bims-imicid 2024-06-23 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–06–23
25 papers selected by
Dylan Ryan, University of Cambridge

A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance.
Oleic acid enhances proliferation and calcium mobilization of CD3/CD28 activated CD4+ T cells through incorporation into membrane lipids.
3-Hydroxykynurenine targets kainate receptors to promote defense against infection.
Metabolic Adaptations and Functional Activity of Macrophages in Homeostasis and Inflammation.
Fasting reshapes tissue-specific niches to improve NK cell-mediated anti-tumor immunity.
Suppression of HIV-TAT and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters.
The PP2A regulatory subunit PPP2R2A controls NAD+ biosynthesis to regulate T cell subset differentiation in systemic autoimmunity.
Polyamine metabolism in macrophage-adipose tissue function and homeostasis.
Carboxylesterase 1 mediates a distinctive metabolic profile of dendritic cells to attain an inflammatory phenotype.
Cholesterol efflux from C1QB-expressing macrophages is associated with resistance to chimeric antigen receptor T cell therapy in primary refractory diffuse large B cell lymphoma.
USP18 induction regulates immunometabolism to attenuate M1 signal-polarized macrophages and enhance IL-4-polarized macrophages in systemic lupus erythematosus.
Metabolic shifts during coffee consumption refresh the immune response: insight from comprehensive multiomics analysis.
A metabolomics pipeline highlights microbial metabolism in bloodstream infections.
Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer.
Cell type-specific modulation of metabolic, immune-regulatory and anti-microbial pathways by CD101.
The tryptophan metabolic pathway of the microbiome and host cells in health and disease.
Immunometabolism unveiled: Pioneering breakthroughs in cancer therapeutics.
MAIT cells monitor intestinal dysbiosis and contribute to host protection during colitis.
Transcriptional profiling of lung macrophages following ozone exposure in mice identifies signaling pathways regulating immunometabolic activation.
Hippo kinases Mst1 and Mst2 maintain NK cell homeostasis by orchestrating metabolic state and transcriptional activity.
The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma.
High recallability of memory B cells requires ZFP318-dependent transcriptional regulation of mitochondrial function.
Associations between TCA cycle plasma metabolites and fatigue in black females with systemic lupus erythematosus: An untargeted metabolomics pilot study.
SHH induces macrophage oxidative phosphorylation and efferocytosis to promote scar formation.
A pre-vaccination immune metabolic interplay determines the protective antibody response to a dengue virus vaccine.

Immunity. 2024 Jun 19. pii: S1074-7613(24)00305-4. [Epub ahead of print]

A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance.

Randall T Mertens, Aditya Misra, Peng Xiao, Seungbyn Baek, Joseph M Rone, Davide Mangani, Kisha N Sivanathan, Adedamola S Arojojoye, Samuel G Awuah, Insuk Lee, Guo-Ping Shi, Boryana Petrova, Jeannette R Brook, Ana C Anderson, Richard A Flavell, Naama Kanarek, Martin Hemberg, Roni Nowarski.

  Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2'3'-cyclic GMP-AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation.

Keywords:  IL-18; SLC12A3; bistable circuit; cGAMP; fatty acid oxidation; immunometabolism; intestinal tolerance; macrophage; metabolic reprogramming; metabolic switch

DOI:  https://doi.org/10.1016/j.immuni.2024.06.001
Eur J Immunol. 2024 Jun 18. e2350685

Oleic acid enhances proliferation and calcium mobilization of CD3/CD28 activated CD4+ T cells through incorporation into membrane lipids.

Johannes Hendrick von Hegedus, Anja J de Jong, Anna T Hoekstra, Eric Spronsen, Wahwah Zhu, Birol Cabukusta, Joanneke C Kwekkeboom, Marieke Heijink, Erik Bos, Celia R Berkers, Martin A Giera, Rene E M Toes, Andreea Ioan-Facsinay.

  Unsaturated fatty acids (UFA) are crucial for T-cell effector functions, as they can affect the growth, differentiation, survival, and function of T cells. Nonetheless, the mechanisms by which UFA affects T-cell behavior are ill-defined. Therefore, we analyzed the processing of oleic acid, a prominent UFA abundantly present in blood, adipocytes, and the fat pads surrounding lymph nodes, in CD4+ T cells. We found that exogenous oleic acid increases proliferation and enhances the calcium flux response upon CD3/CD28 activation. By using a variety of techniques, we found that the incorporation of oleic acid into membrane lipids, rather than regulation of cellular metabolism or TCR expression, is essential for its effects on CD4+ T cells. These results provide novel insights into the mechanism through which exogenous oleic acid enhances CD4+ T-cell function.

Keywords:  CD4 T cells; Cellular proliferation; Fatty acids; Immune regulation; Metabolomics; Oleic acid; TCR

DOI:  https://doi.org/10.1002/eji.202350685
Nat Chem Biol. 2024 Jun 19.

3-Hydroxykynurenine targets kainate receptors to promote defense against infection.

Margarita Parada-Kusz, Anne E Clatworthy, Emily R Goering, Stephanie M Blackwood, Jack Y Shigeta, Eivgeni Mashin, Elizabeth J Salm, Catherine Choi, Senya Combs, Jenny S W Lee, Carlos Rodriguez-Osorio, Clary Clish, Susumu Tomita, Deborah T Hung.

