bims-imicid 2023-04-02 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–04–02
38 papers selected by
Dylan Ryan, University of Cambridge

Prostaglandin E 2 controls the metabolic adaptation of T cells to the intestinal microenvironment.
Early infiltration of innate immune cells to the liver depletes HNF4a and promotes extra-hepatic carcinogenesis.
Resting natural killer cell homeostasis relies on tryptophan/NAD+ metabolism and HIF-1α.
Decoding the crosstalk between mevalonate metabolism and T cell function.
Sirtuin-dependent metabolic and epigenetic regulation of macrophages during tuberculosis.
The role of metabolic reprogramming of tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment.
Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes.
Fatty acid metabolism and radiation-induced anti-tumor immunity.
Metabolic Reprogramming and Its Regulatory Mechanism in Sepsis-Mediated Inflammation.
Metabolic regulation of dendritic cell activation and immune function during inflammation.
P2RX7 signaling drives the differentiation of Th1 cells through metabolic reprogramming for aerobic glycolysis.
MicroRNA-124 Enhances T Cells Functions by Manipulating the Lactic Acid Metabolism of Tumor Cells.
2-DG Re-Normalized IFN-γ Production in T Cells Excluding TEMRA Cells from Patients with Aplastic Anemia.
Ensemble-based genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer.
Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells.
Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function.
Microbial metabolites and immunotherapy: Basic rationale and clinical indications.
Mitochondrial Methionyl-tRNA Formyltransferase Deficiency Alleviates Metaflammation by Modulating Mitochondrial Activity in Mice.
VMP1 prevents Ca2+ overload in endoplasmic reticulum and maintains naive T cell survival.
Quercetin Reprograms Immunometabolism of Macrophages via the SIRT1/PGC-1α Signaling Pathway to Ameliorate Lipopolysaccharide-Induced Oxidative Damage.
An immunometabolism subtyping system identifies S100A9+ macrophage as an immune therapeutic target in colorectal cancer based on multiomics analysis.
Eriocitrin attenuates sepsis-induced acute lung injury in mice by regulating MKP1/MAPK pathway mediated-glycolysis.
Development of an Untargeted Metabolomics Strategy to Study the Metabolic Rewiring of Dendritic Cells upon Lipopolysaccharide Activation.
A single-cell atlas reveals shared and distinct immune responses and metabolic profiles in SARS-CoV-2 and HIV-1 infections.
Cholesterol suppresses human iTreg differentiation and nTreg function through mitochondria-related mechanisms.
Analysis of temporal metabolic rewiring for human respiratory syncytial virus infection by integrating metabolomics and proteomics.
Putrescine supplementation shifts macrophage L-arginine metabolism related-genes reducing Leishmania amazonensis infection.
Hypercapnia alters mitochondrial gene expression and acylcarnitine production in monocytes.
The diverse roles of macrophages in metabolic inflammation and its resolution.
S-allylmercaptocysteine promotes anti-tumor immunity by suppressing PD-L1 expression.
Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages.
Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to control local Peyer's patch development.
Mitochondrial pyruvate dehydrogenase kinases contribute to platelet function and thrombosis in mice by regulating aerobic glycolysis.
Association between Tryptophan Metabolism and Inflammatory Biomarkers in Dairy Cows with Ketosis.
Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T-cells.
Involvement of the secosteroid vitamin D in autoimmune rheumatic diseases and COVID-19.
Spermidine ameliorates colitis via induction of anti-inflammatory macrophages and prevention of intestinal dysbiosis.
d-mannose blocks the interaction between keratinocytes and Th17 cells to alleviate psoriasis by inhibiting HIF-1α/CCL20 in mice.

bioRxiv. 2023 Mar 15. pii: 2023.03.13.532431. [Epub ahead of print]

Prostaglandin E 2 controls the metabolic adaptation of T cells to the intestinal microenvironment.

Matteo Villa, David E Sanin, Petya Apostolova, Mauro Corrado, Agnieszka M Kabat, Carmine Cristinzio, Annamaria Regina, Gustavo E Carrizo, Nisha Rana, Michal A Stanczak, Francesc Baixauli, Katarzyna M Grzes, Jovana Cupovic, Francesca Solagna, Alexandra Hackl, Anna-Maria Globig, Fabian Hässler, Daniel J Puleston, Beth Kelly, Nina Cabezas-Wallscheid, Peter Hasselblatt, Bertram Bengsch, Robert Zeiser, Sagar, Joerg M Buescher, Edward J Pearce, Erika L Pearce.

Immune cells must adapt to different environments during the course of an immune response. We studied the adaptation of CD8 + T cells to the intestinal microenvironment and how this process shapes their residency in the gut. CD8 + T cells progressively remodel their transcriptome and surface phenotype as they acquire gut residency, and downregulate expression of mitochondrial genes. Human and mouse gut-resident CD8 + T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We found that the intestinal microenvironment is rich in prostaglandin E 2 (PGE 2 ), which drives mitochondrial depolarization in CD8 + T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE 2 sensing promotes CD8 + T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell population. Thus, a PGE 2 -autophagy-glutathione axis defines the metabolic adaptation of CD8 + T cells to the intestinal microenvironment, to ultimately influence the T cell pool.

DOI: https://doi.org/10.1101/2023.03.13.532431
Cancer Discov. 2023 Mar 27. pii: CD-22-1062. [Epub ahead of print]

Early infiltration of innate immune cells to the liver depletes HNF4a and promotes extra-hepatic carcinogenesis.

Omer Goldman, Lital N Adler, Emma Hajaj, Tommaso Croese, Naama Darzi, Sivan Galai, Hila Tishler, Yarden Ariav, Dor Lavie, Liat Fellus-Alyagor, Roni Oren, Yuri Kuznetsov, Eyal David, Rami Jaschek, Chani Stossel, Oded Singer, Sergey Malitsky, Renana Barak, Rony Seger, Neta Erez, Ido Amit, Amos Tanay, Ann Saada, Talia Golan, Tamar Rubinek, Joo Sang Lee, Shay Ben-Shachar, Ido Wolf, Ayelet Erez.

Multiple studies identified metabolic changes within the tumor and its microenvironment during carcinogenesis. Yet, the mechanisms by which tumors affect the host metabolism are unclear. We find that systemic inflammation induced by the cancer leads to liver infiltration of myeloid cells at early extrahepatic carcinogenesis. The infiltrating immune cells via IL-6-pSTAT3 immune-hepatocyte crosstalk cause the depletion of a master metabolic regulator, HNF4a, consequently leading to systemic metabolic changes that promote breast and pancreatic cancer proliferation and a worse outcome. Preserving HNF4 levels maintains liver metabolism and restricts carcinogenesis. Standard liver biochemical tests can identify early metabolic changes and predict patients' outcomes and weight loss. Thus, the tumor induces early metabolic changes in its macro-environment with diagnostic and potentially therapeutic implications for the host.

DOI: https://doi.org/10.1158/2159-8290.CD-22-1062
EMBO Rep. 2023 Mar 29. e56156

Resting natural killer cell homeostasis relies on tryptophan/NAD+ metabolism and HIF-1α.

Abigaelle Pelletier, Eric Nelius, Zheng Fan, Ekaterina Khatchatourova, Abdiel Alvarado-Diaz, Jingyi He, Ewelina Krzywinska, Michal Sobecki, Shunmugam Nagarajan, Yann Kerdiles, Joachim Fandrey, Dagmar Gotthardt, Veronika Sexl, Katrien de Bock, Christian Stockmann.

  Natural killer (NK) cells are forced to cope with different oxygen environments even under resting conditions. The adaptation to low oxygen is regulated by oxygen-sensitive transcription factors, the hypoxia-inducible factors (HIFs). The function of HIFs for NK cell activation and metabolic rewiring remains controversial. Activated NK cells are predominantly glycolytic, but the metabolic programs that ensure the maintenance of resting NK cells are enigmatic. By combining in situ metabolomic and transcriptomic analyses in resting murine NK cells, our study defines HIF-1α as a regulator of tryptophan metabolism and cellular nicotinamide adenine dinucleotide (NAD+ ) levels. The HIF-1α/NAD+ axis prevents ROS production during oxidative phosphorylation (OxPhos) and thereby blocks DNA damage and NK cell apoptosis under steady-state conditions. In contrast, in activated NK cells under hypoxia, HIF-1α is required for glycolysis, and forced HIF-1α expression boosts glycolysis and NK cell performance in vitro and in vivo. Our data highlight two distinct pathways by which HIF-1α interferes with NK cell metabolism. While HIF-1α-driven glycolysis is essential for NK cell activation, resting NK cell homeostasis relies on HIF-1α-dependent tryptophan/NAD+ metabolism.

