Macrophages.
A metabolically engineered bacterium controls autoimmunity and inflammation by remodeling the pro-inflammatory microenvironment.
Inosine, Gut Microbiota, and Cancer Immunometabolism.
Computational modeling of complex bioenergetic mechanisms that modulate CD4+ T cell effector and regulatory functions.
Targeting the CD47/thrombospondin-1 signaling axis regulates immune cell bioenergetics in the tumor microenvironment to potentiate antitumor immune response.
Exogenous D-ribose promotes gentamicin treatment of several drug-resistant Salmonella.
Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation.
A deubiquitination module essential for Treg fitness in the tumor microenvironment.
Systematic single-cell pathway analysis to characterize early T cell activation.
Colonocyte-derived lactate promotes E. coli fitness in the context of inflammation-associated gut microbiota dysbiosis.
Mitochondrial connections with immune system in Zebrafish.
GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages.
Elucidating the mitochondrial function of murine lymphocyte subsets and the heterogeneity of the mitophagy pathway inherited from hematopoietic stem cells.
Physiological mechanisms of TLR4 in glucolipid metabolism regulation: Potential use in metabolic syndrome prevention.
Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling.
Metabolic control of innate lymphoid cells in health and disease.
A central role for STAT5 in the transcriptional programing of T helper cell metabolism.
Dysregulated energy metabolism impairs chondrocyte function in osteoarthritis.
Survivin promotes a glycolytic switch in CD4+ T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis.

Sci Adv. 2022 Nov 25. 8(47): eabq1984

Macrophage acetyl-CoA carboxylase regulates acute inflammation through control of glucose and lipid metabolism.

Scott Yeudall, Clint M Upchurch, Philip V Seegren, Caitlin M Pavelec, Jan Greulich, Michael C Lemke, Thurl E Harris, Bimal N Desai, Kyle L Hoehn, Norbert Leitinger.

Acetyl-CoA carboxylase (ACC) regulates lipid synthesis; however, its role in inflammatory regulation in macrophages remains unclear. We generated mice that are deficient in both ACC isoforms in myeloid cells. ACC deficiency altered the lipidomic, transcriptomic, and bioenergetic profile of bone marrow-derived macrophages, resulting in a blunted response to proinflammatory stimulation. In response to lipopolysaccharide (LPS), ACC is required for the early metabolic switch to glycolysis and remodeling of the macrophage lipidome. ACC deficiency also resulted in impaired macrophage innate immune functions, including bacterial clearance. Myeloid-specific deletion or pharmacological inhibition of ACC in mice attenuated LPS-induced expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1β, while pharmacological inhibition of ACC increased susceptibility to bacterial peritonitis in wild-type mice. Together, we identify a critical role for ACC in metabolic regulation of the innate immune response in macrophages, and thus a clinically relevant, unexpected consequence of pharmacological ACC inhibition.

DOI: https://doi.org/10.1126/sciadv.abq1984
Open Biol. 2022 Nov;12(11): 220248

How neutrophil metabolism affects bacterial killing.

Juliana E Toller-Kawahisa, Luke A J O'Neill.

  Neutrophils are front line cells in immunity that quickly recognize and eliminate pathogens, relying mainly on glycolysis to exert their killing functions. Even though investigations into the influence of metabolic pathways in neutrophil function started in the 1930s, the knowledge of how neutrophils metabolically adapt during a bacterial infection remains poorly understood. In this review, we discuss the current knowledge about the metabolic regulation underlying neutrophils response to bacterial infection. Glycogen metabolism has been shown to be important for multiple neutrophil functions. The potential contribution of metabolic pathways other than glycolysis, such as mitochondrial metabolism, for neutrophil function has recently been explored, including fatty acid oxidation in neutrophil differentiation. Complex III in the mitochondria might also control glycolysis via glycerol-3-phosphate oxidation. Future studies should yield new insights into the role of metabolic change in the anti-bacterial response in neutrophils.

Keywords:  bacterial infection; glucose metabolism; glutamine metabolism; mitochondrial metabolism; neutrophil function

DOI:  https://doi.org/10.1098/rsob.220248
Clin Exp Immunol. 2022 Nov 24. pii: uxac107. [Epub ahead of print]

Mitochondria as disease-relevant organelles in rheumatoid arthritis.

Cornelia M Weyand, Bowen Wu, Tao Huang, Zhaolan Hu, Jörg J Goronzy.

  Mitochondria are the controllers of cell metabolism and are recognized as decision makers in cell death pathways, organizers of cytoplasmic signaling networks, managers of cellular stress responses and regulators of nuclear gene expression. Cells of the immune system are particularly dependent on mitochondrial resources, as they must swiftly respond to danger signals with activation, trafficking, migration, and generation of daughter cells. Analogously, faulty immune responses that lead to autoimmunity and tissue inflammation rely on mitochondria to supply energy, cell building blocks and metabolic intermediates. Emerging data endorse the concept that mitochondrial fitness, and the lack of it, is of particular relevance in the autoimmune disease rheumatoid arthritis (RA) where deviations of bioenergetic and biosynthetic flux affect T cells during early and late stages of disease. During early stages of RA, mitochondrial deficiency allows naïve RA T cells to lose self-tolerance, biasing fundamental choices of the immune system towards immune-mediated tissue damage and away from host protection. During late stages of RA, mitochondrial abnormalities shape the response patterns of RA effector T cells engaged in the inflammatory lesions, enabling chronicity of tissue damage and tissue remodeling. In the inflamed joint, autoreactive T cells partner with metabolically reprogrammed tissue macrophages that specialize in antigen-presentation and survive by adapting to the glucose-deplete tissue microenvironment. Here, we summarize recent data on dysfunctional mitochondria and mitochondria-derived signals relevant in the RA disease process that offer novel opportunities to deter autoimmune tissue inflammation by metabolic interference.

Keywords:  T cells; autoimmunity; macrophages; mitochondria; rheumatoid arthritis; tumor necrosis factor

DOI:  https://doi.org/10.1093/cei/uxac107
J Immunol. 2022 Dec 01. 209(11): 2181-2191

FABP5 Deficiency Impaired Macrophage Inflammation by Regulating AMPK/NF-κB Signaling Pathway.

Yangxiao Hou, Dong Wei, Elhusseny A Bossila, Zhaoqi Zhang, Sihong Li, Jiaming Bao, Huawen Xu, Lianfeng Zhang, Yong Zhao.