Bacterial infection involves a complex interaction between the pathogen and host where the outcome of infection is not solely determined by pathogen eradication. To identify small molecules that promote host survival by altering the host-pathogen dynamic, we conducted an in vivo chemical screen using zebrafish embryos and found that treatment with 3-hydroxykynurenine (3-HK) protects from lethal bacterial infection. 3-HK, a metabolite produced through host tryptophan metabolism, has no direct antibacterial activity but enhances host survival by restricting bacterial expansion in macrophages through a systemic mechanism that targets kainate-sensitive glutamate receptors. These findings reveal a new pathway by which tryptophan metabolism and kainate-sensitive glutamate receptors function and interact to modulate immunity, with important implications for the coordination between the immune and nervous systems in pathological conditions.

DOI: https://doi.org/10.1038/s41589-024-01635-z
Biochemistry (Mosc). 2024 May;89(5): 817-838

Metabolic Adaptations and Functional Activity of Macrophages in Homeostasis and Inflammation.

Taisiya R Yurakova, Ekaterina A Gorshkova, Maxim A Nosenko, Marina S Drutskaya.

  In recent years, the role of cellular metabolism in immunity has come into the focus of many studies. These processes form a basis for the maintenance of tissue integrity and homeostasis, as well as represent an integral part of the immune response, in particular, inflammation. Metabolic adaptations not only ensure energy supply for immune response, but also affect the functions of immune cells by controlling transcriptional and post-transcriptional programs. Studying the immune cell metabolism facilitates the search for new treatment approaches, especially for metabolic disorders. Macrophages, innate immune cells, are characterized by a high functional plasticity and play a key role in homeostasis and inflammation. Depending on the phenotype and origin, they can either perform various regulatory functions or promote inflammation state, thus exacerbating the pathological condition. Furthermore, their adaptations to the tissue-specific microenvironment influence the intensity and type of immune response. The review examines the effect of metabolic reprogramming in macrophages on the functional activity of these cells and their polarization. The role of immunometabolic adaptations of myeloid cells in tissue homeostasis and in various pathological processes in the context of inflammatory and metabolic diseases is specifically discussed. Finally, modulation of the macrophage metabolism-related mechanisms reviewed as a potential therapeutic approach.

Keywords:  immunometabolism; macrophage polarization; proinflammatory cytokines

DOI:  https://doi.org/10.1134/S0006297924050043
Immunity. 2024 Jun 12. pii: S1074-7613(24)00275-9. [Epub ahead of print]

Fasting reshapes tissue-specific niches to improve NK cell-mediated anti-tumor immunity.

Rebecca B Delconte, Mark Owyong, Endi K Santosa, Katja Srpan, Sam Sheppard, Tomi J McGuire, Aamna Abbasi, Carlos Diaz-Salazar, Jerold Chun, Inez Rogatsky, Katharine C Hsu, Stefan Jordan, Miriam Merad, Joseph C Sun.

  Fasting is associated with improved outcomes in cancer. Here, we investigated the impact of fasting on natural killer (NK) cell anti-tumor immunity. Cyclic fasting improved immunity against solid and metastatic tumors in an NK cell-dependent manner. During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM). In humans, fasting also reduced circulating NK cell numbers. NK cells in the spleen of fasted mice were metabolically rewired by elevated concentrations of fatty acids and glucocorticoids, augmenting fatty acid metabolism via increased expression of the enzyme CPT1A, and Cpt1a deletion impaired NK cell survival and function in this setting. In parallel, redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4. These cells were primed by an increased pool of interleukin (IL)-12-expressing BM myeloid cells, which improved IFN-γ production. Our findings identify a link between dietary restriction and optimized innate immune responses, with the potential to enhance immunotherapy strategies.

Keywords:  NK cells; anti-tumor responses; fasting; immunometabolism; innate immunity; metabolism

DOI:  https://doi.org/10.1016/j.immuni.2024.05.021
J Neurovirol. 2024 Jun 17.

Suppression of HIV-TAT and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters.

B Celia Cui, Marina Aksenova, Aliaksandra Sikirzhytskaya, Diana Odhiambo, Elizaveta Korunova, Vitali Sikirzhytski, Hao Ji, Diego Altomare, Eugenia Broude, Norma Frizzell, Rosemarie Booze, Michael D Wyatt, Michael Shtutman.

  HIV-associated neurological disorder (HAND) is a serious complication of HIV infection marked by neurotoxicity induced by viral proteins like Tat. Substance abuse exacerbates neurocognitive impairment in people living with HIV. There is an urgent need for therapeutic strategies to combat HAND comorbid with Cocaine Use Disorder (CUD). Our analysis of HIV and cocaine-induced transcriptomes in primary cortical cultures revealed significant overexpression of the macrophage-specific gene aconitate decarboxylase 1 (Acod1). The ACOD1 protein converts the tricarboxylic acid intermediate cis-aconitate into itaconate during the activation of inflammation. Itaconate then facilitates cytokine production and activates anti-inflammatory transcription factors, shielding macrophages from infection-induced cell death. However, the immunometabolic function of itaconate was unexplored in HIV and cocaine-exposed microglia. We assessed the potential of 4-octyl-itaconate (4OI), a cell-penetrable ester form of itaconate known for its anti-inflammatory properties. When primary cortical cultures exposed to Tat and cocaine were treated with 4OI, microglial cell number increased and the morphological altercations induced by Tat and cocaine were reversed. Microglial cells also appeared more ramified, resembling the quiescent microglia. 4OI treatment inhibited secretion of the proinflammatory cytokines IL-1α, IL-1β, IL-6, and MIP1-α induced by Tat and cocaine. Transcriptome profiling determined that Nrf2 target genes were significantly activated in Tat and 4OI treated cultures relative to Tat alone. Further, genes associated with cytoskeleton dynamics in inflammatory microglia were downregulated by 4OI treatment. Together, the results strongly suggest 4-octyl-itaconate holds promise as a potential candidate for therapeutic development to treat HAND coupled with CUD comorbidities.