Keywords:  HIF; immunometabolism; natural killer cells; nicotinamide adenine dinucleotide; tryptophan

DOI:  https://doi.org/10.15252/embr.202256156
Immunol Rev. 2023 Mar 31.

Decoding the crosstalk between mevalonate metabolism and T cell function.

Kelly T Kennewick, Steven J Bensinger.

  The mevalonate pathway is an essential metabolic pathway in T cells regulating development, proliferation, survival, differentiation, and effector functions. The mevalonate pathway is a complex, branched pathway composed of many enzymes that ultimately generate cholesterol and nonsterol isoprenoids. T cells must tightly control metabolic flux through the branches of the mevalonate pathway to ensure sufficient isoprenoids and cholesterol are available to meet cellular demands. Unbalanced metabolite flux through the sterol or the nonsterol isoprenoid branch is metabolically inefficient and can have deleterious consequences for T cell fate and function. Accordingly, there is tight regulatory control over metabolic flux through the branches of this essential lipid synthetic pathway. In this review we provide an overview of how the branches of the mevalonate pathway are regulated in T cells and discuss our current understanding of the relationship between mevalonate metabolism, cholesterol homeostasis and T cell function.

Keywords:  T cells; cholesterol; isoprenoids; mevalonate pathway; statins

DOI:  https://doi.org/10.1111/imr.13200
Front Immunol. 2023 ;14 1121495

Sirtuin-dependent metabolic and epigenetic regulation of macrophages during tuberculosis.

Kangling Zhang, Mark L Sowers, Ellie I Cherryhomes, Vipul K Singh, Abhishek Mishra, Blanca I Restrepo, Arshad Khan, Chinnaswamy Jagannath.

  Macrophages are the preeminent phagocytic cells which control multiple infections. Tuberculosis a leading cause of death in mankind and the causative organism Mycobacterium tuberculosis (MTB) infects and persists in macrophages. Macrophages use reactive oxygen and nitrogen species (ROS/RNS) and autophagy to kill and degrade microbes including MTB. Glucose metabolism regulates the macrophage-mediated antimicrobial mechanisms. Whereas glucose is essential for the growth of cells in immune cells, glucose metabolism and its downsteam metabolic pathways generate key mediators which are essential co-substrates for post-translational modifications of histone proteins, which in turn, epigenetically regulate gene expression. Herein, we describe the role of sirtuins which are NAD+-dependent histone histone/protein deacetylases during the epigenetic regulation of autophagy, the production of ROS/RNS, acetyl-CoA, NAD+, and S-adenosine methionine (SAM), and illustrate the cross-talk between immunometabolism and epigenetics on macrophage activation. We highlight sirtuins as emerging therapeutic targets for modifying immunometabolism to alter macrophage phenotype and antimicrobial function.

Keywords:  SIRTUIN; autophagy; glycolysis; histone modifications; human macrophages; metabolism

DOI:  https://doi.org/10.3389/fimmu.2023.1121495
Biomed Pharmacother. 2023 May;pii: S0753-3322(23)00292-5. [Epub ahead of print]161 114504

The role of metabolic reprogramming of tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment.

Lunxu Li, Yu Tian.

  Macrophages are potent immune effector cells in innate immunity and exert dual-effects in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) make up a significant portion of TME immune cells. Similar to M1/M2 macrophages, TAMs are also highly plastic, and their functions are regulated by cytokines, chemokines and other factors in the TME. The metabolic changes in TAMs are significantly associated with polarization towards a protumour or antitumour phenotype. The metabolites generated via TAM metabolic reprogramming in turn promote tumor progression and immune tolerance. In this review, we explore the metabolic reprogramming of TAMs in terms of energy, amino acid and fatty acid metabolism and the potential roles of these changes in immune suppression.

Keywords:  Immunosuppression; Metabolism; Tumor microenvironment; Tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.biopha.2023.114504
Front Immunol. 2023 ;14 1121565

Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes.

Priyanka Maridhi Nanjireddy, Scott H Olejniczak, Nataliya Prokopenko Buxbaum.

  Genetically engineered chimeric antigen receptor (CAR) T cells can cure patients with cancers that are refractory to standard therapeutic approaches. To date, adoptive cell therapies have been less effective against solid tumors, largely due to impaired homing and function of immune cells within the immunosuppressive tumor microenvironment (TME). Cellular metabolism plays a key role in T cell function and survival and is amenable to manipulation. This manuscript provides an overview of known aspects of CAR T metabolism and describes potential approaches to manipulate metabolic features of CAR T to yield better anti-tumor responses. Distinct T cell phenotypes that are linked to cellular metabolism profiles are associated with improved anti-tumor responses. Several steps within the CAR T manufacture process are amenable to interventions that can generate and maintain favorable intracellular metabolism phenotypes. For example, co-stimulatory signaling is executed through metabolic rewiring. Use of metabolic regulators during CAR T expansion or systemically in the patient following adoptive transfer are described as potential approaches to generate and maintain metabolic states that can confer improved in vivo T cell function and persistence. Cytokine and nutrient selection during the expansion process can be tailored to yield CAR T products with more favorable metabolic features. In summary, improved understanding of CAR T cellular metabolism and its manipulations have the potential to guide the development of more effective adoptive cell therapies.

Keywords:  CAR T cell; adoptive cell therapy (ACT); cell metabolism; immunometabolism; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1121565
Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(23)00003-5. [Epub ahead of print]376 121-141

Fatty acid metabolism and radiation-induced anti-tumor immunity.

Mara De Martino, Camille Daviaud, Edgar Hajjar, Claire Vanpouille-Box.

  Fatty acid metabolic reprogramming has emerged as a major regulator of anti-tumor immune responses with large body of evidence that demonstrate its ability to impact the differentiation and function of immune cells. Therefore, depending on the metabolic cues that stem in the tumor microenvironment, the tumor fatty acid metabolism can tilt the balance of inflammatory signals to either promote or impair anti-tumor immune responses. Oxidative stressors such as reactive oxygen species generated from radiation therapy can rewire the tumor energy supply, suggesting that radiation therapy can further perturb the energy metabolism of a tumor by promoting fatty acid production. In this review, we critically discuss the network of fatty acid metabolism and how it regulates immune response especially in the context of radiation therapy.

Keywords:  Fatty acid metabolism; Immunostimulation; Immunosuppression; Nucleic acid sensing; Radiation therapy; Radioresistance

DOI:  https://doi.org/10.1016/bs.ircmb.2023.01.003
J Inflamm Res. 2023 ;16 1195-1207

Metabolic Reprogramming and Its Regulatory Mechanism in Sepsis-Mediated Inflammation.

Wenzhang Liu, Tianyi Liu, Yongjun Zheng, Zhaofan Xia.

  Sepsis is a systemic inflammatory disease caused by an infection that can lead to multiple organ failure. Sepsis alters energy metabolism, leading to metabolic reprogramming of immune cells, which consequently disrupts innate and adaptive immune responses, triggering hyperinflammation and immunosuppression. This review summarizes metabolic reprogramming and its regulatory mechanism in sepsis-induced hyperinflammation and immunosuppression, highlights the significance and intricacies of immune cell metabolic reprogramming, and emphasizes the pivotal role of mitochondria in metabolic regulation and treatment of sepsis. This review provides an up-to-date overview of the relevant literature to inform future research directions in understanding the regulation of sepsis immunometabolism. Metabolic reprogramming has great promise as a new target for sepsis treatment in the future.

Keywords:  hyperinflammation; immune cell; immunometabolism; immunosuppression; mitochondria

DOI:  https://doi.org/10.2147/JIR.S403778
Front Immunol. 2023 ;14 1140749

Metabolic regulation of dendritic cell activation and immune function during inflammation.

Lili Wu, Ziqi Yan, Yiyang Jiang, Yingyi Chen, Juan Du, Lijia Guo, Junji Xu, Zhenhua Luo, Yi Liu.

  Dendritic cells (DCs) are antigen-presenting cells that bridge innate and adaptive immune responses. Multiple cell types, including DCs, rely on cellular metabolism to determine their fate. DCs substantially alter cellular metabolic pathways during activation, such as oxidative phosphorylation, glycolysis, fatty acid and amino acid metabolism, which have crucial implications for their functionality. In this review, we summarize and discuss recent progress in DC metabolic studies, focusing on how metabolic reprogramming influences DC activation and functionality and the potential metabolic differences among DC subsets. Improving the understanding of the relationship between DC biology and metabolic regulation may provide promising therapeutic targets for immune-mediated inflammatory diseases.

