bims-imicid 2024-03-17 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–03–17
25 papers selected by
Dylan Ryan, University of Cambridge

Mitochondrial complex I activity in microglia sustains neuroinflammation.
Metabolic regulation of type I interferon production.
Immuno-metabolic Reprogramming of T Cell: A New Frontier for Pharmacotherapy of Rheumatoid Arthritis.
Unlocking the potential of T-cell metabolism reprogramming: Advancing single-cell approaches for precision immunotherapy in tumour immunity.
Metabolic reprogramming of the inflammatory response in the nervous system: the crossover between inflammation and metabolism.
T-Cell Metabolism in Rheumatoid Arthritis: Focus on Mitochondrial and Lysosomal Dysfunction.
Mitochondria: the gatekeepers between metabolism and immunity.
The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection.
Control of immune cell signaling by the immuno-metabolite itaconate.
Metabolic reprogramming and signalling cross-talks in tumour-immune interaction: a system-level exploration.
Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy.
Hepatitis B virus e antigen induces atypical metabolism and differentially regulates programmed cell deaths of macrophages.
Understanding the pathogenic significance of altered calcium-calmodulin signaling in T cells in autoimmune diseases.
Restriction of Glycolysis Increases Serial Killing Capacity of Natural Killer Cells.
Dexamethasone protects against asthma via regulating Hif-1α-glycolysis-lactate axis and protein lactylation.
Human Macrophages Activate Bystander Neutrophils' Metabolism and Effector Functions When Challenged with Mycobacterium tuberculosis.
The ecto-enzyme CD38 modulates CD4 T cell immunometabolic responses and participates in HIV pathogenesis.
The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.
Mitochondrial perturbation in immune cells enhances cell-mediated innate immunity in Drosophila.
Enteric coronavirus PDCoV evokes a non-Warburg effect by hijacking pyruvic acid as a metabolic hub.
Itaconate as a potential target for antimalarial therapy.
Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.
Nicotinamide Riboside Augments Human Macrophage Migration via SIRT3-Mediated Prostaglandin E2 Signaling.
Metabolic Deficiencies Underlie Plasmacytoid Dendritic Cell Exhaustion After Viral Infection.
HSPA9 reduction exacerbates symptoms and cell death in DSS-Induced inflammatory colitis.

Nature. 2024 Mar 13.

Mitochondrial complex I activity in microglia sustains neuroinflammation.

L Peruzzotti-Jametti, C M Willis, G Krzak, R Hamel, L Pirvan, R-B Ionescu, J A Reisz, H A Prag, M E Garcia-Segura, V Wu, Y Xiang, B Barlas, A M Casey, A M R van den Bosch, A M Nicaise, L Roth, G R Bates, H Huang, P Prasad, A E Vincent, C Frezza, C Viscomi, G Balmus, Z Takats, J C Marioni, A D'Alessandro, M P Murphy, I Mohorianu, S Pluchino.

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.

DOI: https://doi.org/10.1038/s41586-024-07167-9
Immunol Rev. 2024 Mar 11.

Metabolic regulation of type I interferon production.

Shane M O'Carroll, Fiona D R Henkel, Luke A J O'Neill.

  Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function in health and disease, establishing the field of immunometabolism. Specifically, pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and those involving lipid metabolism have been implicated in regulating immune cell function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about how metabolic changes regulate interferon responses. Interferons are critical cytokines in host defense, rapidly induced upon pathogen recognition, but are also involved in autoimmune diseases. This review summarizes how metabolic change impacts interferon production. We describe how glycolysis, lipid metabolism (specifically involving eicosanoids and cholesterol), and the TCA cycle-linked intermediates itaconate and fumarate impact type I interferons. Targeting these metabolic changes presents new therapeutic possibilities to modulate type I interferons during host defense or autoimmune disorders.

Keywords:  Immunometabolism; interferons; macrophage; metabolism

DOI:  https://doi.org/10.1111/imr.13318
Immunopharmacol Immunotoxicol. 2024 Mar 13. 1-32

Immuno-metabolic Reprogramming of T Cell: A New Frontier for Pharmacotherapy of Rheumatoid Arthritis.

Sourav Mondal, Sarthak Saha, Debjeet Sur.

  Rheumatoid arthritis (RA) is a persistent autoimmune condition characterized by ongoing inflammation primarily affecting the synovial joint. This inflammation typically arises from an increase in immune cells such as neutrophils, macrophages, and T cells (TC). TC is recognised as a major player in RA pathogenesis. The involvement of HLA-DRB1 and PTPN-2 among RA patients confirms the TC involvement in RA. Metabolism of TC is maintained by various other factors like cytokines, mitochondrial proteins & other metabolites. Different TC subtypes utilise different metabolic pathways like glycolysis, oxidative phosphorylation and fatty acid oxidation for their activation from naive TC (T0). Although all subsets of TC are not deleterious for synovium, some subsets of TC are involved in joint repair using their anti-inflammatory properties. Hence artificially reprogramming of TC subset by interfering with their metabolic status poised a hope in future to design new molecules against RA.