Keywords:  Acod 1; HAND; HIV; Itaconate; Microglia; Neuroinflammation; Tat

DOI:  https://doi.org/10.1007/s13365-024-01216-9
Cell Rep. 2024 Jun 17. pii: S2211-1247(24)00707-1. [Epub ahead of print]43(7): 114379

The PP2A regulatory subunit PPP2R2A controls NAD+ biosynthesis to regulate T cell subset differentiation in systemic autoimmunity.

Wenliang Pan, Maria G Tsokos, Marc Scherlinger, Wei Li, George C Tsokos.

  The protein phosphatase 2A (PP2A) regulatory subunit PPP2R2A is involved in the regulation of immune response. We report that lupus-prone mice with T cells deficient in PPP2R2A display less autoimmunity and nephritis. PPP2R2A deficiency promotes NAD+ biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells. NR inhibits murine Th17 and promotes Treg cell differentiation, in vitro, by PΑRylating histone H1.2 and causing its reduced occupancy in the Foxp3 loci and increased occupancy in the Il17a loci, leading to increased Foxp3 and decreased Il17a transcription. NR treatment suppresses disease in MRL.lpr mice and restores NAD+-dependent poly [ADP-ribose] polymerase 1 (PARP1) activity in CD4 T cells from patients with systemic lupus erythematosus (SLE), while reducing interferon (IFN)-γ and interleukin (IL)-17 production. We conclude that PPP2R2A controls the level of NAD+ through the NR-directed salvage pathway and promotes systemic autoimmunity. Translationally, NR suppresses lupus nephritis in mice and limits the production of proinflammatory cytokines by SLE T cells.

Keywords:  CP: Immunology; CP: Metabolism; NAD(+); NR; PARP1; PP2A; PPP2R2A; Th17; Treg; histone H1.2; systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.celrep.2024.114379
Trends Endocrinol Metab. 2024 Jun 18. pii: S1043-2760(24)00126-7. [Epub ahead of print]

Polyamine metabolism in macrophage-adipose tissue function and homeostasis.

Didier F Pisani, Daniele Lettieri-Barbato, Stoyan Ivanov.

  Intracellular metabolism is a crucial regulator of macrophage function. Recent evidence revealed that the polyamine pathway and subsequent hypusination of eukaryotic initiation factor 5A (eIF5A) are master regulators of immune cell functions. In brown adipose tissue (BAT), macrophages show an impressive degree of heterogenicity, with specific subsets supporting adaptive thermogenesis during cold exposure. In this review, we discuss the impact of polyamine metabolism on macrophage diversity and function, with a particular focus on their role in adipose tissue homeostasis. Thus, we highlight the exploration of how polyamine metabolism in macrophages contributes to BAT homeostasis as an attractive and exciting new field of research.

Keywords:  eIF5A; hypusination; inflammation; monocyte; thermogenesis

DOI:  https://doi.org/10.1016/j.tem.2024.05.008
J Leukoc Biol. 2024 Jun 13. pii: qiae137. [Epub ahead of print]

Carboxylesterase 1 mediates a distinctive metabolic profile of dendritic cells to attain an inflammatory phenotype.

Ahmed M I Elfiky, Jessica López Canñizares, Jiarong Li, Andrew Y F Li Yim, Arthur J Verhoeven, Mohammed Ghiboub, Wouter J de Jonge.

The metabolic profile of dendritic cells (DCs) shapes their phenotype and functions. Carboxylestrase 1 (CES1) enzyme is highly expressed in mononuclear myeloid cells however its exact role in DCs is elusive. We used a CES1 inhibitor (WWL113) and genetic overexpression to explore the role of CES1 in DCs differentiation in inflammatory models. CES1 expression was analyzed during CD14+ monocytes differentiation to DCs (MoDCs) using quantitative PCR. CES1 Inhibitor (WWL113) was applied during MoDCs differentiation. Surface markers, secreted cytokines, lactic acid production, phagocytic and T cell polarization capacity were analyzed. Transcriptomic and metabolic profile were assessed with RNA-sequencing and mass spectrometry. Cellular respiration was assessed with seahorse respirometry. Transgenic mice were used to assess CES1 overexpression in DCs in inflammatory models. CES1 expression peaks early during MoDCs differentiation. Pharmacological inhibition of CES1 led to higher expression of CD209, CD86 and MHCII. WWL113 treated MoDCs secreted higher quantities of IL6, IL8, TNF and IL10 and demonstrated stronger phagocytic ability and higher capacity to polarize Th17 differentiation in autologous DCs-T cells co-culture model. Transcriptomic profiling revealed enrichment of multiple inflammatory and metabolic pathways. Functional metabolic analysis shows impaired maximal mitochondrial respiration capacity, increased lactate production and decreased intracellular amino acids and TCA intermediates. Transgenic human CES1 overexpression in murine DCs generated less inflammatory phenotype and increased resistance to T cell mediated colitis. In conclusion, CES1 inhibition directs DCs differentiation towards more inflammatory phenotype, that shows stronger phagocytic capacity and supports Th17 skewing. This is associated with disrupted mitochondrial respiration and amino acids depletion.

DOI: https://doi.org/10.1093/jleuko/qiae137
Nat Commun. 2024 Jun 18. 15(1): 5183

Cholesterol efflux from C1QB-expressing macrophages is associated with resistance to chimeric antigen receptor T cell therapy in primary refractory diffuse large B cell lymphoma.