Fatty acid binding protein 5 (FABP5) is mainly involved in the uptake, transport, and metabolism of fatty acid in the cytoplasm, and its role in immune cells has been recognized in recent years. However, the role of FABP5 in macrophage inflammation and its underlying mechanisms were not fully addressed. In our study, the acute liver injury and sepsis mouse models were induced by i.p. injection of LPS and cecal contents, respectively. Oleic acid (0.6 g/kg) was injected four times by intragastric administration every week, and this lasted for 1 wk before the LPS or cecal content challenge. We found that myeloid-specific deletion of FABP5 mitigated LPS-induced acute liver injury with reduced mortality of mice, histological liver damage, alanine aminotransferase, and proinflammatory factor levels. Metabolic analysis showed that FABP5 deletion increased the intracellular unsaturated fatty acids, especially oleic acid, in LPS-induced macrophages. The addition of oleic acid also decreased LPS-stimulated macrophage inflammation in vitro and reduced acute liver injury in LPS-induced or cecal content-induced sepsis mice. RNA-sequencing and molecular mechanism studies showed that FABP5 deletion or oleic acid supplementation increased the AMP/ATP ratio and AMP-activated protein kinase (AMPK) activation and inhibited the NF-κB pathway during the inflammatory response to LPS stimulation of macrophages. Inhibiting AMPK activation or expression by chemical or genetic approaches significantly rescued the decreased NF-κB signaling pathway and inflammatory response in LPS-treated FABP5-knockout macrophages. Our present study indicated that inhibiting FABP5 or supplementation of oleic acid might be used for the treatment of sepsis-caused acute liver injury.

DOI: https://doi.org/10.4049/jimmunol.2200182
JCI Insight. 2022 Nov 24. pii: e154773. [Epub ahead of print]

The tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 regulates polycystic kidney disease progression.

Dustin T Nguyen, Emily K Kleczko, Nidhi Dwivedi, Marie-Louise T Monaghan, Berenice Y Gitomer, Michel B Chonchol, Eric T Clambey, Raphael A Nemenoff, Jelena Klawitter, Katharina Hopp.

  Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic nephropathy, is characterized by phenotypic variability exceeding genic effects. Dysregulated metabolism and immune cell function are key disease modifiers. The tryptophan metabolites, kynurenines, produced through IDO1, are known immunomodulators. Here, we study the role of tryptophan metabolism in PKD using an orthologous disease model (C57Bl/6J Pkd1RC/RC). We found elevated kynurenine and IDO1 levels in Pkd1RC/RC kidneys versus wildtype. Further, IDO1 levels were increased in ADPKD cell lines. Genetic Ido1 loss in Pkd1RC/RC animals resulted in reduced PKD severity as measured by %kidney weight/body weight and cystic index. Consistent with an immunomodulatory role of kynurenines, Pkd1RC/RC;Ido1-/- mice presented with significant changes in the cystic immune microenvironment (CME) versus controls. Kidney macrophage numbers decreased and CD8+ T cell numbers increased, both known PKD modulators. Also, pharmacological IDO1 inhibition in Pkd1RC/RC mice and kidney specific Pkd2 knockout mice with rapidly progressive PKD resulted in less severe PKD versus controls with similar changes in the CME as in the genetic model. Our data suggest that tryptophan metabolism is dysregulated in ADPKD and that its inhibition results in changes to the CME and slows disease progression, making IDO1 a novel therapeutic target for ADPKD.

Keywords:  Amino acid metabolism; Cellular immune response; Monogenic diseases; Nephrology

DOI:  https://doi.org/10.1172/jci.insight.154773
Mol Metab. 2022 Nov 17. pii: S2212-8778(22)00211-3. [Epub ahead of print] 101642

Adipose tissue macrophages: Regulators of adipose tissue immunometabolism during obesity.

Sierra A Nance, Lindsey Muir, Carey Lumeng.

  Adipose tissue macrophages (ATMs) are a well characterized regulator of adipose tissue inflammatory tone. Previously defined by the M1 vs M2 classification, we now have a better understanding of ATM diversity that departs from the old paradigm and reports a spectrum of ATM function and phenotypes in both brown and white adipose tissue. While the paradigm that resident ATMs predominate in the lean state and obesity leads to the accumulation of lipid-associated and inflammatory ATMs still broadly remains rigorously supported, the details of this model continue to be refined and single cell data provide new insight into ATM subtypes and states. This review provides an updated overview of ATM activation and function, ATM diversity in humans and rodents, and novel ATM functions that contribute to metabolic homeostasis and disease.

Keywords:  Adipose tissue; Inflammation; Lipids; Macrophage; Obesity

DOI:  https://doi.org/10.1016/j.molmet.2022.101642
Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01577-7. [Epub ahead of print]41(8): 111703

DOT1L regulates lipid biosynthesis and inflammatory responses in macrophages and promotes atherosclerotic plaque stability.

Lisa Willemsen, Koen H M Prange, Annette E Neele, Cindy P A A van Roomen, Marion Gijbels, Guillermo R Griffith, Myrthe den Toom, Linda Beckers, Ricky Siebeler, Nathanael J Spann, Hung-Jen Chen, Laura A Bosmans, Andrej Gorbatenko, Suzanne van Wouw, Noam Zelcer, Heinz Jacobs, Fred van Leeuwen, Menno P J de Winther.

  Macrophages are critical immune cells in inflammatory diseases, and their differentiation and function are tightly regulated by histone modifications. H3K79 methylation is a histone modification associated with active gene expression, and DOT1L is the only histone methyltransferase for H3K79. Here we determine the role of DOT1L in macrophages by applying a selective DOT1L inhibitor in mouse and human macrophages and using myeloid-specific Dot1l-deficient mice. We found that DOT1L directly regulates macrophage function by controlling lipid biosynthesis gene programs including central lipid regulators like sterol regulatory element-binding proteins SREBP1 and SREBP2. DOT1L inhibition also leads to macrophage hyperactivation, which is associated with disrupted SREBP pathways. In vivo, myeloid Dot1l deficiency reduces atherosclerotic plaque stability and increases the activation of inflammatory plaque macrophages. Our data show that DOT1L is a crucial regulator of macrophage inflammatory responses and lipid regulatory pathways and suggest a high relevance of H3K79 methylation in inflammatory disease.

Keywords:  CP: Molecular biology; DOT1L; H3K79; atherosclerosis; epigenetics; immune system; inflammation; lipid metabolism; macrophage; methyltransferase

DOI:  https://doi.org/10.1016/j.celrep.2022.111703
Nat Commun. 2022 Nov 25. 13(1): 7272

Alveolar macrophage metabolic programming via a C-type lectin receptor protects against lipo-toxicity and cell death.