Keywords:  T cell metabolism; T cell reprogramming; cytokines; immunometabolism; rheumatoid arthritis

DOI:  https://doi.org/10.1080/08923973.2024.2330636
Clin Transl Med. 2024 Mar;14(3): e1620

Unlocking the potential of T-cell metabolism reprogramming: Advancing single-cell approaches for precision immunotherapy in tumour immunity.

Lihaoyun Huang, Haitao Li, Cangang Zhang, Quan Chen, Zaoqu Liu, Jian Zhang, Peng Luo, Ting Wei.

  As single-cell RNA sequencing enables the detailed clustering of T-cell subpopulations and facilitates the analysis of T-cell metabolic states and metabolite dynamics, it has gained prominence as the preferred tool for understanding heterogeneous cellular metabolism. Furthermore, the synergistic or inhibitory effects of various metabolic pathways within T cells in the tumour microenvironment are coordinated, and increased activity of specific metabolic pathways generally corresponds to increased functional activity, leading to diverse T-cell behaviours related to the effects of tumour immune cells, which shows the potential of tumour-specific T cells to induce persistent immune responses. A holistic understanding of how metabolic heterogeneity governs the immune function of specific T-cell subsets is key to obtaining field-level insights into immunometabolism. Therefore, exploring the mechanisms underlying the interplay between T-cell metabolism and immune functions will pave the way for precise immunotherapy approaches in the future, which will empower us to explore new methods for combating tumours with enhanced efficacy.

Keywords:  T-cell metabolism; immunotherapy; metabolic reprogramming; single-cell RNA sequencing; tumour immunity

DOI:  https://doi.org/10.1002/ctm2.1620
Neural Regen Res. 2024 Oct 01. 19(10): 2189-2201

Metabolic reprogramming of the inflammatory response in the nervous system: the crossover between inflammation and metabolism.

Jesus Amo-Aparicio, Charles A Dinarello, Ruben Lopez-Vales.

Metabolism is a fundamental process by which biochemicals are broken down to produce energy (catabolism) or used to build macromolecules (anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.

DOI: https://doi.org/10.4103/1673-5374.391330
Immunopharmacol Immunotoxicol. 2024 Mar 13. 1-10

T-Cell Metabolism in Rheumatoid Arthritis: Focus on Mitochondrial and Lysosomal Dysfunction.

Asmita Parab, Lokesh Kumar Bhatt.

  Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by immune cell dysregulation, synovial hyperplasia, and progressive cartilage destruction. The loss of immunological self-tolerance against autoantigens is the crucial insult responsible for the pathogenesis of RA. These immune abnormalities are experienced many years before the onset of clinical arthritis. T-cells are identified as the primary initiators of immunological abnormalities in RA. These RA T-cells show a distinct metabolic pattern compared to the healthy individuals. Dampened glycolytic flux, poor ATP production, and shifting of glucose to the pentose phosphate pathway resulting in increased NADPH and decreased ROS levels are the common metabolic patterns observed in RA T-cells. Defective mtDNA due to lack of MRE11A gene, a key molecular actor for resection, and inefficient lysosomal function due to misplacement of AMPK on the lysosomal surface were found to be responsible for mitochondrial and lysosome dysfunction in RA. Targeting this mechanism in RA can alleviate aggressive T-cell phenotype and may control the severity of RA.

Keywords:  Lysosomal Dysfunction; Mitochondrial dysfunction; Rheumatoid arthritis; T-cell metabolism

DOI:  https://doi.org/10.1080/08923973.2024.2330645
Front Immunol. 2024 ;15 1334006

Mitochondria: the gatekeepers between metabolism and immunity.

Giovanna Trinchese, Fabiano Cimmino, Angela Catapano, Gina Cavaliere, Maria Pina Mollica.

  Metabolism and immunity are crucial monitors of the whole-body homeodynamics. All cells require energy to perform their basic functions. One of the most important metabolic skills of the cell is the ability to optimally adapt metabolism according to demand or availability, known as metabolic flexibility. The immune cells, first line of host defense that circulate in the body and migrate between tissues, need to function also in environments in which nutrients are not always available. The resilience of immune cells consists precisely in their high adaptive capacity, a challenge that arises especially in the framework of sustained immune responses. Pubmed and Scopus databases were consulted to construct the extensive background explored in this review, from the Kennedy and Lehninger studies on mitochondrial biochemistry of the 1950s to the most recent findings on immunometabolism. In detail, we first focus on how metabolic reconfiguration influences the action steps of the immune system and modulates immune cell fate and function. Then, we highlighted the evidence for considering mitochondria, besides conventional cellular energy suppliers, as the powerhouses of immunometabolism. Finally, we explored the main immunometabolic hubs in the organism emphasizing in them the reciprocal impact between metabolic and immune components in both physiological and pathological conditions.