Keywords:  cellular metabolism; dendritic cells (DC); glycolysis; inflammation; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2023.1140749
Front Immunol. 2023 ;14 1140426

P2RX7 signaling drives the differentiation of Th1 cells through metabolic reprogramming for aerobic glycolysis.

Érika Machado de Salles, Paulo Lisboa Raeder, Claudia Blanes Angeli, Verônica Feijoli Santiago, Cristiane Naffah de Souza, Theresa Ramalho, Niels Olsen Saraiva Câmara, Giuseppe Palmisano, José Maria Álvarez, Maria Regina D'Império Lima.

   Introduction: This study provides evidence of how Th1 cell metabolism is modulated by the purinergic receptor P2X7 (P2RX7), a cation cannel activated by high extracellular concentrations of adenosine triphosphate (ATP).
Methods: In vivo analysis was performed in the Plasmodium chabaudi model of malaria in view of the great relevance of this infectious disease for human health, as well as the availability of data concerning Th1/Tfh differentiation.
Results: We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-conditioned CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, in vitro ATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7.
Conclusion: These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response.

Keywords:  CD4 T cell; P2X7 signaling; Th1 cell differentiation; aerobic glycolysis; malaria

DOI:  https://doi.org/10.3389/fimmu.2023.1140426
Iran J Allergy Asthma Immunol. 2023 Feb 20. 22(1): 62-71

MicroRNA-124 Enhances T Cells Functions by Manipulating the Lactic Acid Metabolism of Tumor Cells.

Mohammad Khakpoor-Koosheh, Hosein Rostamian, Elham Masoumi, Leila Jafarzadeh, Keyvan Fallah-Mehrjardi, Mohammad Javad Tavassolifar, Farshid Noorbakhsh, Hamid Reza Mirzaei, Jamshid Hadjati, Nima Rezaei.

  High production of lactic acid is a common feature of various tumors. Lactic acid is an immunosuppressive molecule with crucial roles in tumor cells' immune escape, which could largely be attributed to its negative effects on the T cells present in the tumor microenvironment (TME). Strategies that decrease the glycolysis rate of tumor cells could enhance immunosurveillance and limit tumor growth. Pyruvate kinase M2 (PKM2) is a key enzyme in the glycolysis pathway, and it plays a vital role in lactic acid buildup in the TME. MicroRNA (miR)-124 has been shown to be able to decrease tumor cell lactic acid synthesis indirectly by reducing PKM2 levels. In this study, we first overexpressed miR-124 in the tumor cells and evaluated its effects on the PKM2 expression and lactic acid production of the tumor cells using quantitative real-time polymerase chain reaction (qRT-PCR) and spectrophotometry, respectively. Then, we cocultured miR-124-treated tumor cells with T cells to investigate the effects of miR-124 overexpression on T cell proliferation, cytokine production, and apoptosis. Our results demonstrated that miR-124 overexpression could significantly reduce the amount of lactic acid produced by tumor cells by manipulating their glucose metabolism, which led to the augmented proliferation and IFN-γ production of T cells. Moreover, it rescued T cells from lactic acid-induced apoptosis. Our data suggest that lactic acid is a hindering factor for T-cell-based immunotherapies; however, manipulating tumor cells' metabolism via miR-124 could be a promising way to improve antitumor responses of T cells.

Keywords:  Lactic acid; MIRN124 microRNA, human; Metabolism; T-lymphocytes; Tumor microenvironment

DOI:  https://doi.org/10.18502/ijaai.v22i1.12007
Immunol Invest. 2023 Mar 29. 1-15

2-DG Re-Normalized IFN-γ Production in T Cells Excluding TEMRA Cells from Patients with Aplastic Anemia.

Yue Zhang, Yuping Zhang, Xueqin Li, Xiaohui Chen, Yikai Zhang, Xiaoen Liu, Shujuan Wu, Yangqiu Li, Bo Li.

  Aplastic anemia (AA) is a T cell immune mediated autoimmune disease in which cytokines, particularly IFN-γ are pathogenesis factors. Glucose metabolism is closely related to effector functions of activated T cells, such as IFN-γ production. The characteristics of glucose metabolism and whether interfering with glucose metabolism could affect T cells produce IFN-γ ability in AA patients remains unknown. In this study, we examined the characteristics of glucose metabolism in T cells from AA patients and the effects of the glucose metabolism inhibitor 2-deoxy-D-glucose (2-DG) on the ability of T cell production IFN-γ. Our data demonstrated abnormal glucose metabolism in stimulated T cells from AA patients, mainly reflected by increased glucose uptake and lactate secretion. In addition, EM and TEMRA cells exhibit higher glucose uptake in patients with AA compared with healthy individuals. Moreover, the frequency of IFN-γ+ was reduced by 2-DG in T cell from AA patients. Unexpectedly, 2-DG re-normalized the frequency of IFN-γ+ in other T cell subsets, except for in the TEMRA. In conclusion, our study reveals for the first time the existence of enhanced aerobic glycolysis in T cells from AA patients, and different T cell subsets exhibit different extent glucose uptake requirements. Aerobic glycolysis regulation may be a potential therapeutic strategy for aberrant T cell immunity. Moreover, TEMRA may have specific metabolic abnormalities, which should receive more attention in future targeted immune metabolism research.

Keywords:  2-deoxy-D-glucose; Aplastic anemia; effector memory cells re-expressing CD45RA cells; interferon γ

DOI:  https://doi.org/10.1080/08820139.2023.2195436
bioRxiv. 2023 Mar 11. pii: 2023.03.09.532000. [Epub ahead of print]

Ensemble-based genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer.

Patrick E Gelbach, Stacey D Finley.

1Colorectal cancer (CRC) shows high incidence and mortality, partly due to the tumor microenvironment, which is viewed as an active promoter of disease progression. Macrophages are among the most abundant cells in the tumor microenvironment. These immune cells are generally categorized as M1, with inflammatory and anti-cancer properties, or M2, which promote tumor proliferation and survival. Although the M1/M2 subclassification scheme is strongly influenced by metabolism, the metabolic divergence between the subtypes remains poorly understood. Therefore, we generated a suite of computational models that characterize the M1- and M2-specific metabolic states. Our models show key differences between the M1 and M2 metabolic networks and capabilities. We leverage the models to identify metabolic perturbations that cause the metabolic state of M2 macrophages to more closely resemble M1 cells. Overall, this work increases understanding of macrophage metabolism in CRC and elucidates strategies to promote the metabolic state of anti-tumor macrophages.

DOI: https://doi.org/10.1101/2023.03.09.532000
bioRxiv. 2023 Mar 21. pii: 2023.03.17.532101. [Epub ahead of print]

Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

Liliana M Sanmarco, Joseph M Rone, Carolina M Polonio, Federico Giovannoni, Gonzalo Fernandez Lahore, Kylynne Ferrara, Cristina Gutierrez-Vazquez, Ning Li, Anna Sokolovska, Agustin Plasencia, Camilo Faust Akl, Payal Nanda, Evelin S Heck, Zhaorong Li, Hong-Gyun Lee, Chun-Cheih Chao, Claudia M Rejano-Gordillo, Pedro H Fonseca-Castro, Tomer Illouz, Mathias Linnerbauer, Jessica E Kenison, Rocky M Barilla, Daniel Farrenkopf, Gavin Piester, Lucas Dailey, Vijay K Kuchroo, David Hava, Michael A Wheeler, Clary Clish, Roni Nowarski, Eduardo Balsa, Jose M Lora, Francisco J Quintana.

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1α. NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1α/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation.

DOI: https://doi.org/10.1101/2023.03.17.532101
bioRxiv. 2023 Mar 15. pii: 2023.03.14.532663. [Epub ahead of print]

Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function.

Paul Renauer, Jonathan J Park, Meizhu Bai, Arianny Acosta, Won-Ho Lee, Guang Han Lin, Yueqi Zhang, Xiaoyun Dai, Guangchuan Wang, Youssef Errami, Terence Wu, Paul Clark, Lupeng Ye, Quanjun Yang, Sidi Chen.

Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. ADA -OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA -OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. ADA-OE improves tumor infiltration and clearance by α-HER2 CAR-T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy.
Synopsis: The authors identify the adenosine deaminase gene (ADA) as a regulatory gene that reprograms T cell metabolism. ADA-overexpression (OE) in α-CD19 and α-HER2 CAR-T cells increases proliferation, cytotoxicity, memory, and decreases exhaustion, and ADA-OE α-HER2 CAR-T cells have enhanced clearance of HT29 human colorectal cancer tumors in vivo .