Michal Scur, Ahmad Bakur Mahmoud, Sayanti Dey, Farah Abdalbarri, Iona Stylianides, Daniel Medina-Luna, Gayani S Gamage, Aaron Woblistin, Alexa N M Wilson, Haggag S Zein, Ashley Stueck, Andrew Wight, Oscar A Aguilar, Francesca Di Cara, Brendon D Parsons, Mir Munir A Rahim, James R Carlyle, Andrew P Makrigiannis.

Alveolar macrophages (AM) hold lung homeostasis intact. In addition to the defense against inhaled pathogens and deleterious inflammation, AM also maintain pulmonary surfactant homeostasis, a vital lung function that prevents pulmonary alveolar proteinosis. Signals transmitted between AM and pneumocytes of the pulmonary niche coordinate these specialized functions. However, the mechanisms that guide the metabolic homeostasis of AM remain largely elusive. We show that the NK cell-associated receptor, NKR-P1B, is expressed by AM and is essential for metabolic programming. Nkrp1b-/- mice are vulnerable to pneumococcal infection due to an age-dependent collapse in the number of AM and the formation of lipid-laden AM. The AM of Nkrp1b-/- mice show increased uptake but defective metabolism of surfactant lipids. We identify a physical relay between AM and alveolar type-II pneumocytes that is dependent on pneumocyte Clr-g expression. These findings implicate the NKR-P1B:Clr-g signaling axis in AM-pneumocyte communication as being important for maintaining metabolism in AM.

DOI: https://doi.org/10.1038/s41467-022-34935-w
Cells. 2022 Nov 10. pii: 3556. [Epub ahead of print]11(22):

CD36-Fatty Acid-Mediated Metastasis via the Bidirectional Interactions of Cancer Cells and Macrophages.

Noorzaileen Eileena Zaidi, Nur Aima Hafiza Shazali, Thean-Chor Leow, Mohd Azuraidi Osman, Kamariah Ibrahim, Wan-Hee Cheng, Kok-Song Lai, Nik Mohd Afizan Nik Abd Rahman.

  Tumour heterogeneity refers to the complexity of cell subpopulations coexisting within the tumour microenvironment (TME), such as proliferating tumour cells, tumour stromal cells and infiltrating immune cells. The bidirectional interactions between cancer and the surrounding microenvironment mark the tumour survival and promotion functions, which allow the cancer cells to become invasive and initiate the metastatic cascade. Importantly, these interactions have been closely associated with metabolic reprogramming, which can modulate the differentiation and functions of immune cells and thus initiate the antitumour response. The purpose of this report is to review the CD36 receptor, a prominent cell receptor in metabolic activity specifically in fatty acid (FA) uptake, for the metabolic symbiosis of cancer-macrophage. In this review, we provide an update on metabolic communication between tumour cells and macrophages, as well as how the immunometabolism indirectly orchestrates the tumour metastasis.

Keywords:  CD36; macrophage; metabolism; metastasis; tumour microenvironment

DOI:  https://doi.org/10.3390/cells11223556
Gut Microbes. 2022 Jan-Dec;14(1):14(1): 2143222

A metabolically engineered bacterium controls autoimmunity and inflammation by remodeling the pro-inflammatory microenvironment.

Jugal Kishore Das, Fengguang Guo, Carrie Hunt, Shelby Steinmeyer, Julia A Plocica, Koichi S Kobayashi, Yufang Ding, Arul Jayaraman, Thomas A Ficht, Robert C Alaniz, Paul de Figueiredo, Jianxun Song.

  Immunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative strategies for enhancing the effectiveness of current immunotherapeutic approaches. We have metabolically engineered an attenuated bacterial strain (i.e., Brucella melitensis 16M ∆vjbR, Bm∆vjbR::tnaA) to produce indole, a tryptophan metabolite that controls the fate and function of regulatory T (Treg) cells. We demonstrated that treatment with Bm∆vjbR::tnaA polarized macrophages (Mφ) which produced anti-inflammatory cytokines (e.g., IL-10) and promoted Treg function; moreover, when combined with adoptive cell transfer (ACT) of Treg cells, a single treatment with our engineered bacterial strain dramatically reduced the incidence and score of autoimmune arthritis and decreased joint damage. These findings show how a metabolically engineered bacterium can constitute a powerful vehicle for improving the efficacy of immunotherapy, defeating autoimmunity, and reducing inflammation by remodeling the IME and augmenting Treg cell function.

Keywords:  Microbe; autoimmunity; immunometabolism; inflammation; regulatory T cells

DOI:  https://doi.org/10.1080/19490976.2022.2143222
Am J Physiol Endocrinol Metab. 2022 Nov 23.

Inosine, Gut Microbiota, and Cancer Immunometabolism.

Elham Samami, Elahe Aleebrahim-Dehkordi, Mehdi Mohebalizadeh, Shakila Yaribash, Amene Saghazadeh, Nima Rezaei.

  This article briefly reviews cancer immunity and the role of gut microbiota in carcinogenesis, followed by an understanding of mechanisms by which inosine is involved in cancer immunometabolism. Constitutional cells of immune systems play a paradoxical role in cancer treatment. Anti-tumor immunity depends on the T-cell priming against tumor antigens, while the pro-tumor signaling is triggered by inflammatory mediators present in the tumor microenvironment. Studies link the microbiome with metabolism and immunity-two main factors implicated in carcinogenesis. Gut microbiota has been shown to affect both anti-tumor immunity and pro-tumor immune signaling. Additionally, there is mounting evidence that the human microbiome can play a role in the immunotherapeutic effects, both response and resistance. Inosine-5'-monophosphate dehydrogenase (IMPDH) is a highly conservative enzyme widely expressed in mammals. Cell signaling pathways utilize molecular inosine, which is a crucial secondary metabolite in purine metabolism and a molecular messenger in the process. Recent research has identified inosine as a critical regulator of immune checkpoint inhibition (ICB) therapeutic response in various tumor types. Three bacterial species, Bifidobacterium pseudopodium, Lactobacillus, and Olsenella, were found to produce inosine or its metabolite hypoxanthine and induce Th1 differentiation and effector functions via the inosine-A2AR-cAMP-PKA pathway upon ICB initiation, after being injected into the systemic circulation. Moreover, inosine acts as a substitute carbon source for T cell metabolism in glucose-restricted environments, i.e., the tumor microenvironment, assisting T cell proliferation and differentiation while enhancing sensitivity to ICB, reinforcing the notion that inosine metabolism may contribute to anti-tumor immunity. Also, inosine is a strong agonist of the adenosine receptor, A2AR, and A2AR signaling can affect T cell responses and anti-tumor immunity, making the inosine-A2AR pathway blockage a candidate for cancer treatment. Further research is required to investigate inosine as a cancer immunometabolism therapy.