Zi-Xun Yan, Yan Dong, Niu Qiao, Yi-Lun Zhang, Wen Wu, Yue Zhu, Li Wang, Shu Cheng, Peng-Peng Xu, Zi-Song Zhou, Ling-Shuang Sheng, Wei-Li Zhao.

Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated promising efficacy in early trials for relapsed/refractory diffuse large B cell lymphoma (DLBCL). However, its efficacy in treating primary refractory DLBCL has not been comprehensively investigated, and the underlying resistance mechanisms remain unclear. Here, we report the outcomes of a phase I, open-label, single-arm clinical trial of relmacabtagene autoleucel (relma-cel), a CD19-targeted CAR-T cell product, with safety and efficacy as primary endpoints. Among the 12 enrolled patients, 8 experienced grade 4 hematologic toxicity of treatment-emergent adverse event. No grade ≥3 cytokine release syndrome or neurotoxicity occurred. Single-cell RNA sequencing revealed an increase proportion of C1QB-expressing macrophages in patients with progressive disease before CAR-T cell therapy. Cholesterol efflux from M2 macrophages was found to inhibit CAR-T cells cytotoxicity by inducing an immunosuppressive state in CD8+ T cells, leading to their exhaustion. Possible interactions between macrophages and CD8+ T cells, mediating lipid metabolism (AFR1-FAS), immune checkpoint activation, and T cell exhaustion (LGALS9-HAVCR2, CD86-CTLA4, and NECTIN2-TIGIT) were enhanced during disease progression. These findings suggest that cholesterol efflux from macrophages may trigger CD8+ T cell exhaustion, providing a rationale for metabolic reprogramming to counteract CAR-T treatment failure. Chinadrugtrials.org.cn identifier: CTR20200376.

DOI: https://doi.org/10.1038/s41467-024-49495-4
Clin Immunol. 2024 Jun 14. pii: S1521-6616(24)00394-2. [Epub ahead of print]265 110285

USP18 induction regulates immunometabolism to attenuate M1 signal-polarized macrophages and enhance IL-4-polarized macrophages in systemic lupus erythematosus.

Jenn-Haung Lai, De-Wei Wu, Chuan-Yueh Huang, Li-Feng Hung, Chien-Hsiang Wu, Ling-Jun Ho.

  Effective treatment of systemic lupus erythematosus (SLE) remains an unmet need. Different subsets of macrophages play differential roles in SLE and the modulation of macrophage polarization away from M1 status is beneficial for SLE therapeutics. Given the pathogenic roles of type I interferons (IFN-I) in SLE, this study investigated the effects and mechanisms of a mitochondria localization molecule ubiquitin specific peptidase 18 (USP18) preserving anti-IFN effects and isopeptidase activity on macrophage polarization. After observing USP18 induction in monocytes from SLE patients, we studied mouse bone marrow-derived macrophages and showed that USP18 deficiency increased M1signal (LPS + IFN-γ treatment)-induced macrophage polarization, and the effects involved the induction of glycolysis and mitochondrial respiration and the expression of several glycolysis-associated enzymes and molecules, such as hypoxia-inducible factor-1α. Moreover, the effects on mitochondrial activities, such as mitochondrial DNA release and mitochondrial reactive oxygen species production were observed. In contrast, the overexpression of USP18 inhibited M1signal-mediated and enhanced interleukin-4 (IL-4)-mediated polarization of macrophages and the related cellular events. Moreover, the levels of USP18 mRNA expression showed tendency of correlation with the expression of metabolic enzymes in monocytes from patients with SLE. We thus concluded that by preserving anti-IFN effect and downregulating M1 signaling, promoting USP18 activity may serve as a useful approach for SLE therapeutics.

Keywords:  Immunometabolism; Interferon; Macrophage polarization; Systemic lupus erythematosus; USP18

DOI:  https://doi.org/10.1016/j.clim.2024.110285
MedComm (2020). 2024 Jul;5(7): e617

Metabolic shifts during coffee consumption refresh the immune response: insight from comprehensive multiomics analysis.

Pinglang Ruan, Ming Yang, Xinyi Lv, Kai Shen, Yiran Chen, Hongli Li, Di Zhao, Jianhua Huang, Yang Xiao, Weijun Peng, Haijing Wu, Qianjin Lu.

  Coffee, a widely consumed beverage, has shown benefits for human health but lacks sufficient basic and clinical evidence to fully understand its impacts and mechanisms. Here, we conducted a cross-sectional observational study of coffee consumption and a 1-month clinical trial in humans. We found that coffee consumption significantly reshaped the immune system and metabolism, including reduced levels of inflammatory factors and a reduced frequency of senescent T cells. The frequency of senescent T cells and the levels of the senescence-associated secretory phenotype were lower in both long-term coffee consumers and new coffee consumers than in coffee nondrinking subjects, suggesting that coffee has anti-immunosenescence effects. Moreover, coffee consumption downregulated the activities of the The Janus kinase/signal transduction and activator of transcription (JAK/STAT) and mitogen-activated protein kinases (MAPK) signaling pathways and reduced systemic proinflammatory cytokine levels. Mechanistically, coffee-associated metabolites, such as 1-methylxanthine, 3-methylxanthine, paraxanthine, and ceramide, reduced the frequency of senescent CD4+CD57+ T cells in vitro. Finally, in vivo, coffee intake alleviated inflammation and immunosenescence in imiquimod-induced psoriasis-like mice. Our results provide novel evidence of the anti-inflammatory and anti-immunosenescence effects of coffee, suggesting that coffee consumption could be considered a healthy habit.