DOI: https://doi.org/10.1101/2023.03.14.532663
Semin Immunol. 2023 Mar 27. pii: S1044-5323(23)00046-5. [Epub ahead of print]67 101755

Microbial metabolites and immunotherapy: Basic rationale and clinical indications.

Larisa V Kovtonyuk, Kathy D McCoy.

  Our microbiota has a critical role in shaping host immunity. Microbes that reside in the gut harbor a large metabolic arsenal to aid in physiological functions of the host. Microbial metabolites, which are products of microbial metabolism, such as short chain fatty acids (SCFA), purine metabolites, cyclic dinucleotides, tryptophan derivatives, and secondary bile acids, can tailor the host immune cell landscape in homeostasis and during cancer immunotherapy. The critical role of the microbiome in aiding immune checkpoint blockade therapies has become clearer over the past few years, with the most recent studies providing more detailed mechanistic insight on how microbes and their metabolites control the outcome of immunotherapy. This review summarizes recent studies on how microbial metabolites orchestrate immune responses during cancer immunotherapies.

Keywords:  Cancer immunotherapy; Gut microbiome; Microbial metabolites

DOI:  https://doi.org/10.1016/j.smim.2023.101755
Int J Mol Sci. 2023 Mar 22. pii: 5999. [Epub ahead of print]24(6):

Mitochondrial Methionyl-tRNA Formyltransferase Deficiency Alleviates Metaflammation by Modulating Mitochondrial Activity in Mice.

Xiaoxiao Sun, Suyuan Liu, Jiangxue Cai, Miaoxin Yang, Chenxuan Li, Meiling Tan, Bin He.

  Various studies have revealed the association of metabolic diseases with inflammation. Mitochondria are key organelles involved in metabolic regulation and important drivers of inflammation. However, it is uncertain whether the inhibition of mitochondrial protein translation results in the development of metabolic diseases, such that the metabolic benefits related to the inhibition of mitochondrial activity remain unclear. Mitochondrial methionyl-tRNA formyltransferase (Mtfmt) functions in the early stages of mitochondrial translation. In this study, we reveal that feeding with a high-fat diet led to the upregulation of Mtfmt in the livers of mice and that a negative correlation existed between hepatic Mtfmt gene expression and fasting blood glucose levels. A knockout mouse model of Mtfmt was generated to explore its possible role in metabolic diseases and its underlying molecular mechanisms. Homozygous knockout mice experienced embryonic lethality, but heterozygous knockout mice showed a global reduction in Mtfmt expression and activity. Moreover, heterozygous mice showed increased glucose tolerance and reduced inflammation, which effects were induced by the high-fat diet. The cellular assays showed that Mtfmt deficiency reduced mitochondrial activity and the production of mitochondrial reactive oxygen species and blunted nuclear factor-κB activation, which, in turn, downregulated inflammation in macrophages. The results of this study indicate that targeting Mtfmt-mediated mitochondrial protein translation to regulate inflammation might provide a potential therapeutic strategy for metabolic diseases.

Keywords:  Mitochondrial methionyl-tRNA formyltranse (Mtfmt); metabolic disorder; metaflammation; mitochondria; mitochondrial reactive oxygen species (mROS)

DOI:  https://doi.org/10.3390/ijms24065999
J Exp Med. 2023 Jun 05. pii: e20221068. [Epub ahead of print]220(6):

VMP1 prevents Ca2+ overload in endoplasmic reticulum and maintains naive T cell survival.

Ying Liu, Yuying Ma, Jing Xu, Guangyue Zhang, Xiaocui Zhao, Zihao He, Lixia Wang, Na Yin, Min Peng.

Ca2+ in endoplasmic reticulum (ER) dictates T cell activation, proliferation, and function via store-operated Ca2+ entry. How naive T cells maintain an appropriate level of Ca2+ in ER remains poorly understood. Here, we show that the ER transmembrane protein VMP1 is essential for maintaining ER Ca2+ homeostasis in naive T cells. VMP1 promotes Ca2+ release from ER under steady state, and its deficiency leads to ER Ca2+ overload, ER stress, and secondary Ca2+ overload in mitochondria, resulting in massive apoptosis of naive T cells and defective T cell response. Aspartic acid 272 (D272) of VMP1 is critical for its ER Ca2+ releasing activity, and a knockin mouse strain with D272 mutated to asparagine (D272N) demonstrates all functions of VMP1 in T cells in vivo depend on its regulation of ER Ca2+. These data uncover an indispensable role of VMP1 in preventing ER Ca2+ overload and maintaining naive T cell survival.

DOI: https://doi.org/10.1084/jem.20221068
Int J Mol Sci. 2023 Mar 14. pii: 5542. [Epub ahead of print]24(6):

Quercetin Reprograms Immunometabolism of Macrophages via the SIRT1/PGC-1α Signaling Pathway to Ameliorate Lipopolysaccharide-Induced Oxidative Damage.

Jing Peng, Zhen Yang, Hao Li, Baocheng Hao, Dongan Cui, Ruofeng Shang, Yanan Lv, Yu Liu, Wanxia Pu, Hongjuan Zhang, Jiongjie He, Xuehong Wang, Shengyi Wang.

  The redox system is closely related to changes in cellular metabolism. Regulating immune cell metabolism and preventing abnormal activation by adding antioxidants may become an effective treatment for oxidative stress and inflammation-related diseases. Quercetin is a naturally sourced flavonoid with anti-inflammatory and antioxidant activities. However, whether quercetin can inhibit LPS-induced oxidative stress in inflammatory macrophages by affecting immunometabolism has been rarely reported. Therefore, the present study combined cell biology and molecular biology methods to investigate the antioxidant effect and mechanism of quercetin in LPS-induced inflammatory macrophages at the RNA and protein levels. Firstly, quercetin was found to attenuate the effect of LPS on macrophage proliferation and reduce LPS-induced cell proliferation and pseudopodia formation by inhibiting cell differentiation, as measured by cell activity and proliferation. Subsequently, through the detection of intracellular reactive oxygen species (ROS) levels, mRNA expression of pro-inflammatory factors and antioxidant enzyme activity, it was found that quercetin can improve the antioxidant enzyme activity of inflammatory macrophages and inhibit their ROS production and overexpression of inflammatory factors. In addition, the results of mitochondrial morphology and mitochondrial function assays showed that quercetin could upregulate the mitochondrial membrane potential, ATP production and ATP synthase content decrease induced by LPS, and reverse the mitochondrial morphology damage to a certain extent. Finally, Western blotting analysis demonstrated that quercetin significantly upregulated the protein expressions of SIRT1 and PGC-1α, that were inhibited by LPS. And the inhibitory effects of quercetin on LPS-induced ROS production in macrophages and the protective effects on mitochondrial morphology and membrane potential were significantly decreased by the addition of SIRT1 inhibitors. These results suggested that quercetin reprograms the mitochondria metabolism of macrophages through the SIRT1/PGC-1α signaling pathway, thereby exerting its effect of alleviating LPS-induced oxidative stress damage.

Keywords:  SIRT1/PGC-1α signaling pathway; immunometabolism; inflammation; macrophage; oxidative stress; quercetin; redox

DOI:  https://doi.org/10.3390/ijms24065542
Cell Rep Med. 2023 Mar 24. pii: S2666-3791(23)00093-9. [Epub ahead of print] 100987

An immunometabolism subtyping system identifies S100A9+ macrophage as an immune therapeutic target in colorectal cancer based on multiomics analysis.

Xuanwen Bao, Danyang Wang, Xiaomeng Dai, Chuan Liu, Hangyu Zhang, Yuzhi Jin, Zhou Tong, Bin Li, Chuchu Tong, Shan Xin, Xin Li, Yanfang Wang, Lulu Liu, Xudong Zhu, Qihan Fu, Yi Zheng, Jingwen Deng, Weihong Tian, Tiannan Guo, Peng Zhao, Wenbin Cheng, Weijia Fang.

  Immunometabolism in the tumor microenvironment (TME) and its influence on the immunotherapy response remain uncertain in colorectal cancer (CRC). We perform immunometabolism subtyping (IMS) on CRC patients in the training and validation cohorts. Three IMS subtypes of CRC, namely, C1, C2, and C3, are identified with distinct immune phenotypes and metabolic properties. The C3 subtype exhibits the poorest prognosis in both the training cohort and the in-house validation cohort. The single-cell transcriptome reveals that a S100A9+ macrophage population contributes to the immunosuppressive TME in C3. The dysfunctional immunotherapy response in the C3 subtype can be reversed by combination treatment with PD-1 blockade and an S100A9 inhibitor tasquinimod. Taken together, we develop an IMS system and identify an immune tolerant C3 subtype that exhibits the poorest prognosis. A multiomics-guided combination strategy by PD-1 blockade and tasquinimod improves responses to immunotherapy by depleting S100A9+ macrophages in vivo.