Keywords:  Cancer; Immunity; Immunometabolism; Immunotherapy; Inosine

DOI:  https://doi.org/10.1152/ajpendo.00207.2022
NPJ Syst Biol Appl. 2022 Nov 22. 8(1): 45

Computational modeling of complex bioenergetic mechanisms that modulate CD4+ T cell effector and regulatory functions.

Ryan Baker, Raquel Hontecillas, Nuria Tubau-Juni, Andrew J Leber, Shiv Kale, Josep Bassaganya-Riera.

We built a computational model of complex mechanisms at the intersection of immunity and metabolism that regulate CD4+ T cell effector and regulatory functions by using coupled ordinary differential equations. The model provides an improved understanding of how CD4+ T cells are shaping the immune response during Clostridioides difficile infection (CDI), and how they may be targeted pharmacologically to produce a more robust regulatory (Treg) response, which is associated with improved disease outcomes during CDI and other diseases. LANCL2 activation during CDI decreased the effector response, increased regulatory response, and elicited metabolic changes that favored Treg. Interestingly, LANCL2 activation provided greater immune and metabolic modulation compared to the addition of exogenous IL-2. Additionally, we identified gluconeogenesis via PEPCK-M as potentially responsible for increased immunosuppressive behavior in Treg cells. The model can perturb immune signaling and metabolism within a CD4+ T cell and obtain clinically relevant outcomes that help identify novel drug targets for infectious, autoimmune, metabolic, and neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41540-022-00263-4
J Immunother Cancer. 2022 Nov;pii: e004712. [Epub ahead of print]10(11):

Targeting the CD47/thrombospondin-1 signaling axis regulates immune cell bioenergetics in the tumor microenvironment to potentiate antitumor immune response.

Elizabeth R Stirling, Masaki Terabe, Adam S Wilson, Mitra Kooshki, Liliya M Yamaleyeva, Martha A Alexander-Miller, Wei Zhang, Lance D Miller, Pierre L Triozzi, David R Soto-Pantoja.

  BACKGROUND: CD47 is an integral membrane protein that alters adaptive immunosurveillance when bound to the matricellular glycoprotein thrombospondin-1 (TSP1). We examined the impact of the CD47/TSP1 signaling axis on melanoma patient response to anti-PD-1 therapy due to alterations in T cell activation, proliferation, effector function, and bioenergetics.METHODS: A syngeneic B16 mouse melanoma model was performed to determine if targeting CD47 as monotherapy or in combination with anti-PD-1 impacted tumor burden. Cytotoxic (CD8+) T cells from Pmel-1 transgenic mice were used for T cell activation, cytotoxic T lymphocyte, and cellular bioenergetic assays. Single-cell RNA-sequencing, ELISA, and flow cytometry was performed on peripheral blood mononuclear cells and plasma of melanoma patients receiving anti-PD-1 therapy to examine CD47/TSP1 expression.
RESULTS: Human malignant melanoma tissue had increased CD47 and TSP1 expression within the tumor microenvironment compared with benign tissue. Due to the negative implications CD47/TSP1 can have on antitumor immune responses, we targeted CD47 in a melanoma model and observed a decrease in tumor burden due to increased tumor oxygen saturation and granzyme B secreting CD8+ T cells compared with wild-type tumors. Additionally, Pmel-1 CD8+ T cells exposed to TSP1 had reduced activation, proliferation, and effector function against B16 melanoma cells. Targeting CD47 allowed CD8+ T cells to overcome this TSP1 interaction to sustain these functions. TSP1 exposed CD8+ T cells have a decreased rate of glycolysis; however, targeting CD47 restored glycolysis when CD8+ T cells were exposed to TSP1, suggesting CD47 mediated metabolic reprogramming of T cells. Additionally, non-responding patients to anti-PD-1 therapy had increased T cells expressing CD47 and circulating levels of TSP1 compared with responding patients. Since CD47/TSP1 signaling axis negatively impacts CD8+ T cells and non-responding patients to anti-PD-1 therapy have increased CD47/TSP1 expression, we targeted CD47 in combination with anti-PD-1 in a melanoma model. Targeting CD47 in combination with anti-PD-1 treatment further decreased tumor burden compared with monotherapy and control.
CONCLUSION: CD47/TSP1 expression could serve as a marker to predict patient response to immune checkpoint blockade treatment, and targeting this pathway may preserve T cell activation, proliferation, effector function, and bioenergetics to reduce tumor burden as a monotherapy or in combination with anti-PD-1.

Keywords:  adaptive immunity; immunotherapy; melanoma; metabolic networks and pathways

DOI:  https://doi.org/10.1136/jitc-2022-004712
Front Microbiol. 2022 ;13 1053330

Exogenous D-ribose promotes gentamicin treatment of several drug-resistant Salmonella.

Yanhong Zhou, Yan Yong, Chunyang Zhu, Heng Yang, Binghu Fang.

  The metabolic microenvironment of bacteria impacts drug efficacy. However, the metabolic mechanisms of drug-resistant Salmonella spp. remain largely unknown. This study characterized the metabolic mechanism of gentamicin-resistant Salmonella Choleraesuis and found that D-ribose increased the gentamicin-mediated killing of this bacteria. Non-targeted metabolomics of homologous gentamicin-susceptible Salmonella Choleraesuis (SCH-S) and gentamicin-resistant S. Choleraesuis (SCH-R) was performed using UHPLC-Q-TOF MS. The metabolic signature of SCH-R included disrupted central carbon metabolism and energy metabolism, along with dysregulated amino acid and nucleotide metabolism, vitamin and cofactor metabolism, and fatty acid synthesis. D-ribose, the most suppressed metabolite in SCH-R, was shown to strengthen gentamicin efficacy against SCH-R and a clinically isolated multidrug-resistant strain. This metabolite had a similar impact on Salmonella. Derby and Salmonella. Typhimurium. D-ribose activates central carbon metabolism including glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid cycle (TCA cycle), increases the abundance of NADH, polarizes the electron transport chain (ETC), and elevates the proton motive force (PMF) of cells, and induces drug uptake and cell death. These findings suggest that central carbon metabolism plays a critical role in the acquisition of gentamicin resistance by Salmonella, and that D-ribose may serve as an antibiotic adjuvant for gentamicin treatment of resistant bacterial infections.