Keywords:  immunometabolism; metabolic flexibility; metabolic reprogramming; mitochondrial dynamics; mitochondrial function

DOI:  https://doi.org/10.3389/fimmu.2024.1334006
bioRxiv. 2024 Feb 29. pii: 2024.02.26.582124. [Epub ahead of print]

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection.

Arijit Chakraborty, Arunava Bandyopadhaya, Vijay K Singh, Filip Kovacic, Sujin Cha, William M Oldham, Aria A Tzika, Laurence G Rahme.

How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in macrophages' mitochondrial respiration and bioenergetics. We found that the 2-AA tolerization impairs oxidative phosphorylation (OXPHOS), leading to decreased generation of the crucial energy metabolite ATP and histone acetylation acetyl-CoA. We provide evidence that these effects result from reduced pyruvate flux into mitochondria due to the decreased expression of the mitochondrial pyruvate carrier (MPC1) mediated via the reduced expression and nuclear presence of its transcriptional regulator estrogen-related nuclear receptor (ERRα), leading to the weaker binding of ERRα to MPC1 promoter. This is the outcome of the hampered interaction of ERRα with the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) that ultimately leads to reduced pyruvate flux into mitochondria and ATP production in tolerized macrophages. Exogenously added ATP in 2-AA exposed macrophages restores the transcript levels of MPC1 and ERR-α and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic impairment and PA persistence. These findings unveil 2-AA as a negative modulator of cellular immunometabolism implicating the PGC-1α/ERRα axis in its influence on MPC1/OXPHOS-dependent energy production and PA clearance. These findings shed light on the underlying mechanisms of host tolerance and on potential therapeutic strategies to combat persistent PA infections.

DOI: https://doi.org/10.1101/2024.02.26.582124
Front Immunol. 2024 ;15 1352165

Control of immune cell signaling by the immuno-metabolite itaconate.

Roland Lang, Md Nur A Alam Siddique.

  Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell's metabolic activity to provide energy and biomolecules for inflammatory and proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns and cytokines upregulate expression of the enzyme ACOD1 that generates the immune-metabolite itaconate by decarboxylation of the TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well as immunomodulatory activities, which makes it attractive as endogenous effector metabolite fighting infection and restraining inflammation. Here, we first summarize the pathways and stimuli inducing ACOD1 expression in macrophages. The focus of the review then lies on the mechanisms by which itaconate, and its synthetic derivatives and endogenous isomers, modulate immune cell signaling and metabolic pathways. Multiple targets have been revealed, from inhibition of enzymes to the post-translational modification of many proteins at cysteine or lysine residues. The modulation of signaling proteins like STING, SYK, JAK1, RIPK3 and KEAP1, transcription regulators (e.g. Tet2, TFEB) and inflammasome components (NLRP3, GSDMD) provides a biochemical basis for the immune-regulatory effects of the ACOD1-itaconate pathway. While the field has intensely studied control of macrophages by itaconate in infection and inflammation models, neutrophils have now entered the scene as producers and cellular targets of itaconate. Furthermore, regulation of adaptive immune responses by endogenous itaconate, as well as by exogenously added itaconate and derivatives, can be mediated by direct and indirect effects on T cells and antigen-presenting cells, respectively. Taken together, research in ACOD1-itaconate to date has revealed its relevance in diverse immune cell signaling pathways, which now provides opportunities for potential therapeutic or preventive manipulation of host defense and inflammation.

Keywords:  ACOD1; IRG1; itaconate; macrophages; metabolism; post-translational modification; signal transduction; transport

DOI:  https://doi.org/10.3389/fimmu.2024.1352165
R Soc Open Sci. 2024 Mar;11(3): 231574

Metabolic reprogramming and signalling cross-talks in tumour-immune interaction: a system-level exploration.

Mudita Shukla, Rupa Bhowmick, Piyali Ganguli, Ram Rup Sarkar.