Keywords:  CRC; IMS; S100A9(+) macrophage; TME; colorectal cancer; immunometabolism subtyping; immunotherapy; multiomics; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2023.100987
Int Immunopharmacol. 2023 Mar 23. pii: S1567-5769(23)00342-9. [Epub ahead of print]118 110021

Eriocitrin attenuates sepsis-induced acute lung injury in mice by regulating MKP1/MAPK pathway mediated-glycolysis.

Donghang Li, Liu Yang, Wei Wang, Congkuan Song, Rui Xiong, Shize Pan, Ning Li, Qing Geng.

  Metabolic reprogramming has been shown to aggravate sepsis-induced acute lung injury. In particular, enhanced glycolysis is closely associated with inflammation and oxidative stress. Eriocitrin (ERI) is a natural flavonoid found in citrus fruit that exhibits various pharmacological activities, with antioxidant, anti-inflammatory, anti-diabetic, and anti-tumor properties. However, the role of ERI in lung injury is not well understood. We established a septic mouse model of acute lung injury (ALI) using lipopolysaccharide (LPS) for induction. Primary peritoneal macrophages were isolated to verify the relevant molecular mechanism. Tissues were assessed for lung pathology, pro-inflammatory cytokines, markers of oxidative stress, and protein and mRNA expression levels. In vivo experiments showed that ERI effectively alleviated LPS-induced pathological injury, suppress the inflammatory response (TNF-α, IL-1β, IL-6 levels) and decreased oxidative stress (MDA, ROS) in murine lung tissue. In vitro, ERI increased the resistance of LPS-treated cells to excessive inflammation and oxidative stress by inhibiting the enhancement of glycolysis (indicated by expression levels of HIF-1α, HK2, LDHA, PFKFB3, and PKM2). Specifically, the beneficial effects of ERI following LPS-induced lung injury occurred through promoting the expression of MKP1, which mediates the inactivation of the MAPK pathway to inhibit enhanced glycolysis. These results demonstrate that ERI has a protective effect on sepsis-induced ALI by regulating MKP1/MAPK pathway mediated-glycolysis. Hence, ERI is a promising candidate against ALI via inhibiting glycolysis.

Keywords:  Eriocitrin; Glycolysis; MKP1; Sepsis-induced ALI

DOI:  https://doi.org/10.1016/j.intimp.2023.110021
Metabolites. 2023 Feb 21. pii: 311. [Epub ahead of print]13(3):

Development of an Untargeted Metabolomics Strategy to Study the Metabolic Rewiring of Dendritic Cells upon Lipopolysaccharide Activation.

Jessica Michieletto, Aurélie Delvaux, Emeline Chu-Van, Christophe Junot, François Fenaille, Florence A Castelli.

  Dendritic cells (DCs) are essential immune cells for defense against external pathogens. Upon activation, DCs undergo profound metabolic alterations whose precise nature remains poorly studied at a large scale and is thus far from being fully understood. The goal of the present work was to develop a reliable and accurate untargeted metabolomics workflow to get a deeper insight into the metabolism of DCs when exposed to an infectious agent (lipopolysaccharide, LPS, was used to mimic bacterial infection). As DCs transition rapidly from a non-adherent to an adherent state upon LPS exposure, one of the leading analytical challenges was to implement a single protocol suitable for getting comparable metabolomic snapshots of those two cellular states. Thus, a thoroughly optimized and robust sample preparation method consisting of a one-pot solvent-assisted method for the simultaneous cell lysis/metabolism quenching and metabolite extraction was first implemented to measure intracellular DC metabolites in an unbiased manner. We also placed special emphasis on metabolome coverage and annotation by using a combination of hydrophilic interaction liquid chromatography and reverse phase columns coupled to high-resolution mass spectrometry in conjunction with an in-house developed spectral database to identify metabolites at a high confidence level. Overall, we were able to characterize up to 171 unique meaningful metabolites in DCs. We then preliminarily compared the metabolic profiles of DCs derived from monocytes of 12 healthy donors upon in vitro LPS activation in a time-course experiment. Interestingly, the resulting data revealed differential and time-dependent activation of some particular metabolic pathways, the most impacted being nucleotides, nucleotide sugars, polyamines pathways, the TCA cycle, and to a lesser extent, the arginine pathway.

Keywords:  adherent cells; dendritic cells; high-resolution mass spectrometry; immunometabolomics; liquid chromatography; metabolomics; sample preparation

DOI:  https://doi.org/10.3390/metabo13030311
Front Genet. 2023 ;14 1105673

A single-cell atlas reveals shared and distinct immune responses and metabolic profiles in SARS-CoV-2 and HIV-1 infections.

Tony Pan, Guoshuai Cao, Erting Tang, Yu Zhao, Pablo Penaloza-MacMaster, Yun Fang, Jun Huang.

  Introduction: Within the inflammatory immune response to viral infection, the distribution and cell type-specific profiles of immune cell populations and the immune-mediated viral clearance pathways vary according to the specific virus. Uncovering the immunological similarities and differences between viral infections is critical to understanding disease progression and developing effective vaccines and therapies. Insight into COVID-19 disease progression has been bolstered by the integration of single-cell (sc)RNA-seq data from COVID-19 patients with data from related viruses to compare immune responses. Expanding this concept, we propose that a high-resolution, systematic comparison between immune cells from SARS-CoV-2 infection and an inflammatory infectious disease with a different pathophysiology will provide a more comprehensive picture of the viral clearance pathways that underscore immunological and clinical differences between infections. Methods: Using a novel consensus single-cell annotation method, we integrate previously published scRNA-seq data from 111,566 single PBMCs from 7 COVID-19, 10 HIV-1+, and 3 healthy patients into a unified cellular atlas. We compare in detail the phenotypic features and regulatory pathways in the major immune cell clusters. Results: While immune cells in both COVID-19 and HIV-1+ cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activity, and downregulated mitophagy. Discussion: Our results indicate that differential IFN-I signaling regulates the distinct immune responses in the two diseases, revealing insight into fundamental disease biology and potential therapeutic candidates.

Keywords:  HIV; SARS-CoV-2; Single-cell RNA sequencing; inflammation; metabolic signaling; type 1 interferon

DOI:  https://doi.org/10.3389/fgene.2023.1105673
J Transl Med. 2023 Mar 27. 21(1): 224

Cholesterol suppresses human iTreg differentiation and nTreg function through mitochondria-related mechanisms.

Huanzhi Zhang, Ni Xia, Tingting Tang, Shaofang Nie, Lingfeng Zha, Min Zhang, Bingjie Lv, Yuzhi Lu, Jiao Jiao, Jingyong Li, Xiang Cheng.

   BACKGROUND: Both the crystalline and soluble forms of cholesterol increase macrophage secretion of interleukin 1β (IL-1β), aggravating the inflammatory response in atherosclerosis (AS). However, the link between cholesterol and regulatory T cells (Tregs) remains unclear. This study aimed to investigate the effect of cholesterol treatment on Tregs.
METHODS: Differentiation of induced Tregs (iTregs) was analyzed using flow cytometry. The expression of hypoxia-inducible factor-1a (HIF-1a) and its target genes was measured by western blotting and/or RT-qPCR. Two reporter jurkat cell lines were constructed by lentiviral transfection. Mitochondrial function and the structure of natural Tregs (nTregs) were determined by tetramethylrhodamine (TMRM) and mitoSOX staining, Seahorse assay, and electron microscopy. The immunoregulatory function of nTregs was determined by nTreg-macrophage co-culture assay and ELISA.
RESULTS: Cholesterol treatment suppressed iTreg differentiation and impaired nTreg function. Mechanistically, cholesterol induced the production of mitochondrial reactive oxygen species (mtROS) in naïve T cells, inhibiting the degradation of HIF-1α and unleashing its inhibitory effects on iTreg differentiation. Furthermore, cholesterol-induced mitochondrial oxidative damage impaired the immunosuppressive function of nTregs. Mixed lymphocyte reaction and nTreg-macrophage co-culture assays revealed that cholesterol treatment compromised the ability of nTregs to inhibit pro-inflammatory conventional T cell proliferation and promote the anti-inflammatory functions of macrophages. Finally, mitoTEMPO (MT), a specific mtROS scavenger, restored iTreg differentiation and protected nTreg from further deterioration.
CONCLUSION: Our findings suggest that cholesterol may aggravate inflammation within AS plaques by acting on both iTregs and nTregs, and that MT may be a promising anti-atherogenic drug.