Keywords:  D-ribose; Salmonella; gentamicin; metabolomics; resistance

DOI:  https://doi.org/10.3389/fmicb.2022.1053330
Front Immunol. 2022 ;13 966067

Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation.

Zhou Zhou, Leonie G Plug, Thiago A Patente, Eveline S M de Jonge-Muller, Amir Abou Elmagd, Andrea E van der Meulen-de Jong, Bart Everts, Marieke C Barnhoorn, Lukas J A C Hawinkels.

  Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the intestinal tract with currently not well-understood pathogenesis. In addition to the involvement of immune cells, increasing studies show an important role for fibroblasts in the pathogenesis of IBD. Previous work showed that glycolysis is the preferred energy source for fibroblasts in fibrotic diseases. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) is a key kinase supporting glycolysis. Increased expression of PFKFB3 in several cancers and inflammatory diseases has been previously reported, but the metabolic status of fibroblasts and the role of PFKFB3 in patients with IBD are currently unknown. Therefore, in this study, we evaluated the role of glycolysis and PFKFB3 expression in IBD. Single-sample gene set enrichment analysis (ssGSEA) revealed that glycolysis was significantly higher in IBD intestinal samples, compared to healthy controls, which was confirmed in the validation cohorts of IBD patients. Single-cell sequencing data indicated that PFKFB3 expression was higher in IBD-derived stromal cells. In vitro, PFKFB3 expression in IBD-derived fibroblasts was increased after the stimulation with pro-inflammatory cytokines. Using seahorse real-time cell metabolic analysis, inflamed fibroblasts were shown to have a higher extracellular acidification rate and a lower oxygen consumption rate, which could be reversed by inhibition of JAK/STAT pathway. Furthermore, increased expression of pro-inflammatory cytokines and chemokines in fibroblasts could be reverted by PFK15, a specific inhibitor of PFKFB3. In vivo experiments showed that PFK15 reduced the severity of dextran sulfate sodium (DSS)- and Tcell transfer induced colitis, which was accompanied by a reduction in immune cell infiltration in the intestines. These findings suggest that increased stromal PFKFB3 expression contributes to inflammation and the pathological function of fibroblasts in IBD. Inhibition of PFKFB3 suppressed their inflammatory characteristics.

Keywords:  PFKFB3; fibroblast; glycolysis; inflammatory bowel disease; stromal cells

DOI:  https://doi.org/10.3389/fimmu.2022.966067
Sci Adv. 2022 Nov 25. 8(47): eabo4116

A deubiquitination module essential for Treg fitness in the tumor microenvironment.

Elena Montauti, Samuel E Weinberg, Peng Chu, Shuvam Chaudhuri, Nikita L Mani, Radhika Iyer, Yuanzhang Zhou, Yusi Zhang, Changhong Liu, Chen Xin, Shana Gregory, Juncheng Wei, Yana Zhang, Wantao Chen, Zhaolin Sun, Ming Yan, Deyu Fang.

The tumor microenvironment (TME) enhances regulatory T (Treg) cell stability and immunosuppressive functions through up-regulation of lineage transcription factor Foxp3, a phenomenon known as Treg fitness or adaptation. Here, we characterize previously unknown TME-specific cellular and molecular mechanisms underlying Treg fitness. We demonstrate that TME-specific stressors including transforming growth factor-β (TGF-β), hypoxia, and nutrient deprivation selectively induce two Foxp3-specific deubiquitinases, ubiquitin-specific peptidase 22 (Usp22) and Usp21, by regulating TGF-β, HIF, and mTOR signaling, respectively, to maintain Treg fitness. Simultaneous deletion of both USPs in Treg cells largely diminishes TME-induced Foxp3 up-regulation, alters Treg metabolic signatures, impairs Treg-suppressive function, and alleviates Treg suppression on cytotoxic CD8+ T cells. Furthermore, we developed the first Usp22-specific small-molecule inhibitor, which dramatically reduced intratumoral Treg Foxp3 expression and consequently enhanced antitumor immunity. Our findings unveil previously unappreciated mechanisms underlying Treg fitness and identify Usp22 as an antitumor therapeutic target that inhibits Treg adaptability in the TME.

DOI: https://doi.org/10.1126/sciadv.abo4116
Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01571-6. [Epub ahead of print]41(8): 111697

Systematic single-cell pathway analysis to characterize early T cell activation.

Jack A Bibby, Divyansh Agarwal, Tilo Freiwald, Natalia Kunz, Nicolas S Merle, Erin E West, Parul Singh, Andre Larochelle, Fariba Chinian, Somabha Mukherjee, Behdad Afzali, Claudia Kemper, Nancy R Zhang.

  Pathway analysis is a key analytical stage in the interpretation of omics data, providing a powerful method for detecting alterations in cellular processes. We recently developed a sensitive and distribution-free statistical framework for multisample distribution testing, which we implement here in the open-source R package single-cell pathway analysis (SCPA). We demonstrate the effectiveness of SCPA over commonly used methods, generate a scRNA-seq T cell dataset, and characterize pathway activity over early cellular activation. This reveals regulatory pathways in T cells, including an intrinsic type I interferon system regulating T cell survival and a reliance on arachidonic acid metabolism throughout T cell activation. A systems-level characterization of pathway activity in T cells across multiple tissues also identifies alpha-defensin expression as a hallmark of bone-marrow-derived T cells. Overall, this work provides a widely applicable tool for single-cell pathway analysis and highlights regulatory mechanisms of T cells.

Keywords:  CP: Immunology; SCPA; T cell; arachidonic acid; cytokines; gene set; metabolism; pathway analysis; single-cell RNA-seq; single-cell pathway analysis; type I interferon

DOI:  https://doi.org/10.1016/j.celrep.2022.111697
Microbiome. 2022 Nov 26. 10(1): 200

Colonocyte-derived lactate promotes E. coli fitness in the context of inflammation-associated gut microbiota dysbiosis.

Savannah J Taylor, Maria G Winter, Caroline C Gillis, Laice Alves da Silva, Amanda L Dobbins, Matthew K Muramatsu, Angel G Jimenez, Rachael B Chanin, Luisella Spiga, Ernesto M Llano, Vivian K Rojas, Jiwoong Kim, Renato L Santos, Wenhan Zhu, Sebastian E Winter.