  Tumour-immune microenvironment (TIME) is pivotal in tumour progression and immunoediting. Within TIME, immune cells undergo metabolic adjustments impacting nutrient supply and the anti-tumour immune response. Metabolic reprogramming emerges as a promising approach to revert the immune response towards a pro-inflammatory state and conquer tumour dominance. This study proposes immunomodulatory mechanisms based on metabolic reprogramming and employs the regulatory flux balance analysis modelling approach, which integrates signalling, metabolism and regulatory processes. For the first time, a comprehensive system-level model is constructed to capture signalling and metabolic cross-talks during tumour-immune interaction and regulatory constraints are incorporated by considering the time lag between them. The model analysis identifies novel features to enhance the immune response while suppressing tumour activity. Particularly, altering the exchange of succinate and oxaloacetate between glioma and macrophage enhances the pro-inflammatory response of immune cells. Inhibition of glutamate uptake in T-cells disrupts the antioxidant mechanism of glioma and reprograms metabolism. Metabolic reprogramming through adenosine monophosphate (AMP)-activated protein kinase (AMPK), coupled with glutamate uptake inhibition, was identified as the most impactful combination to restore T-cell function. A comprehensive understanding of metabolism and gene regulation represents a favourable approach to promote immune cell recovery from tumour dominance.

Keywords:  metabolic reprogramming; signalling-metabolic cross-talks; system modelling; tumour–immune interaction

DOI:  https://doi.org/10.1098/rsos.231574
Cell Rep Med. 2024 Mar 01. pii: S2666-3791(24)00109-5. [Epub ahead of print] 101465

Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy.

Michael St Paul, Samuel D Saibil, Meghan Kates, SeongJun Han, Scott C Lien, Rob C Laister, Kebria Hezaveh, Andreas Kloetgen, Susanne Penny, Tingxi Guo, Carlos Garcia-Batres, Logan K Smith, Douglas C Chung, Alisha R Elford, Azin Sayad, Devanand Pinto, Tak W Mak, Naoto Hirano, Tracy McGaha, Pamela S Ohashi.

  The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ T cells ex vivo using the general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+ T cells into tumor-bearing mice led to robust tumor control and curative responses. Halo-treated T cells synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halo can enhance T cell metabolism and anti-tumor activity.

Keywords:  4-1BB; CD8(+) T cell; GCN2; Halofuginone; adoptive Cell therapy; autophagy; immunometabolism; immunotherapy

DOI:  https://doi.org/10.1016/j.xcrm.2024.101465
PLoS Pathog. 2024 Mar 11. 20(3): e1012079

Hepatitis B virus e antigen induces atypical metabolism and differentially regulates programmed cell deaths of macrophages.

Yumei Li, Christine Wu, Jiyoung Lee, Qiqi Ning, Juhyeon Lim, Hyungjin Eoh, Sean Wang, Benjamin P Hurrell, Omid Akbari, Jing-Hsiung James Ou.

Macrophages can undergo M1-like proinflammatory polarization with low oxidative phosphorylation (OXPHOS) and high glycolytic activities or M2-like anti-inflammatory polarization with the opposite metabolic activities. Here we show that M1-like macrophages induced by hepatitis B virus (HBV) display high OXPHOS and low glycolytic activities. This atypical metabolism induced by HBV attenuates the antiviral response of M1-like macrophages and is mediated by HBV e antigen (HBeAg), which induces death receptor 5 (DR5) via toll-like receptor 4 (TLR4) to induce death-associated protein 3 (DAP3). DAP3 then induces the expression of mitochondrial genes to promote OXPHOS. HBeAg also enhances the expression of glutaminases and increases the level of glutamate, which is converted to α-ketoglutarate, an important metabolic intermediate of the tricarboxylic acid cycle, to promote OXPHOS. The induction of DR5 by HBeAg leads to apoptosis of M1-like and M2-like macrophages, although HBeAg also induces pyroptosis of the former. These findings reveal novel activities of HBeAg, which can reprogram mitochondrial metabolism and trigger different programmed cell death responses of macrophages depending on their phenotypes to promote HBV persistence.

DOI: https://doi.org/10.1371/journal.ppat.1012079
Clin Immunol. 2024 Mar 07. pii: S1521-6616(24)00068-8. [Epub ahead of print] 110177

Understanding the pathogenic significance of altered calcium-calmodulin signaling in T cells in autoimmune diseases.

Tomohiro Koga.

  Calcium/calmodulin-dependent protein kinase IV (CaMK4) serves as a pivotal mediator in the regulation of gene expression, influencing the activity of transcription factors within a variety of immune cells, including T cells. Altered CaMK4 signaling is implicated in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, which are characterized by dysregulated immune responses and clinical complexity. These conditions share common disturbances in immune cell functionality, cytokine production, and autoantibody generation, all of which are associated with disrupted calcium-calmodulin signaling. This review underscores the consequences of dysregulated CaMK4 signaling across these diseases, with an emphasis on its impact on Th17 differentiation and T cell metabolism-processes central to maintaining immune homeostasis. A comprehensive understanding of roles of CaMK4 in gene regulation across various autoimmune disorders holds promise for the development of targeted therapies, particularly for diseases driven by Th17 cell dysregulation.