Keywords:  Atherosclerosis; Cholesterol; Mitochondrial reactive oxygen species; Regulatory T cells; mitoTEMPO

DOI:  https://doi.org/10.1186/s12967-023-03896-z
Metabolomics. 2023 Mar 29. 19(4): 30

Analysis of temporal metabolic rewiring for human respiratory syncytial virus infection by integrating metabolomics and proteomics.

Yao Lu, Shan Xu, Huan Sun, Jinjun Shan, Cunsi Shen, Jianjian Ji, Lili Lin, Jianya Xu, Linxiu Peng, Chen Dai, Tong Xie.

   INTRODUCTION: Human respiratory syncytial virus (HRSV) infection causes significant morbidity, and no effective treatments are currently available. Viral infections induce substantial metabolic changes in the infected cells to optimize viral production. Metabolites that reflect the interactions between host cells and viruses provided an opportunity to identify the pathways underlying severe infections.
OBJECTIVE: To better understand the metabolic changes caused by HRSV infection, we analyzed temporal metabolic profiling to provide novel targets for therapeutic strategies for inhaled HRSV infection.
METHODS: The epithelial cells and BALB/c mice were infected with HRSV. Protein and mRNA levels of inflammation factors were measured by using quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Untargeted metabolomics, lipidomics and proteomics were performed using liquid chromatography coupled with mass spectrometry to profile the metabolic phenotypic alterations in HRSV infection.
RESULTS: In this study, we evaluated the inflammatory responses in vivo and in vitro and investigated the temporal metabolic rewiring of HRSV infection in epithelial cells. We combined metabolomics and proteomic analyses to demonstrate that the redox imbalance was further provoked by increasing glycolysis and anaplerotic reactions. These responses created an oxidant-rich microenvironment that elevated reactive oxygen species levels and exacerbated glutathione consumption.
CONCLUSION: These observations indicate that adjusting for metabolic events during a viral infection could represent a valuable approach for reshaping the outcome of infections.

Keywords:  Glutamine and glutamate metabolism; Human respiratory syncytial virus; Metabolic remodeling; Metabolomics

DOI:  https://doi.org/10.1007/s11306-023-01991-2
PLoS One. 2023 ;18(3): e0283696

Putrescine supplementation shifts macrophage L-arginine metabolism related-genes reducing Leishmania amazonensis infection.

Jonathan Miguel Zanatta, Stephanie Maia Acuña, Yan de Souza Angelo, Camilla de Almeida Bento, Jean Pierre Schatzman Peron, Beatriz Simonsen Stolf, Sandra Marcia Muxel.

Leishmania is a protozoan that causes leishmaniasis, a neglected tropical disease with clinical manifestations classified as cutaneous, mucocutaneous, and visceral leishmaniasis. In the infection context, the parasite can modulate macrophage gene expression affecting the microbicidal activity and immune response. The metabolism of L-arginine into polyamines putrescine, spermidine, and spermine reduces nitric oxide (NO) production, favoring Leishmania survival. Here, we investigate the effect of supplementation with L-arginine and polyamines in infection of murine BALB/c macrophages by L. amazonensis and in the transcriptional regulation of genes involved in arginine metabolism and proinflammatory response. We showed a reduction in the percentage of infected macrophages upon putrescine supplementation compared to L-arginine, spermidine, and spermine supplementation. Unexpectedly, deprivation of L-arginine increased nitric oxide synthase (Nos2) gene expression without changes in NO production. Putrescine supplementation increased transcript levels of polyamine metabolism-related genes Arg2, ornithine decarboxylase (Odc1), Spermidine synthase (SpdS), and Spermine synthase (SpmS), but reduced Arg1 in L. amazonensis infected macrophages, while spermidine and spermine promoted opposite effects. Putrescine increased Nos2 expression without leading to NO production, while L-arginine plus spermine led to NO production in uninfected macrophages, suggesting that polyamines can induce NO production. Besides, L-arginine supplementation reduced Il-1b during infection, and L-arginine or L-arginine plus putrescine increased Mcp1 at 24h of infection, suggesting that polyamines availability can interfere with cytokine/chemokine production. Our data showed that putrescine shifts L-arginine-metabolism related-genes on BALB/c macrophages and affects infection by L. amazonensis.

DOI: https://doi.org/10.1371/journal.pone.0283696
Immunol Cell Biol. 2023 Mar 26.

Hypercapnia alters mitochondrial gene expression and acylcarnitine production in monocytes.

David E Phelan, Catarina Mota, Moritz J Strowitzki, Masahiko Shigemura, Jacob I Sznajder, Louise Crowe, Joanne C Masterson, Sophie E Hayes, Ben Reddan, Xiaofei Yin, Lorraine Brennan, Daniel Crean, Eoin P Cummins.

  CO2 is produced during aerobic respiration. Normally, levels of CO2 in the blood are tightly regulated but pCO2 can rise (hypercapnia, pCO2 > 45 mmHg) in patients with lung diseases e.g. Chronic Obstructive Pulmonary Disease (COPD). Hypercapnia is a risk factor in COPD but may be of benefit in the context of destructive inflammation. The effects of CO2 per se, on transcription, independent of pH change are poorly understood and warrant further investigation. Here we elucidate the influence of hypercapnia on monocytes and macrophages through integration of state-of-the-art RNA-sequencing, metabolic and metabolomic approaches. THP-1 monocytes and IL4 polarised primary murine macrophages were exposed to 5% CO2 Vs 10% CO2 for up to 24 h in pH- buffered conditions. In hypercapnia, we identified ~370 differentially expressed genes (DEGs) under basal and ~1889 DEGs under LPS-stimulated conditions in monocytes. Transcripts relating to both mitochondrial and nuclear-encoded gene expression were enhanced in hypercapnia in basal and LPS-stimulated cells. Mitochondrial DNA content was not enhanced, but acylcarnitine species and genes associated with fatty acid metabolism were increased in hypercapnia. Primary macrophages exposed to hypercapnia also increased activation of genes associated with fatty acid metabolism and reduced activation of genes associated with glycolysis. Thus, hypercapnia elicits metabolic shifts in lipid metabolism in monocytes and macrophages under pH buffered conditions. These data indicate that CO2 is an important modulator of monocyte transcription that can influence immunometabolic signalling in immune cells in hypercapnia. These immunometabolic insights may be of benefit in the treatment of patients experiencing hypercapnia.

Keywords:  CO2; RNA-Seq; acylcarnitine; carbon dioxide; gene expression; hypercapnia; mitochondria; monocyte

DOI:  https://doi.org/10.1111/imcb.12642
Front Cell Dev Biol. 2023 ;11 1147434

The diverse roles of macrophages in metabolic inflammation and its resolution.

Aleepta Guha Ray, Oluwatomilayo Patience Odum, Destini Wiseman, Ada Weinstock.

  Macrophages are one of the most functionally diverse immune cells, indispensable to maintain tissue integrity and metabolic health. Macrophages perform a myriad of functions ranging from promoting inflammation, through inflammation resolution to restoring and maintaining tissue homeostasis. Metabolic diseases encompass a growing list of diseases which develop from a mix of genetics and environmental cues leading to metabolic dysregulation and subsequent inflammation. In this review, we summarize the contributions of macrophages to four metabolic conditions-insulin resistance and adipose tissue inflammation, atherosclerosis, non-alcoholic fatty liver disease and neurodegeneration. The role of macrophages is complex, yet they hold great promise as potential therapies to address these growing health concerns.

Keywords:  atherosclerosis; diabetes; inflammation; macrophage; neuroinflammation; non-alcoholic fatty liver disease; obesity

DOI:  https://doi.org/10.3389/fcell.2023.1147434
Biomed Pharmacother. 2023 May;pii: S0753-3322(23)00234-2. [Epub ahead of print]161 114446

S-allylmercaptocysteine promotes anti-tumor immunity by suppressing PD-L1 expression.

Jianxiong Zhao, Yueyue Sun, Peng Gao, Zhongxi Zhao, Guangwei Wei.