  BACKGROUND: Intestinal inflammation disrupts the microbiota composition leading to an expansion of Enterobacteriaceae family members (dysbiosis). Associated with this shift in microbiota composition is a profound change in the metabolic landscape of the intestine. It is unclear how changes in metabolite availability during gut inflammation impact microbial and host physiology.RESULTS: We investigated microbial and host lactate metabolism in murine models of infectious and non-infectious colitis. During inflammation-associated dysbiosis, lactate levels in the gut lumen increased. The disease-associated spike in lactate availability was significantly reduced in mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells. Commensal E. coli and pathogenic Salmonella, representative Enterobacteriaceae family members, utilized lactate via the respiratory L-lactate dehydrogenase LldD to increase fitness. Furthermore, mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells exhibited lower levels of inflammation in a model of non-infectious colitis.
CONCLUSIONS: The release of lactate by intestinal epithelial cells during gut inflammation impacts the metabolism of gut-associated microbial communities. These findings suggest that during intestinal inflammation and dysbiosis, changes in metabolite availability can perpetuate colitis-associated disturbances of microbiota composition. Video Abstract.

Keywords:  Gut inflammation; Host-microbe interactions; Lactate metabolism

DOI:  https://doi.org/10.1186/s40168-022-01389-7
Fish Shellfish Immunol Rep. 2021 Dec;2 100019

Mitochondrial connections with immune system in Zebrafish.

Mariana Abrantes do Amaral, Lais Cavalieri Paredes, Barbara Nunes Padovani, Juliana Moreira Mendonça-Gomes, Luan Fávero Montes, Niels Olsen Saraiva Câmara, Camila Morales Fénero.

  Mitochondria are organelles commonly associated with adenosine triphosphate (ATP) formation through the oxidative phosphorylation (OXPHOS) process. However, mitochondria are also responsible for functions such as calcium homeostasis, apoptosis, autophagy, and production of reactive oxygen species (ROS) that, in conjunction, can lead to different cell fate decisions. Mitochondrial morphology changes rely on nutrients' availability and the bioenergetics demands of the cells, in a process known as mitochondrial dynamics, which includes both fusion and fission. This organelle senses the microenvironment and can modify the cells to either a pro or anti-inflammatory profile. The zebrafish has been increasingly used to research mitochondrial dynamics and its connection with the immune system since the pathways and molecules involved in these processes are conserved on this fish. Several genetic tools and technologies are currently available to analyze the behavior of mitochondria in zebrafish. However, even though zebrafish presents several similar processes known in mammals, the effect of the mitochondria in the immune system has not been so broadly studied in this model. In this review, we summarize the current knowledge in zebrafish studies regarding mitochondrial function and immuno metabolism.

Keywords:  Fish; Immuno metabolism; Immunology; Metabolism; Mitochondria; Mitochondrial functions

DOI:  https://doi.org/10.1016/j.fsirep.2021.100019
Nat Commun. 2022 Nov 25. 13(1): 7260

GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages.

Jing Yan, Yuemei Zhang, Hairong Yu, Yicen Zong, Daixi Wang, Jiangfei Zheng, Li Jin, Xiangtian Yu, Caizhi Liu, Yi Zhang, Feng Jiang, Rong Zhang, Xiangnan Fang, Ting Xu, Mingyu Li, Jianzhong Di, Yan Lu, Xinran Ma, Jian Zhang, Weiping Jia, Cheng Hu.

G-protein-signaling modulator 1 (GPSM1) exhibits strong genetic association with Type 2 diabetes (T2D) and Body Mass Index in population studies. However, how GPSM1 carries out such control and in which types of cells are poorly understood. Here, we demonstrate that myeloid GPSM1 promotes metabolic inflammation to accelerate T2D and obesity development. Mice with myeloid-specific GPSM1 ablation are protected against high fat diet-induced insulin resistance, glucose dysregulation, and liver steatosis via repression of adipose tissue pro-inflammatory states. Mechanistically, GPSM1 deficiency mainly promotes TNFAIP3 transcription via the Gαi3/cAMP/PKA/CREB axis, thus inhibiting TLR4-induced NF-κB signaling in macrophages. In addition, we identify a small-molecule compound, AN-465/42243987, which suppresses the pro-inflammatory phenotype by inhibiting GPSM1 function, which could make it a candidate for metabolic therapy. Furthermore, GPSM1 expression is upregulated in visceral fat of individuals with obesity and is correlated with clinical metabolic traits. Overall, our findings identify macrophage GPSM1 as a link between metabolic inflammation and systemic homeostasis.

DOI: https://doi.org/10.1038/s41467-022-34998-9
Front Immunol. 2022 ;13 1061448

Elucidating the mitochondrial function of murine lymphocyte subsets and the heterogeneity of the mitophagy pathway inherited from hematopoietic stem cells.

Haoyue Liang, Weichao Fu, Wenying Yu, Zhijie Cao, Ertao Liu, Fanfan Sun, Xiaodong Kong, Yingdai Gao, Yuan Zhou.

  Background: Mitochondria are mainly involved in ATP production to meet the energy demands of cells. Researchers are increasingly recognizing the important role of mitochondria in the differentiation and activation of hematopoietic cells, but research on how mitochondrial metabolism influence different subsets of lymphocyte at different stages of differentiation and activation are yet to be carried out. In this work, the mitochondrial functions of lymphocytes were compared at different differentiation and activation stages and included CD8+ T lymphocytes, CD4+ T lymphocytes, B lymphocytes, NK cells as well as their subsets. For this purpose, a complete set of methods was used to comprehensively analyze mitophagy levels, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and the mitochondrial mass (MM) of subsets of lymphocytes. It is expected that this will provide a complete set of standards, and drawing the mitochondrial metabolic map of lymphocyte subsets at different stages of differentiation and activation.Results and discussion: Of all lymphocytes, B cells had a relatively high mitochondrial metabolic activity which was evident from the higher levels of mitophagy, ROS, MMP and MM, and this reflected the highly heterogeneous nature of the mitochondrial metabolism in lymphocytes. Among the B cell subsets, pro-B cells had relatively higher levels of MM and MMP, while the mitochondrial metabolism level of mature B cells was relatively low. Similarly, among the subsets of CD4+ T cell, a relatively higher level of mitochondrial metabolism was noted for naive CD4+ T cells. Finally, from the CD8+ T cell subsets, CD8+ Tcm had relatively high levels of MM and MMP but relatively low ones for mitophagy, with effector T cells displaying the opposite characteristics. Meanwhile, the autophagy-related genes of lymphoid hematopoietic cells including hematopoietic stem cells, hematopoietic progenitor cells and lymphocyte subsets were analyzed, which preliminarily showed that these cells were heterogeneous in the selection of mitophagy related Pink1/Park2, BNIP3/NIX and FUNDC1 pathways. The results showed that compared with CD4+ T, CD8+ T and NK cells, B cells were more similar to long-term hematopoietic stem cell (LT-HSC) and short-term hematopoietic stem cell (ST-HSC) in terms of their participation in the Pink1/Park2 pathway, as well as the degree to which the characteristics of autophagy pathway were inherited from HSC. Compared with CLP and B cells, HSC are less involved in BNIP3/NIX pathway. Among the B cell subsets, pro-B cells inherited the least characteristics of HSC in participating in Pink1/Park2 pathway compared with pre-B, immature B and immature B cells. Among CD4+ T cell subsets, nTreg cells inherited the least characteristics of HSC in participating in Pink1/Park2 pathway compared with naive CD4+ T and memory CD4+ T cells. Among the CD8+ T cell subsets, compared with CLP and effector CD8+ T cells, CD8+ Tcm inherit the least characteristics of HSC in participating in Pink1/Park2 pathway. Meanwhile, CLP, naive CD4+ T and effector CD8+ T were more involved in BNIP3/NIX pathway than other lymphoid hematopoietic cells.
Conclusion: This study is expected to provide a complete set of methods and basic reference values for future studies on the mitochondrial functions of lymphocyte subsets at different stages of differentiation and activation in physiological state, and also provides a standard and reference for the study of infection and immunity based on mitochondrial metabolism.