Keywords:  Calcium/calmodulin-dependent protein kinase IV (CaMK4); Interleukin (IL)-17; Rheumatoid arthritis (RA); Systemic lupus erythematosus (SLE); T cells

DOI:  https://doi.org/10.1016/j.clim.2024.110177
Int J Mol Sci. 2024 Mar 02. pii: 2917. [Epub ahead of print]25(5):

Restriction of Glycolysis Increases Serial Killing Capacity of Natural Killer Cells.

Lea Katharina Picard, Jens Alexander Niemann, Elisabeth Littwitz-Salomon, Herbert Waldmann, Carsten Watzl.

  Tumor cells rely heavily on glycolysis to meet their high metabolic demands. While this results in nutrient deprivation within the tumor microenvironment and has negative effects on infiltrating immune cells such as natural killer (NK) cells, it also creates a potential target for cancer therapies. Here we use Glupin, an inhibitor of glucose transporters, to study the effect of limited glucose uptake on NK cells and their anti-tumor functions. Glupin treatment effectively inhibited glucose uptake and restricted glycolysis in NK cells. However, acute treatment had no negative effect on NK cell cytotoxicity or cytokine production. Long-term restriction of glucose uptake via Glupin treatment only delayed NK cell proliferation, as they could switch to glutaminolysis as an alternative energy source. While IFN-γ production was partially impaired, long-term Glupin treatment had no negative effect on degranulation. Interestingly, the serial killing activity of NK cells was even slightly enhanced, possibly due to changes in NAD metabolism. This demonstrates that NK cell cytotoxicity is remarkably robust and insensitive to metabolic disturbances, which makes cellular metabolism an attractive target for immune-mediated tumor therapies.

Keywords:  cytokines; cytotoxicity; degranulation; glucose transporter; metabolism

DOI:  https://doi.org/10.3390/ijms25052917
Int Immunopharmacol. 2024 Mar 08. pii: S1567-5769(24)00309-6. [Epub ahead of print]131 111791

Dexamethasone protects against asthma via regulating Hif-1α-glycolysis-lactate axis and protein lactylation.

Ning Chen, Qiu-Meng Xie, Si-Ming Song, Si-Nuo Guo, Yu Fang, Guang-He Fei, Hui-Mei Wu.

   PURPOSE: Asthma can not be eradicated till now and its control primarily relies on the application of corticosteroids. Recently, glycolytic reprogramming has been reportedly contributed to asthma, this study aimed to reveal whether the effect of corticosteroids on asthma control is related to their regulation of glycolysis and glycolysis-dependent protein lactylation.
METHODS: Ovalbumin (OVA) aeroallergen was used to challenge mice and stimulate human macrophage cell line THP-1 following dexamethasone (DEX) treatment. Airway hyperresponsiveness, airway inflammation, the expressions of key glycolytic enzymes and pyroptosis markers, the level of lactic acid, real-time glycolysis and oxidative phosphorylation (OXPHOS), and protein lactylation were analyzed.
RESULTS: DEX significantly attenuated OVA-induced eosinophilic airway inflammation, including airway hyperresponsiveness, leukocyte infiltration, goblet cell hyperplasia, Th2 cytokines production and pyroptosis markers expression. Meanwhile, OVA-induced Hif-1α-glycolysis axis was substantially downregulated by DEX, which resulted in low level of lactic acid. Besides, key glycolytic enzymes in the lungs of asthmatic mice were notably co-localized with F4/80-positive macrophages, indicating metabolic shift to glycolysis in lung macrophages during asthma. This was confirmed in OVA-stimulated THP-1 cells that DEX treatment resulted in reductions in pyroptosis, glycolysis and lactic acid level. Finally, protein lactylation was found significantly increased in the lungs of asthmatic mice and OVA-stimulated THP-1 cells, which were both inhibited by DEX.
CONCLUSION: Our present study revealed that the effect of DEX on asthma control was associated with its suppressing of Hif-1α-glycolysis-lactateaxis and subsequent protein lactylation, which may open new avenues for the therapy of eosinophilic asthma.

Keywords:  Allergic asthma; Glycolysis; Hif-1α; Macrophage; Protein lactylation

DOI:  https://doi.org/10.1016/j.intimp.2024.111791
Int J Mol Sci. 2024 Mar 01. pii: 2898. [Epub ahead of print]25(5):

Human Macrophages Activate Bystander Neutrophils' Metabolism and Effector Functions When Challenged with Mycobacterium tuberculosis.

Dearbhla M Murphy, Anastasija Walsh, Laura Stein, Andreea Petrasca, Donal J Cox, Kevin Brown, Emily Duffin, Gráinne Jameson, Sarah A Connolly, Fiona O'Connell, Jacintha O'Sullivan, Sharee A Basdeo, Joseph Keane, James J Phelan.