Keywords:  anti‐immunosenescence; anti‐inflammatory; coffee consumption; coffee‐related metabolism; immune remodeling

DOI:  https://doi.org/10.1002/mco2.617
Cell. 2024 Jun 11. pii: S0092-8674(24)00579-8. [Epub ahead of print]

A metabolomics pipeline highlights microbial metabolism in bloodstream infections.

Jared R Mayers, Jack Varon, Ruixuan R Zhou, Martin Daniel-Ivad, Courtney Beaulieu, Amrisha Bholse, Nathaniel R Glasser, Franziska M Lichtenauer, Julie Ng, Mayra Pinilla Vera, Curtis Huttenhower, Mark A Perrella, Clary B Clish, Sihai D Zhao, Rebecca M Baron, Emily P Balskus.

  The growth of antimicrobial resistance (AMR) highlights an urgent need to identify bacterial pathogenic functions that may be targets for clinical intervention. Although severe infections profoundly alter host metabolism, prior studies have largely ignored microbial metabolism in this context. Here, we describe an iterative, comparative metabolomics pipeline to uncover microbial metabolic features in the complex setting of a host and apply it to investigate gram-negative bloodstream infection (BSI) in patients. We find elevated levels of bacterially derived acetylated polyamines during BSI and discover the enzyme responsible for their production (SpeG). Blocking SpeG activity reduces bacterial proliferation and slows pathogenesis. Reduction of SpeG activity also enhances bacterial membrane permeability and increases intracellular antibiotic accumulation, allowing us to overcome AMR in culture and in vivo. This study highlights how tools to study pathogen metabolism in the natural context of infection can reveal and prioritize therapeutic strategies for addressing challenging infections.

Keywords:  N-acetylputrescine; antibiotic resistance; diacetylspermidine; metabolomics; polyamine/diamine acetyltransferase; polyamines; sepsis

DOI:  https://doi.org/10.1016/j.cell.2024.05.035
Cell Metab. 2024 Jun 12. pii: S1550-4131(24)00189-X. [Epub ahead of print]

Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer.

Yu Jiang, Yawen Wang, Guofeng Chen, Fei Sun, Qijing Wu, Qiong Huang, Dongqiang Zeng, Wenjun Qiu, Jiao Wang, Zhiqi Yao, Bishan Liang, Shaowei Li, Jianhua Wu, Na Huang, Yuanyuan Wang, Jingsong Chen, Xiaohui Zhai, Li Huang, Beibei Xu, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Wangjun Liao, Min Shi.

  Immune checkpoint blockade has led to breakthroughs in the treatment of advanced gastric cancer. However, the prominent heterogeneity in gastric cancer, notably the heterogeneity of the tumor microenvironment, highlights the idea that the antitumor response is a reflection of multifactorial interactions. Through transcriptomic analysis and dynamic plasma sample analysis, we identified a metabolic "face-off" mechanism within the tumor microenvironment, as shown by the dual prognostic significance of nicotinamide metabolism. Specifically, macrophages and fibroblasts expressing the rate-limiting enzymes nicotinamide phosphoribosyltransferase and nicotinamide N-methyltransferase, respectively, regulate the nicotinamide/1-methylnicotinamide ratio and CD8+ T cell function. Mechanistically, nicotinamide N-methyltransferase is transcriptionally activated by the NOTCH pathway transcription factor RBP-J and is further inhibited by macrophage-derived extracellular vesicles containing nicotinamide phosphoribosyltransferase via the SIRT1/NICD axis. Manipulating nicotinamide metabolism through autologous injection of extracellular vesicles restored CD8+ T cell cytotoxicity and the anti-PD-1 response in gastric cancer.

Keywords:  crosstalk; face-off; fibroblast; gastric cancer; immune checkpoint blockade; macrophage; nicotinamide metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cmet.2024.05.013
Mucosal Immunol. 2024 Jun 18. pii: S1933-0219(24)00058-8. [Epub ahead of print]

Cell type-specific modulation of metabolic, immune-regulatory and anti-microbial pathways by CD101.

Marius Wrage, Tim Holland, Björn Nüse, Johanna Kaltwasser, Jessica Fröhlich, Harald Arnold, Claudia Gießler, Cindy Flamann, Heiko Bruns, Johannes Berges, Christoph Daniel, Markus H Hoffmann, Chakkumkal Anish, Peter H Seeberger, Christian Bogdan, Katja Dettmer, Manfred Rauh, Jochen Mattner.

  T lymphocytes and myeloid cells express the Ig-like glycoprotein CD101, notably in the gut. Here, we investigated the cell-specific functions of CD101 during DSS-induced colitis and Salmonella enterica Typhimurium infection. Similar to conventional CD101-/- mice, animals with a Treg-specific Cd101 deletion developed more severe intestinal pathology than littermate controls in both models. While the accumulation of Th1 cytokines in a CD101-deficient environment entertained DSS-induced colitis, it impeded the replication of Salmonella as revealed by studying CD101-/- x IFN- γ-/- mice. Moreover, CD101-expressing neutrophils were capable to restrain Salmonella infection in vitro and in vivo. Both cell-intrinsic and -extrinsic mechanisms of CD101 contributed to the control of bacterial growth and spreading. The CD101-dependent containment of Salmonella infection required the expression of Irg-1 and Nox2 and the production of itaconate and reactive oxygen species. The level of intestinal microbial antigens in the sera of IBD patients correlated inversely with the expression of CD101 on myeloid cells, which is in line with the suppression of CD101 seen in mice following DSS application or Salmonella infection. Thus, depending on the experimental or clinical setting, CD101 helps to limit inflammatory insults or bacterial infections due to cell type-specific modulation of metabolic, immune-regulatory and anti-microbial pathways.