Keywords:  hematopoietic stem cell; lymphocyte subsets; metabolic map; mitochondrial functions; mitophagy

DOI:  https://doi.org/10.3389/fimmu.2022.1061448
Nutr Metab Cardiovasc Dis. 2022 Oct 18. pii: S0939-4753(22)00423-9. [Epub ahead of print]

Physiological mechanisms of TLR4 in glucolipid metabolism regulation: Potential use in metabolic syndrome prevention.

Feng Zeng, Jiawei Zheng, Li Shen, Daniela D Herrera-Balandrano, Wuyang Huang, Zhongquan Sui.

  Over-nourishment or an unbalanced diet has been linked to an increase in the prevalence of metabolic syndrome. An imbalance in glucolipid metabolism is a major cause of metabolic syndrome, which has consequences for human health. Toll-like receptor 4 (TLR4), a member of the innate immune pattern recognition receptor family, is involved in inflammation-related disorders, autoimmune diseases, and tumors. Recent research has shown that TLR4 plays a key role in glucolipid metabolism, which is linked to insulin resistance, intestinal flora, and the development of chronic inflammation. TLR4 activation regulates glucolipid metabolism and contributes to the dynamic relationship between innate immunity and nutrition-related disorders. Further, TLR4 regulates glucolipid metabolism by controlling glycolysis and pyruvate oxidative decarboxylation, interfering with insulin signaling, regulating adipogenic gene expression levels, influencing preadipocyte differentiation and lipid accumulation, and altering the intestinal microbiota and permeability. TLR4 functions may provide new therapeutic applications for the prevention and treatment of metabolic syndrome. The purpose of this review is to enrich mechanistic research of diabetes, atherosclerosis, and other nutrition-related disorders by summarizing the role of TLR4 in the regulation of glucolipid metabolism as well as its physiological mechanisms.

Keywords:  Glucose metabolism; Inflammation; Insulin resistance; Lipid metabolism; Metabolic syndrome; Nutrition-related diseases; Toll-like receptor4 (TLR4)

DOI:  https://doi.org/10.1016/j.numecd.2022.10.011
Circulation. 2022 Nov 23.

Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling.

Alberto Canfrán-Duque, Noemi Rotllan, Xinbo Zhang, Irene Andrés-Blasco, Bonne M Thompson, Jonathan Sun, Nathan L Price, Marta Fernández-Fuertes, Joseph W Fowler, Diego Gómez-Coronado, William C Sessa, Chiara Giannarelli, Robert J Schneider, George Tellides, Jeffrey G McDonald, Carlos Fernández-Hernando, Yajaira Suárez.

  BACKGROUND: Cross-talk between sterol metabolism and inflammatory pathways has been demonstrated to significantly affect the development of atherosclerosis. Cholesterol biosynthetic intermediates and derivatives are increasingly recognized as key immune regulators of macrophages in response to innate immune activation and lipid overloading. 25-Hydroxycholesterol (25-HC) is produced as an oxidation product of cholesterol by the enzyme cholesterol 25-hydroxylase (CH25H) and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. Despite the major role of 25-HC as a mediator of innate and adaptive immune responses, its contribution during the progression of atherosclerosis remains unclear.METHODS: The levels of 25-HC were analyzed by liquid chromatography-mass spectrometry, and the expression of CH25H in different macrophage populations of human or mouse atherosclerotic plaques, respectively. The effect of CH25H on atherosclerosis progression was analyzed by bone marrow adoptive transfer of cells from wild-type or Ch25h-/- mice to lethally irradiated Ldlr-/- mice, followed by a Western diet feeding for 12 weeks. Lipidomic, transcriptomic analysis and effects on macrophage function and signaling were analyzed in vitro from lipid-loaded macrophage isolated from Ldlr-/- or Ch25h-/-;Ldlr-/- mice. The contribution of secreted 25-HC to fibrous cap formation was analyzed using a smooth muscle cell lineage-tracing mouse model, Myh11ERT2CREmT/mG;Ldlr-/-, adoptively transferred with wild-type or Ch25h-/- mice bone marrow followed by 12 weeks of Western diet feeding.
RESULTS: We found that 25-HC accumulated in human coronary atherosclerotic lesions and that macrophage-derived 25-HC accelerated atherosclerosis progression, promoting plaque instability through autocrine and paracrine actions. 25-HC amplified the inflammatory response of lipid-loaded macrophages and inhibited the migration of smooth muscle cells within the plaque. 25-HC intensified inflammatory responses of lipid-laden macrophages by modifying the pool of accessible cholesterol in the plasma membrane, which altered Toll-like receptor 4 signaling, promoted nuclear factor-κB-mediated proinflammatory gene expression, and increased apoptosis susceptibility. These effects were independent of 25-HC-mediated modulation of liver X receptor or SREBP (sterol regulatory element-binding protein) transcriptional activity.
CONCLUSIONS: Production of 25-HC by activated macrophages amplifies their inflammatory phenotype, thus promoting atherogenesis.