  Neutrophils are dynamic cells, playing a critical role in pathogen clearance; however, neutrophil infiltration into the tissue can act as a double-edged sword. They are one of the primary sources of excessive inflammation during infection, which has been observed in many infectious diseases including pneumonia and active tuberculosis (TB). Neutrophil function is influenced by interactions with other immune cells within the inflammatory lung milieu; however, how these interactions affect neutrophil function is unclear. Our study examined the macrophage-neutrophil axis by assessing the effects of conditioned medium (MΦ-CM) from primary human monocyte-derived macrophages (hMDMs) stimulated with LPS or a whole bacterium (Mycobacterium tuberculosis) on neutrophil function. Stimulated hMDM-derived MΦ-CM boosts neutrophil activation, heightening oxidative and glycolytic metabolism, but diminishes migratory potential. These neutrophils exhibit increased ROS production, elevated NET formation, and heightened CXCL8, IL-13, and IL-6 compared to untreated or unstimulated hMDM-treated neutrophils. Collectively, these data show that MΦ-CM from stimulated hMDMs activates neutrophils, bolsters their energetic profile, increase effector and inflammatory functions, and sequester them at sites of infection by decreasing their migratory capacity. These data may aid in the design of novel immunotherapies for severe pneumonia, active tuberculosis and other diseases driven by pathological inflammation mediated by the macrophage-neutrophil axis.

Keywords:  Mycobacterium tuberculosis; glycolysis; granulocytes; immunometabolism; infection; neutrophil function; neutrophil metabolism; neutrophil priming and activation; polymorphonuclear cells; tuberculosis

DOI:  https://doi.org/10.3390/ijms25052898
J Leukoc Biol. 2024 Mar 11. pii: qiae060. [Epub ahead of print]

The ecto-enzyme CD38 modulates CD4 T cell immunometabolic responses and participates in HIV pathogenesis.

Fernando Díaz-Basilio, Moisés Vergara-Mendoza, Jessica Romero-Rodríguez, Sharik Hernández-Rizo, Alejandro Escobedo-Calvario, Luis-León Fuentes-Romero, Santiago Pérez-Patrigeon, Akio Murakami-Ogasawara, María Gomez-Palacio, Gustavo Reyes-Terán, Wei Jiang, Joel-Armando Vázquez-Pérez, Álvaro Marín-Hernández, Dámaris-Priscila Romero-Rodríguez, María-Concepción Gutiérrez-Ruiz, Mónica Viveros-Rogel, Enrique Espinosa.

  Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4 T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after TCR-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular NAD and NMN concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the OCR/ECAR ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ectoCD38 catalytic activity in memory CD4 T cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous pro-inflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morpho-functionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4 T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.

Keywords:  Acquired Immunodeficiency Syndrome; CD38 Antigen; Immunity; Memory T Cells; Metabolism; Receptor-CD3 Complex

DOI:  https://doi.org/10.1093/jleuko/qiae060
bioRxiv. 2024 Mar 01. pii: 2024.02.26.582122. [Epub ahead of print]

The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.

Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens O Watzlawik, Yin Maggie Chen, Ariel L Raybuck, Daniel Billadeau, Virginia Shapiro, Wolfdieter Springer, Jie Sun, Mark R Boothby, Hu Zeng.

During the humoral immune response, B cells undergo rapid metabolic reprogramming with a high demand for nutrients, which are vital to sustain the formation of the germinal centers (GCs). Rag-GTPases sense amino acid availability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway and suppress transcription factor EB (TFEB) and transcription factor enhancer 3 (TFE3), members of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors. However, how Rag-GTPases coordinate amino acid sensing, mTORC1 activation, and TFEB/TFE3 activity in humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and generate plasmablasts in both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish Rag-GTPase-TFEB/TFE3 pathway as an mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

DOI: https://doi.org/10.1101/2024.02.26.582122
BMC Biol. 2024 Mar 13. 22(1): 60

Mitochondrial perturbation in immune cells enhances cell-mediated innate immunity in Drosophila.

Laura Vesala, Yuliya Basikhina, Tea Tuomela, Anssi Nurminen, Emilia Siukola, Pedro F Vale, Tiina S Salminen.