Keywords:  CD101; IBD; Salmonella infection; colitis; intestinal metabolome

DOI:  https://doi.org/10.1016/j.mucimm.2024.06.004
Int Immunol. 2024 Jun 13. pii: dxae035. [Epub ahead of print]

The tryptophan metabolic pathway of the microbiome and host cells in health and disease.

Kentaro Miyamoto, Tomohisa Sujino, Takanori Kanai.

  The intricate and dynamic tryptophan (Trp) metabolic pathway in both the microbiome and host cells highlights its profound implications for health and disease. This pathway involves complex interactions between host cellular and bacteria processes, producing bioactive compounds such as 5-Hydroxytryptamine (5-HT) and kynurenine (Kyn) derivatives. Immune responses to Trp metabolites through specific receptors have been explored, highlighting the role of the aryl hydrocarbon receptor (AHR) in inflammation modulation. Dysregulation of this pathway is implicated in various diseases, such as Alzheimer's and Parkinson's diseases, mood disorders, neuronal diseases, autoimmune diseases such as multiple sclerosis (MS), and cancer. In this article, we describe the impact of the 5-HT, Trp, indole, and Trp metabolites on health and disease. Further, we review the impact of microbiome-derived Trp metabolites that affect immune responses and contribute to maintaining homeostasis, especially in an experimental autoimmune encephalitis (EAE) model of MS.

Keywords:  Brain disease; GPR35; Immune cell; Kynurenic acid

DOI:  https://doi.org/10.1093/intimm/dxae035
Mol Oncol. 2024 Jun 13.

Immunometabolism unveiled: Pioneering breakthroughs in cancer therapeutics.

Eric Eldering, Jean-Ehrland Ricci.

The field of immunometabolism cannot be considered 'emerging' anymore; it is at the moment one of the most active and rapidly evolving areas of biomedical research. Its hottest zone is cancer immunometabolism. This is partly due to the clinical application of immunotherapy, with either antibodies (checkpoint blockade) or cellular therapies (e.g., CAR-T cells). In addition, the proliferating tumor cells create a nutrient-deprived microenvironment that impairs the metabolic fitness and functionality of infiltrating immune cells such as T cells, NK cells, and macrophages. The key concepts are bidirectional metabolic signaling, plus the conviction that a better understanding of these processes will improve current immunotherapies, and foster new tools and targets for treatment. This collection of reviews will address various exciting aspects from junior and established scientists in the field.

DOI: https://doi.org/10.1002/1878-0261.13670
Sci Immunol. 2024 Jun 21. 9(96): eadi8954

MAIT cells monitor intestinal dysbiosis and contribute to host protection during colitis.

Yara El Morr, Mariela Fürstenheim, Martin Mestdagh, Katarzyna Franciszkiewicz, Marion Salou, Claire Morvan, Thierry Dupré, Alexey Vorobev, Bakhos Jneid, Virginie Premel, Aurélie Darbois, Laetitia Perrin, Stanislas Mondot, Ludovic Colombeau, Hélène Bugaut, Anastasia du Halgouet, Sophie Richon, Emanuele Procopio, Mathieu Maurin, Catherine Philippe, Raphael Rodriguez, Olivier Lantz, François Legoux.

Intestinal inflammation shifts microbiota composition and metabolism. How the host monitors and responds to such changes remains unclear. Here, we describe a protective mechanism by which mucosal-associated invariant T (MAIT) cells detect microbiota metabolites produced upon intestinal inflammation and promote tissue repair. At steady state, MAIT ligands derived from the riboflavin biosynthesis pathway were produced by aerotolerant bacteria residing in the colonic mucosa. Experimental colitis triggered luminal expansion of riboflavin-producing bacteria, leading to increased production of MAIT ligands. Modulation of intestinal oxygen levels suggested a role for oxygen in inducing MAIT ligand production. MAIT ligands produced in the colon rapidly crossed the intestinal barrier and activated MAIT cells, which expressed tissue-repair genes and produced barrier-promoting mediators during colitis. Mice lacking MAIT cells were more susceptible to colitis and colitis-driven colorectal cancer. Thus, MAIT cells are sensitive to a bacterial metabolic pathway indicative of intestinal inflammation.

DOI: https://doi.org/10.1126/sciimmunol.adi8954
Toxicol Sci. 2024 Jun 19. pii: kfae081. [Epub ahead of print]

Transcriptional profiling of lung macrophages following ozone exposure in mice identifies signaling pathways regulating immunometabolic activation.

L Cody Smith, Helen Abramova, Kinal Vayas, Jessica Rodriguez, Benjamin Gelfand-Titiyevksiy, Troy Roepke, Jeffrey D Laskin, Andrew J Gow, Debra L Laskin.