Keywords:  25-hydroxycholesterol; atherosclerosis; inflammation; macrophages

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.122.059062
Nat Metab. 2022 Nov 24.

Metabolic control of innate lymphoid cells in health and disease.

Lei Zhou, Qingxia Lin, Gregory F Sonnenberg.

Innate lymphoid cells (ILCs) are a family of predominantly tissue-resident lymphocytes that critically orchestrate immunity, inflammation, tolerance and repair at barrier surfaces of the mammalian body. Heterogeneity among ILC subsets is comparable to that of adaptive CD4+ T helper cell counterparts, and emerging studies demonstrate that ILC biology is also dictated by cellular metabolism that adapts bioenergetic requirements during activation, proliferation or cytokine production. Accumulating evidence in mouse models and human samples indicates that ILCs exhibit profound roles in shaping states of metabolic health and disease. Here we summarize and discuss our current knowledge of the cell-intrinsic and cell-extrinsic metabolic factors controlling ILC responses, as well as highlight contributions of ILCs to organismal metabolism. It is expected that continued research in this area will advance our understanding of how to manipulate ILCs or their metabolism for therapeutic strategies that benefit human health.

DOI: https://doi.org/10.1038/s42255-022-00685-8
Sci Immunol. 2022 Nov 25. 7(77): eabl9467

A central role for STAT5 in the transcriptional programing of T helper cell metabolism.

Alejandro V Villarino, Arian Dj Laurence, Fred P Davis, Luis Nivelo, Stephen R Brooks, Hong-Wei Sun, Kan Jiang, Behdad Afzali, Daniela Frasca, Lothar Hennighausen, Yuka Kanno, John J O'Shea.

Activated lymphocytes adapt their metabolism to meet the energetic and biosynthetic demands imposed by rapid growth and proliferation. Common gamma chain (cγ) family cytokines are central to these processes, but the role of downstream signal transducer and activator of transcription 5 (STAT5) signaling, which is engaged by all cγ members, is poorly understood. Using genome-, transcriptome-, and metabolome-wide analyses, we demonstrate that STAT5 is a master regulator of energy and amino acid metabolism in CD4+ T helper cells. Mechanistically, STAT5 localizes to an array of enhancers and promoters for genes encoding essential enzymes and transporters, where it facilitates p300 recruitment and epigenetic remodeling. We also find that STAT5 licenses the activity of two other key metabolic regulators, the mTOR signaling pathway and the MYC transcription factor. Building on the latter, we present evidence for transcriptome-wide cooperation between STAT5 and MYC in both normal and transformed T cells. Together, our data provide a molecular framework for transcriptional programing of T cell metabolism downstream of cγ cytokines and highlight the JAK-STAT pathway in mediating cellular growth and proliferation.

DOI: https://doi.org/10.1126/sciimmunol.abl9467
Osteoarthritis Cartilage. 2022 Nov 18. pii: S1063-4584(22)00927-X. [Epub ahead of print]

Dysregulated energy metabolism impairs chondrocyte function in osteoarthritis.

Xiaoxin Wu, Chamikara Liyanage, Manuel Plan, Terra Stark, Tim McCubbin, Roberto A Barrero, Jyotsna Batra, Ross Crawford, Yin Xiao, Indira Prasadam.

  OBJECTIVES: Metabolic pathways are a series of chemical reactions by which cells take in nutrient substrates for energy and building blocks needed to maintain critical cellular processes. Details of chondrocyte metabolism and how it rewires during the progression of osteoarthritis (OA) are unknown. This research aims to identify what changes in the energy metabolic state occur in OA cartilage.METHODS: Patient matched OA and non-OA cartilage specimens were harvested from total knee replacement patients. Cartilage was first collected for metabolomics, proteomics, and transcriptomics analyses to study global alterations in OA metabolism. We then determined the metabolic routes by tracking [U-13C] isotope with liquid chromatography-mass spectrometry (LC-MS). We further evaluated cellular bioenergetic profiles by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) and investigated the effects of low-dose and short-term effects of 2-deoxyglucose (2DG) on chondrocytes.
RESULTS: OA chondrocytes showed increased basal ECAR and more lactate production compared to non-OA chondrocytes. [U-13C] glucose labelling revealed that less glucose-derived carbon entered the TCA cycle. On the other hand, mitochondrial respiratory rates were markedly decreased in the OA chondrocytes compared to non-OA chondrocytes. These changes were accompanied by decreased cellular ATP production, mitochondrial membrane potential and disrupted mitochondrial morphology. We further demonstrated in vitro that short-term inhibition of glycolysis suppressed matrix degeneration gene expression in chondrocytes and bovine cartilage explants cultured under inflammatory conditions.
CONCLUSION: This study represents the first comprehensive comparative analysis of metabolism in OA chondrocytes and lays the groundwork for therapeutic targeting of metabolism in OA.

Keywords:  Chondrocyte; Energy metabolism; Glycolysis; Osteoarthritis; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.joca.2022.11.004
iScience. 2022 Dec 22. 25(12): 105526

Survivin promotes a glycolytic switch in CD4+ T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis.

Malin C Erlandsson, Karin M E Andersson, Nina Y Oparina, Venkataragavan Chandrasekaran, Tibor Saghy, Anastasios Damdimopoulos, Maria-Jose Garcia-Bonete, Zakaria Einbeigi, Sofia T Silfverswärd, Marcela Pekna, Gergely Katona, Maria I Bokarewa.

  In this study, we explore the role of nuclear survivin in maintaining the effector phenotype of IFNγ-producing T cells acting through the transcriptional control of glucose utilization. High expression of survivin in CD4+T cells was associated with IFNγ-dependent phenotype and anaerobic glycolysis. Transcriptome of CD4+ cells and sequencing of survivin-bound chromatin showed that nuclear survivin had a genome-wide and motif-specific binding to regulatory regions of the genes controlling cell metabolism. Survivin coprecipitates with transcription factors IRF1 and SMAD3, which repressed the transcription of the metabolic check-point enzyme phosphofructokinase 2 gene PFKFB3 and promoted anaerobic glycolysis. Combining transcriptome analyses of CD4+ cells and functional studies in glucose metabolism, we demonstrated that the inhibition of survivin reverted PFKFB3 production, inhibited glucose uptake, and reduces interferon effects in CD4+ cells. These results present a survivin-dependent mechanism in coordinating the metabolic adaptation of CD4+T cells and propose an attractive strategy to counteract IFNγ-dependent inflammation in autoimmunity.

Keywords:  Biological sciences; Immunology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2022.105526