   BACKGROUND: Mitochondria participate in various cellular processes including energy metabolism, apoptosis, autophagy, production of reactive oxygen species, stress responses, inflammation and immunity. However, the role of mitochondrial metabolism in immune cells and tissues shaping the innate immune responses are not yet fully understood. We investigated the effects of tissue-specific mitochondrial perturbation on the immune responses at the organismal level. Genes for oxidative phosphorylation (OXPHOS) complexes cI-cV were knocked down in the fruit fly Drosophila melanogaster, targeting the two main immune tissues, the fat body and the immune cells (hemocytes).
RESULTS: While OXPHOS perturbation in the fat body was detrimental, hemocyte-specific perturbation led to an enhanced immunocompetence. This was accompanied by the formation of melanized hemocyte aggregates (melanotic nodules), a sign of activation of cell-mediated innate immunity. Furthermore, the hemocyte-specific OXPHOS perturbation induced immune activation of hemocytes, resulting in an infection-like hemocyte profile and an enhanced immune response against parasitoid wasp infection. In addition, OXPHOS perturbation in hemocytes resulted in mitochondrial membrane depolarization and upregulation of genes associated with the mitochondrial unfolded protein response.
CONCLUSIONS: Overall, we show that while the effects of mitochondrial perturbation on immune responses are highly tissue-specific, mild mitochondrial dysfunction can be beneficial in immune-challenged individuals and contributes to variation in infection outcomes among individuals.

Keywords:   Leptopilina boulardi ; UQCR-C1 ; Aerobic glycolysis; Hemocyte; Infection; Lamellocyte; Mitochondrial membrane potential; Mitochondrial unfolded protein response; Oxidative phosphorylation; RNA sequencing; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12915-024-01858-5
Redox Biol. 2024 Mar 04. pii: S2213-2317(24)00088-0. [Epub ahead of print]71 103112

Enteric coronavirus PDCoV evokes a non-Warburg effect by hijacking pyruvic acid as a metabolic hub.

Guanning Su, Jiao Liu, Chenrui Duan, Puxian Fang, Liurong Fang, Yanrong Zhou, Shaobo Xiao.

  The Warburg effect, also referred as aerobic glycolysis, is a common metabolic program during viral infection. Through targeted metabolomics combined with biochemical experiments and various cell models, we investigated the central carbon metabolism (CCM) profiles of cells infected with porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus with zoonotic potential. We found that PDCoV infection required glycolysis but decreased glycolytic flux, exhibiting a non-Warburg effect characterized by pyruvic acid accumulation. Mechanistically, PDCoV enhanced pyruvate kinase activity to promote pyruvic acid anabolism, a process that generates pyruvic acid with concomitant ATP production. PDCoV also hijacked pyruvic acid catabolism to increase biosynthesis of non-essential amino acids (NEAAs), suggesting that pyruvic acid is an essential hub for PDCoV to scavenge host energy and metabolites. Furthermore, PDCoV facilitated glutaminolysis to promote the synthesis of NEAA and pyrimidines for optimal proliferation. Our work supports a novel CCM model after viral infection and provides potential anti-PDCoV drug targets.

Keywords:  Antiviral drug target; Central carbon metabolism; Metabolomic; Porcine deltacoronavirus; Pyruvic acid

DOI:  https://doi.org/10.1016/j.redox.2024.103112
Trends Parasitol. 2024 Mar 13. pii: S1471-4922(24)00057-6. [Epub ahead of print]

Itaconate as a potential target for antimalarial therapy.

Jonathon P Bernardi, Taylen J Nappi, Noah S Butler.

  In a recent publication, Ramalho et al. investigated monocyte-derived dendritic cell (MODC) mobilization in response to Plasmodium infection. The authors showed that elevated levels of itaconate in MODCs results in reduced CD8 T cell activation and that the absence of itaconate is associated with enhanced parasite control.

Keywords:  PD-L1; itaconate; malaria; metabolism; mitochondria; monocyte-derived dendritic cells

DOI:  https://doi.org/10.1016/j.pt.2024.03.003
Nat Commun. 2024 Mar 11. 15(1): 2203

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.

Luca Simula, Mattia Fumagalli, Lene Vimeux, Irena Rajnpreht, Philippe Icard, Gary Birsen, Dongjie An, Frédéric Pendino, Adrien Rouault, Nadège Bercovici, Diane Damotte, Audrey Lupo-Mansuet, Marco Alifano, Marie-Clotilde Alves-Guerra, Emmanuel Donnadieu.

The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.

DOI: https://doi.org/10.1038/s41467-024-46377-7
Cells. 2024 Mar 05. pii: 455. [Epub ahead of print]13(5):

Nicotinamide Riboside Augments Human Macrophage Migration via SIRT3-Mediated Prostaglandin E2 Signaling.

Jing Wu, Maximilian Bley, Russell S Steans, Allison M Meadows, Rebecca D Huffstutler, Rong Tian, Julian L Griffin, Michael N Sack.