  Macrophages play a key role in ozone-induced lung injury by regulating both the initiation and resolution of inflammation. These distinct activities are mediated by pro-inflammatory and anti-inflammatory/proresolution macrophages which sequentially accumulate in injured tissues. Macrophage activation is dependent, in part, on intracellular metabolism. Herein, we used RNA-sequencing (seq) to identify signaling pathways regulating macrophage immunometabolic activity following exposure of mice to ozone (0.8 ppm, 3 hr) or air control. Analysis of lung macrophages using an Agilent Seahorse showed that inhalation of ozone increased macrophage glycolytic activity and oxidative phosphorylation at 24 and 72 hr post exposure. An increase in the percentage of macrophages in S phase of the cell cycle was observed 24 hr post ozone. RNA-seq revealed significant enrichment of pathways involved in innate immune signaling and cytokine production among differentially expressed genes at both 24 and 72 hr after ozone, while pathways involved in cell cycle regulation were upregulated at 24 hr and intracellular metabolism at 72 hr. An interaction network analysis identified tumor suppressor 53 (TP53), E2F family of transcription factors (E2Fs), Cyclin Dependent Kinase Inhibitor 1A (CDKN1a/p21), and Cyclin D1 (CCND1) as upstream regulators of cell cycle pathways at 24 hr and TP53, nuclear receptor subfamily 4 group a member 1 (NR4A1/Nur77), and estrogen receptor alpha (ESR1/ERα) as central upstream regulators of mitochondrial respiration pathways at 72 hr. To assess whether ERα regulates metabolic activity, we used ERα-/-- mice. In both air and ozone exposed mice, loss of ERα resulted in increases in glycolytic capacity and glycolytic reserve in lung macrophages with no effect on mitochondrial oxidative phosphorylation. Taken together, these results highlight the complex interaction between cell cycle, intracellular metabolism, and macrophage activation which may be important in the initiation and resolution of inflammation following ozone exposure.

Keywords:  RNA-seq; cell cycle; intracellular metabolism; macrophage; ozone

DOI:  https://doi.org/10.1093/toxsci/kfae081
Cell Death Dis. 2024 Jun 19. 15(6): 430

Hippo kinases Mst1 and Mst2 maintain NK cell homeostasis by orchestrating metabolic state and transcriptional activity.

Peiran Feng, Liang Luo, Quanli Yang, Wanqing Meng, Zerong Guan, Zhizhong Li, Guodong Sun, Zhongjun Dong, Meixiang Yang.

Natural killer (NK) cells play a crucial role in immune response against viral infections and tumors. However, further investigation is needed to better understand the key molecules responsible for determining the fate and function of NK cells. In this study, we made an important discovery regarding the involvement of the Hippo kinases Mst1 and Mst2 as novel regulators in maintaining mouse NK cell homeostasis. The presence of high Mst1 and Mst2 (Mst1/2) activity in NK cells is essential for their proper development, survival and function in a canonical Hippo signaling independent mode. Mechanistically, Mst1/2 induce cellular quiescence by regulating the processes of proliferation and mitochondrial metabolism, thereby ensuring the development and survival of NK cells. Furthermore, Mst1/2 effectively sense IL-15 signaling and facilitate the activation of pSTAT3-TCF1, which contributes to NK cell homeostasis. Overall, our investigation highlights the crucial role of Mst1/2 as key regulators in metabolic reprogramming and transcriptional regulation for mouse NK cell survival and function, emphasizing the significance of cellular quiescence during NK cell development and functional maturation.

DOI: https://doi.org/10.1038/s41419-024-06828-x
Int J Mol Sci. 2024 May 21. pii: 5584. [Epub ahead of print]25(11):

The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma.

Nan Hu, Haiyang Li, Changcheng Tao, Ting Xiao, Weiqi Rong.

  As one of the emerging hallmarks of tumorigenesis and tumor progression, metabolic remodeling is common in the tumor microenvironment. Hepatocellular carcinoma (HCC) is the third leading cause of global tumor-related mortality, causing a series of metabolic alterations in response to nutrient availability and consumption to fulfill the demands of biosynthesis and carcinogenesis. Despite the efficacy of immunotherapy in treating HCC, the response rate remains unsatisfactory. Recently, research has focused on metabolic reprogramming and its effects on the immune state of the tumor microenvironment, and immune response rate. In this review, we delineate the metabolic reprogramming observed in HCC and its influence on the tumor immune microenvironment. We discuss strategies aimed at enhancing response rates and overcoming immune resistance through metabolic interventions, focusing on targeting glucose, lipid, or amino acid metabolism, as well as systemic regulation.

Keywords:  hepatocellular carcinoma; immunotherapy; metabolic intervention; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25115584
Immunity. 2024 Jun 13. pii: S1074-7613(24)00276-0. [Epub ahead of print]

High recallability of memory B cells requires ZFP318-dependent transcriptional regulation of mitochondrial function.

Yifeng Wang, Wen Shao, Xin Liu, Qingtai Liang, Jiaqi Lei, Wenjuan Shi, Miao Mei, Ying Li, Xu Tan, Guocan Yu, Li Yu, Linqi Zhang, Hai Qi.

  Expression of the transcriptional regulator ZFP318 is induced in germinal center (GC)-exiting memory B cell precursors and memory B cells (MBCs). Using a conditional ZFP318 fluorescence reporter that also enables ablation of ZFP318-expressing cells, we found that ZFP318-expressing MBCs were highly enriched with GC-derived cells. Although ZFP318-expressing MBCs constituted only a minority of the antigen-specific MBC compartment, their ablation severely impaired recall responses. Deletion of Zfp318 did not alter the magnitude of primary responses but markedly reduced MBC participation in recall. CD40 ligation promoted Zfp318 expression, whereas B cell receptor (BCR) signaling was inhibitory. Enforced ZFP318 expression enhanced recall performance of MBCs that otherwise responded poorly. ZFP318-deficient MBCs expressed less mitochondrial genes, had structurally compromised mitochondria, and were susceptible to reactivation-induced cell death. The abundance of ZFP318-expressing MBCs, instead of the number of antigen-specific MBCs, correlated with the potency of prime-boost vaccination. Therefore, ZFP318 controls the MBC recallability and represents a quality checkpoint of humoral immune memory.