  SAMC (S-allylmercaptocysteine) possesses significant anti-tumor effects and is proven to inhibit inflammation in chronic obstructive pulmonary disease. The potential to regulate the immune system of SAMC inspired us to detect whether SAMC can promote anti-tumor immunity. Here we found that SAMC inhibits tumor development and progression by boosting CD8+ T cell and NK cell infiltration and decreasing the frequency of immune suppressing Treg cells in tumor tissue and enhancing the systemic immune function. Mechanistically, we found that SAMC suppresses PD-L1 expression at transcriptional level to increase the activation of anti-tumor cytotoxic T cells. Finally, we proved that SAMC inhibits PD-L1 transcription by suppressing the phosphorylation activation of STAT3. In conclusion, our findings reveal that SAMC is a potent immunity regulator and a potential agent for immune checkpoint inhibition in tumor therapy.

Keywords:  Immune check-point; Immunotherapy; PD-L1; S-allylmercaptocysteine; Small molecules

DOI:  https://doi.org/10.1016/j.biopha.2023.114446
J Exp Med. 2023 Jun 05. pii: e20221472. [Epub ahead of print]220(6):

Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages.

Michael A Gonzalez, Daniel R Lu, Maryam Yousefi, Ashley Kroll, Chen Hao Lo, Carlos G Briseño, J E Vivienne Watson, Sergey Novitskiy, Vanessa Arias, Hong Zhou, Andres Plata Stapper, Min K Tsai, Emily L Ashkin, Christopher W Murray, Chi-Ming Li, Monte M Winslow, Kristin V Tarbell.

Phagocytosis is a key macrophage function, but how phagocytosis shapes tumor-associated macrophage (TAM) phenotypes and heterogeneity in solid tumors remains unclear. Here, we utilized both syngeneic and novel autochthonous lung tumor models in which neoplastic cells express the fluorophore tdTomato (tdTom) to identify TAMs that have phagocytosed neoplastic cells in vivo. Phagocytic tdTompos TAMs upregulated antigen presentation and anti-inflammatory proteins, but downregulated classic proinflammatory effectors compared to tdTomneg TAMs. Single-cell transcriptomic profiling identified TAM subset-specific and common gene expression changes associated with phagocytosis. We uncover a phagocytic signature that is predominated by oxidative phosphorylation (OXPHOS), ribosomal, and metabolic genes, and this signature correlates with worse clinical outcome in human lung cancer. Expression of OXPHOS proteins, mitochondrial content, and functional utilization of OXPHOS were increased in tdTompos TAMs. tdTompos tumor dendritic cells also display similar metabolic changes. Our identification of phagocytic TAMs as a distinct myeloid cell state links phagocytosis of neoplastic cells in vivo with OXPHOS and tumor-promoting phenotypes.

DOI: https://doi.org/10.1084/jem.20221472
bioRxiv. 2023 Mar 23. pii: 2023.03.19.533339. [Epub ahead of print]

Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to control local Peyer's patch development.

Kelsey Howley, Alyssa Berthelette, Simona Ceglia, Joonsoo Kang, Andrea Reboldi.

Lymphoid tissue inducer (LTi) cells develop during intrauterine life and rely on developmental programs to initiate the organogenesis of secondary lymphoid organs (SLOs). This evolutionary conserved process endows the fetus with the ability to orchestrate the immune response after birth and to react to the triggers present in the environment. While it is established that LTi function can be shaped by maternal-derived cues and is critical to prepare the neonate with a functional scaffold to mount immune response, the cellular mechanisms that control anatomically distinct SLO organogenesis remain unclear. We discovered that LTi cells forming Peyer's patches, gut-specific SLOs, require the coordinated action of two migratory G protein coupled receptors (GPCR) GPR183 and CCR6. These two GPCRs are uniformly expressed on LTi cells across SLOs, but their deficiency specifically impacts Peyer's patch formation, even when restricted to fetal window. The unique CCR6 ligand is CCL20, while the ligand for GPR183 is the cholesterol metabolite 7α,25-Dihydroxycholesterol (7α,25-HC), whose production is controlled by the enzyme cholesterol 25-hydroxylase (CH25H). We identified a fetal stromal cell subset that expresses CH25H and attracts LTi cells in the nascent Peyer's patch anlagen. GPR183 ligand concentration can be modulated by the cholesterol content in the maternal diet and impacts LTi cell maturation in vitro and in vivo, highlighting a link between maternal nutrients and intestinal SLO organogenesis. Our findings revealed that in the fetal intestine, cholesterol metabolite sensing by GPR183 in LTi cells for Peyer's patch formation is dominant in the duodenum, the site of cholesterol absorption in the adult. This anatomic requirement suggests that embryonic, long-lived non-hematopoietic cells might exploit adult metabolic functions to ensure highly specialized SLO development in utero.

DOI: https://doi.org/10.1101/2023.03.19.533339
Blood Adv. 2023 Mar 27. pii: bloodadvances.2023010100. [Epub ahead of print]

Mitochondrial pyruvate dehydrogenase kinases contribute to platelet function and thrombosis in mice by regulating aerobic glycolysis.

Gagan D Flora, Manasa K Nayak, Madankumar Ghatge, Mariia Kumskova, Rakesh B Patel, Anil K Chauhan.

Resting platelets rely on oxidative phosphorylation (OXPHOS) and aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen) for their energy requirements. In contrast, platelet activation exhibits an increased rate of aerobic glycolysis relative to OXPHOS. Mitochondrial enzymes pyruvate dehydrogenase kinases (PDKs) phosphorylate the pyruvate dehydrogenase (PDH) complex to inhibit its activity, thereby diverting the pyruvate flux from OXPHOS to aerobic glycolysis upon platelet activation. Of four PDK isoforms, PDK2 and PDK4 (PDK2/4) are predominantly associated with metabolic diseases. Herein, we report that the combined deletion of PDK2/4 inhibits agonist-induced platelet functions, including aggregation, integrin αIIbβ3 activation, degranulation, spreading, and clot retraction. Additionally, collagen-mediated PLCγ2 phosphorylation and calcium mobilization were significantly reduced in PDK2/4-/- platelets, suggesting impaired GPVI signaling. The PDK2/4-/- mice were less susceptible to FeCl3-induced carotid and laser-induced mesenteric artery thrombosis without any effect on hemostasis. In adoptive transfer experiments, thrombocytopenic hIL-4Rα/GPIbα-transgenic mice transfused with PDK2/4-/- platelets exhibited less susceptibility to FeCl3 injury-induced carotid thrombosis compared to hIL-4Rα/GPIbα-Tg mice transfused with WT platelets, suggesting a platelet-specific role of PDK2/4 in thrombosis. Mechanistically, the inhibitory effects of PDK2/4 deletion on platelet function were associated with reduced PDH phosphorylation and glycoPER in activated platelets, suggesting that PDK2/4 regulates aerobic glycolysis. Finally, using PDK2 or PDK4 single KO mice, we identified that PDK4 plays a more prominent role in regulating platelet secretion and thrombosis compared to PDK2. This study identifies the fundamental role of PDK2/4 in regulating platelet functions and identifies PDK/PDH axis as a potentially novel antithrombotic target.

DOI: https://doi.org/10.1182/bloodadvances.2023010100
Metabolites. 2023 Feb 23. pii: 333. [Epub ahead of print]13(3):

Association between Tryptophan Metabolism and Inflammatory Biomarkers in Dairy Cows with Ketosis.

Zhengzhong Luo, Kang Yong, Zhenlong Du, Yixin Huang, Tao Zhou, Li Ma, Xueping Yao, Liuhong Shen, Shumin Yu, Zuoting Yan, Suizhong Cao.

  Dairy cows with ketosis have high circulating beta-hydroxybutyric acid (BHBA) concentrations alongside which inflammation is concomitantly developed. Tryptophan (Trp) is an essential amino acid that participates in the regulation of the inflammatory response. However, the association between Trp metabolism and inflammation in dairy cows with ketosis remains unclear. Therefore, blood samples from healthy (n = 10) and ketotic (n = 10) primiparous dairy cows were collected at the calving date and the day of ketosis diagnosis (7 days in milk (7 DIM)). Serum levels of non-esterified fatty acids (NEFA), BHBA, haptoglobin (HP), serum amyloid A (SAA), lipopolysaccharide, and cortisol were analyzed. Tryptophan and its metabolites were quantified using liquid chromatography-tandem mass spectrometry. At 7 DIM, the concentrations of NEFA, BHBA, HP, and SAA were higher and the levels of Trp, kynurenine (KYN), indoleacetic acid, indole-3-lactic acid, and 3-indoxyl sulfate were lower in the dairy cows with ketosis compared with those in the healthy cows. However, the KYN/Trp and melatonin/Trp ratios increased in the cows with ketosis. At the calving date, the serum lipopolysaccharide levels did not differ between the healthy and ketotic cows, whereas the levels of NEFA, HP, and cortisol increased in the ketotic cows. Correlation analysis showed that Trp deficiency and elevated Trp metabolism in the dairy cows occurred during ketosis. Overall, our results suggest that abnormal Trp metabolism may contribute to the pathogenesis of ketosis.