  NAD+ boosting via nicotinamide riboside (NR) confers anti-inflammatory effects. However, its underlying mechanisms and therapeutic potential remain incompletely defined. Here, we showed that NR increased the expression of CC-chemokine receptor 7 (CCR7) in human M1 macrophages by flow cytometric analysis of cell surface receptors. Consequently, chemokine ligand 19 (CCL19, ligand for CCR7)-induced macrophage migration was enhanced following NR administration. Metabolomics analysis revealed that prostaglandin E2 (PGE2) was increased by NR in human monocytes and in human serum following in vivo NR supplementation. Furthermore, NR-mediated upregulation of macrophage migration through CCL19/CCR7 was dependent on PGE2 synthesis. We also demonstrated that NR upregulated PGE2 synthesis through SIRT3-dependent post-transcriptional regulation of cyclooxygenase 2 (COX-2). The NR/SIRT3/migration axis was further validated using the scratch-test model where NR and SIRT3 promoted more robust migration across a uniformly disrupted macrophage monolayer. Thus, NR-mediated metabolic regulation of macrophage migration and wound healing may have therapeutic potential for the topical management of chronic wound healing.

Keywords:  NAD+ boosting; SIRT3; chemotaxis; macrophage migration; nicotinamide riboside; prostaglandin E2

DOI:  https://doi.org/10.3390/cells13050455
bioRxiv. 2024 Mar 03. pii: 2024.02.28.582551. [Epub ahead of print]

Metabolic Deficiencies Underlie Plasmacytoid Dendritic Cell Exhaustion After Viral Infection.

Trever T Greene, Yeara Jo, Monica Macal, Ziyan Fang, Fawziyah S Khatri, Alicia L Codrington, Katelynn R Kazane, Carolina Chiale, Elizabeth Akbulut, Shobha Swaminathan, Yu Fujita, Patricia Fitzgerald-Bocarsly, Thekla Cordes, Christian Metallo, David A Scott, Elina I Zuniga.

Type I Interferons (IFN-I) are central to host protection against viral infections 1 . While any cell can produce IFN-I, Plasmacytoid Dendritic Cells (pDCs) make greater quantities and more varieties of these cytokines than any other cell type 2 . However, following an initial burst of IFN- I, pDCs lose their exceptional IFN-I production capacity and become "exhausted", a phenotype that associates with enhanced susceptibility to secondary infections 3-5 . Despite this apparent cost for the host, pDC exhaustion is conserved across multiple species and viral infections, but the underlying mechanisms and the potential evolutionary advantages are not well understood. Here we characterize pDC exhaustion and demonstrate that it is associated with a reduced capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a novel positive regulator of pDC IFN-I production in mice and humans, show that LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following a viral infection, and demonstrate that preservation of LDHB expression is sufficient to partially restore exhausted pDC function in vitro and in vivo . Furthermore, restoring LDHB in vivo in exhausted pDCs increased IFNAR dependent infection- associated pathology. Therefore, our work identifies a novel and conserved mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved but previously unexplained phenomenon of pDC exhaustion.

DOI: https://doi.org/10.1101/2024.02.28.582551
Sci Rep. 2024 03 11. 14(1): 5908

HSPA9 reduction exacerbates symptoms and cell death in DSS-Induced inflammatory colitis.

Soyoung Jang, Soyeon Jang, Jiwon Ko, Ji-Eun Bae, Hyejin Hyung, Ji Yeong Park, Su-Geun Lim, Sijun Park, Song Park, Junkoo Yi, Seonggon Kim, Myoung Ok Kim, Dong-Hyung Cho, Zae Young Ryoo.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that is influenced by various factors, including environmental factors, immune responses, and genetic elements. Among the factors that influence IBD progression, macrophages play a significant role in generating inflammatory mediators, and an increase in the number of activated macrophages contributes to cellular damage, thereby exacerbating the overall inflammatory conditions. HSPA9, a member of the heat shock protein 70 family, plays a crucial role in regulating mitochondrial processes and responding to oxidative stress. HSPA9 deficiency disrupts mitochondrial dynamics, increasing mitochondrial fission and the production of reactive oxygen species. Based on the known functions of HSPA9, we considered the possibility that HSPA9 reduction may contribute to the exacerbation of colitis and investigated its relevance. In a dextran sodium sulfate-induced colitis mouse model, the downregulated HSPA9 exacerbates colitis symptoms, including increased immune cell infiltration, elevated proinflammatory cytokines, decreased tight junctions, and altered macrophage polarization. Moreover, along with the increased mitochondrial fission, we found that the reduction in HSPA9 significantly affected the superoxide dismutase 1 levels and contributed to cellular death. These findings enhance our understanding of the intricate mechanisms underlying colitis and contribute to the development of novel therapeutic approaches for this challenging condition.

DOI: https://doi.org/10.1038/s41598-024-56216-w