Keywords:  ZFP318; ZNF318; antibody response; germinal center; immunological memory; memory B cells; plasma cells; prime-boost vaccine; vaccine

DOI:  https://doi.org/10.1016/j.immuni.2024.05.022
Lupus. 2024 Jun 17. 9612033241260334

Associations between TCA cycle plasma metabolites and fatigue in black females with systemic lupus erythematosus: An untargeted metabolomics pilot study.

Laura P Kimble, Arezou Khosroshahi, Glenna S Brewster, Sandra B Dunbar, Dylan Ryan, Nicole Carlson, Ron Eldridge, Madelyn Houser, Elizabeth Corwin.

   OBJECTIVE: In this pilot study, we used untargeted metabolomics to identify biochemical mechanisms or biomarkers potentially underlying SLE-related fatigue.
METHODS: Metabolon conducted untargeted metabolomic plasma profiling using ultrahigh performance liquid chromatography/tandem mass spectrometry on plasma samples of 23 Black females with systemic lupus erythematosus (SLE) and 21 no SLE controls. Fatigue phenotypes of general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation were measured with the reliable and valid Multidimensional Fatigue Inventory (MFI).
RESULTS: A total of 290 metabolites were significantly different between the SLE and no SLE groups, encompassing metabolites related to glycolysis, TCA cycle activity, heme catabolism, branched chain amino acids, fatty acid metabolism, and steroids. Within the SLE group, controlling for age and co-morbidities, TCA cycle metabolites of alpha-ketoglutarate (AKG) and succinate were statistically significantly associated (p < .05) with physical and general fatigue.
CONCLUSION: While pervasive perturbations in the entire TCA cycle have been implicated as a potential mechanism for fatigue, our results suggest individual metabolites of AKG and succinate may be potential biomarkers or targets of intervention for fatigue symptom management in SLE. Additionally, perturbations in heme metabolism in the SLE group provide additional insights into mechanisms that promote systemic inflammation.

Keywords:  Systemic lupus erythematosus; TCA cycle; bioenergetics; fatigue; metabolomics; patient-reported outcomes

DOI:  https://doi.org/10.1177/09612033241260334
Cell Commun Signal. 2024 Jun 19. 22(1): 336

SHH induces macrophage oxidative phosphorylation and efferocytosis to promote scar formation.

Julei Zhang, Zeliang He, Chenlu Xiong, Yuanyuan Yao, Chengliang Zhang, Wende Yao, Sihan Yang, Xiaodong Li, Yan Han.

  Excessive scar formation such as hypertrophic scars and keloids, resulting from trauma or surgical procedures, present a widespread concern for causing disfigurement, discomfort, and functional limitations. Macrophages play pivotal roles in maintaining tissue homeostasis, orchestrating tissue development, repair, and immune responses, and its transition of function and phenotype plays a critical role in regulating the balance between inflammation and tissue regeneration, which is central to cutaneous scar formation. Recent evidence suggests the involvement of Sonic Hedgehog (SHH) in the induction of anti-inflammatory M2-like macrophage phenotypes within tumor microenvironments. In our study, we observed increased SHH expression in human hypertrophic scars, prompting an investigation into its influence on macrophage polarization, efferocytosis, and cutaneous scar formation. Our findings reveal that SHH can enhance oxidative phosphorylation (OXPHOS) in macrophages, augment macrophage efferocytosis, and promote M2 polarization, finally contributing to the progression of cutaneous scar formation. Notably, targeting SHH signaling with vismodegib exhibited promising potential in mitigating scar formation by reversing the effects of enhanced OXPHOS and M2 polarization in macrophages. In conclusion, this study underscores the critical roles of macrophage metabolism, particularly OXPHOS, efferocytosis and SHH signaling in cutaneous scar formation. Understanding these mechanisms provides new avenues for potential interventions and scar prevention strategies.

Keywords:  Fibrosis; Macrophage; Scar formation; Sonic hedgehog; Vismodegib

DOI:  https://doi.org/10.1186/s12964-024-01692-w
Cell Rep. 2024 Jun 18. pii: S2211-1247(24)00698-3. [Epub ahead of print]43(7): 114370

A pre-vaccination immune metabolic interplay determines the protective antibody response to a dengue virus vaccine.

Adam-Nicolas Pelletier, Gabriela Pacheco Sanchez, Abdullah Izmirly, Mark Watson, Tiziana Di Pucchio, Karina Inacio Carvalho, Abdelali Filali-Mouhim, Eustache Paramithiotis, Maria do Carmo S T Timenetsky, Alexander Roberto Precioso, Jorge Kalil, Michael S Diamond, Elias K Haddad, Esper G Kallas, Rafick Pierre Sekaly.

  Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-β signaling expressed by CD68low monocytes, and the metabolites phosphatidylcholine (PC) and phosphatidylethanolamine (PE) positively correlate with broadly neutralizing antibody responses against DENV. In contrast, expression of pro-inflammatory pathways and cytokines (IFN and IL-1) in CD68hi monocytes and primary and secondary bile acids negatively correlates with broad DENV-specific antibody responses. Induction of TGF-β and IFNs is done respectively by PC/PE and bile acids in CD68low and CD68hi monocytes. The inhibition of viral sensing by PC/PE-induced TGF-β is confirmed in vitro. Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine.

Keywords:  CP: Immunology; bile acids; dengue; immunology; systems biology; vaccine

DOI:  https://doi.org/10.1016/j.celrep.2024.114370