Keywords:  dairy cows; inflammatory biomarkers; ketosis; tryptophan metabolism

DOI:  https://doi.org/10.3390/metabo13030333
JCI Insight. 2023 Mar 28. pii: e158089. [Epub ahead of print]

Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T-cells.

Suzanne E Engelen, Francesca A Ververs, Angela Markovska, B Christoffer Lagerholm, Jordan M Kraaijenhof, Laura Ie Yousif, Yasemin-Xiomara Zurke, Can Mc Gulersonmez, Sander Kooijman, Michael Goddard, Robert J van Eijkeren, Peter J Jervis, Gurdyal S Besra, Saskia Haitjema, Folkert W Asselbergs, Eric Kalkhoven, Hidde L Ploegh, Marianne Boes, Vincenzo Cerundolo, G Kees Hovingh, Mariolina Salio, Edwin Ca Stigter, Patrick Cn Rensen, Claudia Monaco, Henk S Schipper.

  Invariant Natural Killer T (iNKT) cells act at the interface between lipid metabolism and immunity, due to their restriction to lipid antigens presented on CD1d by antigen presenting cells (APC). How foreign lipid antigens are delivered to APC remains elusive. Since lipoproteins routinely bind glycosylceramides structurally similar to lipid antigens, we hypothesized that circulating lipoproteins form complexes with foreign lipid antigens. In this study, we used 2-color fluorescence correlation spectroscopy to show, for the first time, stable complex formation of lipid antigens α-galactosylceramide (αGalCer), Isoglobotrihexosylceramide (iGb3) and OCH, a sphingosine-truncated analogue of αGalCer, with very-low-density (VLDL) and/or low-density (LDL) lipoproteins in vitro and in vivo. We demonstrate LDL receptor (LDLR)-mediated uptake of lipoprotein-αGalCer complexes by APCs, leading to potent complex-mediated activation of iNKT cells in vitro and in vivo. Finally, LDLR-mutant PBMCs of patients with familial hypercholesterolemia showed impaired activation and proliferation of iNKT cells upon stimulation, underscoring the relevance of lipoproteins as a lipid antigen delivery system in humans. Taken together, circulating lipoproteins form complexes with lipid antigens to facilitate their transport and uptake by APCs, leading to enhanced iNKT cell activation. This study thereby reveals a novel mechanism of lipid antigen delivery to APCs, and provides further insight in the immunological capacities of circulating lipoproteins.

Keywords:  Immunology; Lipoproteins; NKT cells

DOI:  https://doi.org/10.1172/jci.insight.158089
Nat Rev Rheumatol. 2023 Mar 28.

Involvement of the secosteroid vitamin D in autoimmune rheumatic diseases and COVID-19.

Maurizio Cutolo, Vanessa Smith, Sabrina Paolino, Emanuele Gotelli.

Evidence supporting the extra-skeletal role of vitamin D in modulating immune responses is centred on the effects of its final metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, also known as calcitriol), which is regarded as a true steroid hormone. 1,25(OH)2D3, the active form of vitamin D, can modulate the innate immune system in response to invading pathogens, downregulate inflammatory responses and support the adaptive arm of the immune system. Serum concentrations of its inactive precursor 25-hydroxyvitamin D3 (25(OH)D3, also known as calcidiol) fluctuate seasonally (being lowest in winter) and correlate negatively with the activation of the immune system as well as with the incidence and severity of autoimmune rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. Thus, a low serum concentration of 25(OH)D3 is considered to be a risk factor for autoimmune rheumatic diseases and vitamin D3 supplementation seems to improve the prognosis; moreover, long-term vitamin D3 supplementation seems to reduce their incidence (i.e. rheumatoid arthritis). In the setting of COVID-19, 1,25(OH)2D3 seems to downregulate the early viral phase (SARS-CoV-2 infection), by enhancing innate antiviral effector mechanisms, as well as the later cytokine-mediated hyperinflammatory phase. This Review provides an update of the latest scientific and clinical evidence concerning vitamin D and immune response in autoimmune rheumatic diseases and COVID-19, which justify the need for monitoring of serum 25(OH)D3 concentrations and for appropriate supplementation following clinical trial-based approaches.

DOI: https://doi.org/10.1038/s41584-023-00944-2
J Crohns Colitis. 2023 Mar 30. pii: jjad058. [Epub ahead of print]

Spermidine ameliorates colitis via induction of anti-inflammatory macrophages and prevention of intestinal dysbiosis.

Anna Niechcial, Marlene Schwarzfischer, Marcin Wawrzyniak, Kirstin Atrott, Andrea Laimbacher, Yasser Morsy, Egle Katkeviciute, Janine Häfliger, Patrick Westermann, Cezmi A Akdis, Michael Scharl, Marianne R Spalinger.

   BACKGROUND AND AIMS: Exacerbated immune activation, intestinal dysbiosis, and a disrupted intestinal barrier are common features among inflammatory bowel disease (IBD) patients. The polyamine spermidine, which is naturally present in all living organisms, is an integral component of the human diet, and exerts beneficial effects in human diseases. Here, we investigated whether spermidine treatment ameliorates intestinal inflammation and offers therapeutic potential for IBD treatment.
METHODS: We assessed the effect of oral spermidine administration on colitis severity in the T cell transfer colitis model in Rag2 -/- mice by analysis of endoscopy, histology, and molecular inflammation markers. The effects on the intestinal microbiome were determined by 16S sequencing of mouse feces. The impact on intestinal barrier integrity was evaluated in co-cultures of patient-derived macrophages with intestinal epithelial cells.
RESULTS: Spermidine administration protected mice from intestinal inflammation in a dose-dependent manner. While T helper cell subsets remained unaffected, spermidine promoted anti-inflammatory macrophages and prevented the microbiome shift from Firmicutes and Bacteroides to Proteobacteria, maintaining a healthy gut microbiome. Consistent with spermidine as a potent activator of the anti-inflammatory molecule protein tyrosine phosphatase non-receptor type 2 (PTPN2), its colitis-protective effect was dependent on PTPN2 in intestinal epithelial cells and in myeloid cells. The loss of PTPN2 in epithelial and myeloid cells, but not in T cells, abrogated the barrier-protective, anti-inflammatory effect of spermidine and prevented the anti-inflammatory polarization of macrophages.
CONCLUSION: Spermidine reduces intestinal inflammation by promoting anti-inflammatory macrophages, maintaining a healthy microbiome, and preserving epithelial barrier integrity in a PTPN2-dependent manner.

Keywords:  IBD; PTPN2; anti-inflammatory macrophages; dysbiosis; spermidine

DOI:  https://doi.org/10.1093/ecco-jcc/jjad058
Int Immunopharmacol. 2023 Mar 29. pii: S1567-5769(23)00408-3. [Epub ahead of print]118 110087

d-mannose blocks the interaction between keratinocytes and Th17 cells to alleviate psoriasis by inhibiting HIF-1α/CCL20 in mice.

Qian Jiang, Benliang Wei, Mengshu You, Xingchen Zhou.

  Psoriasis is an autoimmune chronic inflammatory skin disease with an unclear pathogenesis that is difficult to cure, causing serious physical and mental burdens for patients. Previous research showed that a mutually reinforcing vicious cycle caused by keratinocytes (KC) and a variety of immune cells plays an important role in psoriatic inflammation. d-Mannose, a widely distributed metabolite in the body, has been found to treat several metabolic diseases, but its impact on psoriasis remains unknown. Our study aims to investigate the effects of d-mannose on psoriasis and its specific mechanism. Here, we found that d-mannose alleviates psoriasis in mice both as oral and topical agents. Specifically, d-mannose down-regulated the expression of hypoxia-inducible factor 1A(HIF-1α) and inhibited the expression of chemokine CCL20 in keratinocytes, thereby inhibiting the local infiltration of Th17 cells and breaking the cycle of keratinocytes-Th17 cells. Overall, our study indicates that d-mannose alleviates cutaneous inflammation in psoriasis by inhibiting the HIF-1α/CCL20/Th17 cells axis, and d-mannose has the potential to be used as an oral and topical agent in the treatment of psoriasis.

Keywords:  CCL20; HIF-1α; Keratinocytes; Psoriasis; Th17; d-mannose

DOI:  https://doi.org/10.1016/j.intimp.2023.110087