bims-imicid 2024-02-11 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–02–11
twenty papers selected by
Dylan Ryan, University of Cambridge

Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.
Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production.
Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation.
A break in mitochondrial endosymbiosis as a basis for inflammatory diseases.
Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells.
IMMUNOMETABOLIC REGULATION OF BACTERIAL INFECTION, BIOFILMS, AND ANTIBIOTIC SUSCEPTIBILITY.
Regulation of genes involved in the metabolic adaptation of murine microglial cells in response to elevated HIF-1α mediated activation.
Tumor necrosis factor α-induced protein 8-like-2 controls microglia phenotype via metabolic reprogramming in BV2 microglial cells and responses to neuropathic pain.
Targeting the ACOD1-itaconate axis stabilizes atherosclerotic plaques.
Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases.
Immunometabolic adaptation of CD19-targeted CAR T cells in the central nervous system microenvironment of patients promotes memory development.
Resolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease.
Quantification of the Immunometabolite Protein Modifications S-2-Succinocysteine and 2,3- Dicarboxypropylcysteine.
PKM2 induces mitophagy through the AMPK-mTOR pathway promoting CSFV proliferation.
Mitochondrial Transplantation promotes protective effector and memory CD4 + T cell response during Mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4 + T cells.
1-Pyrroline-5-carboxylate inhibit T cell glycolysis in prostate cancer microenvironment by SHP1/PKM2/LDHB axis.
Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis.
Supplementation of nicotinamide mononucleotide diminishes COX-2 associated inflammatory responses in macrophages by activating kynurenine/AhR signaling.
Metabolic abnormalities in the bone marrow cells of young offspring born to obese mothers.
Newcastle disease virus infection remodels plasma phospholipid metabolism in chickens.

Cell Metab. 2024 Jan 23. pii: S1550-4131(24)00006-8. [Epub ahead of print]

Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.

Cegui Hu, Wen Qiao, Xiang Li, Zhi-Kun Ning, Jiang Liu, Sumiya Dalangood, Hanjun Li, Xiang Yu, Zhen Zong, Zhenke Wen, Jun Gui.

  Tumors employ diverse strategies for immune evasion. Unraveling the mechanisms by which tumors suppress anti-tumor immunity facilitates the development of immunotherapies. Here, we have identified tumor-secreted fibroblast growth factor 21 (FGF21) as a pivotal immune suppressor. FGF21 is upregulated in multiple types of tumors and promotes tumor progression. Tumor-secreted FGF21 significantly disrupts anti-tumor immunity by rewiring cholesterol metabolism of CD8+T cells. Mechanistically, FGF21 sustains the hyperactivation of AKT-mTORC1-sterol regulatory-element-binding protein 1 (SREBP1) signal axis in the activated CD8+T cells, resulting in the augment of cholesterol biosynthesis and T cell exhaustion. FGF21 knockdown or blockade using a neutralizing antibody normalizes AKT-mTORC1 signaling and reduces excessive cholesterol accumulation in CD8+T cells, thus restoring CD8+T cytotoxic function and robustly suppressing tumor growth. Our findings reveal FGF21 as a "secreted immune checkpoint" that hampers anti-tumor immunity, suggesting that inhibiting FGF21 could be a valuable strategy to enhance the cancer immunotherapy efficacy.

Keywords:  CD8(+)T; FGF21; cancer immunotherapy; cholesterol; mTORC1; tumor immune evasion

DOI:  https://doi.org/10.1016/j.cmet.2024.01.005
Nat Commun. 2024 Feb 06. 15(1): 1096

Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production.

Cristina Molina-López, Laura Hurtado-Navarro, Carlos J García, Diego Angosto-Bazarra, Fernando Vallejo, Ana Tapia-Abellán, Joana R Marques-Soares, Carmen Vargas, Segundo Bujan-Rivas, Francisco A Tomás-Barberán, Juan I Arostegui, Pablo Pelegrin.

Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that facilitate IL-1β production. Although these are gain-of-function variants characterized by hypersensitivity to cell priming, patients with CAPS and animal models of the disease may present inflammatory flares without identifiable external triggers. Here we find that CAPS-associated NLRP3 variants are forming constitutively active inflammasome, which induce increased basal cleavage of gasdermin D, IL-18 release and pyroptosis, with a concurrent basal pro-inflammatory gene expression signature, including the induction of nuclear receptors 4 A. The constitutively active NLRP3-inflammasome of CAPS is responsive to the selective NLRP3 inhibitor MCC950 and its activation is regulated by deubiquitination. Despite their preactivated state, the CAPS inflammasomes are responsive to activation of the NF-κB pathway. NLRP3-inflammasomes with CAPS-associated variants affect the immunometabolism of the myeloid compartment, leading to disruptions in lipids and amino acid pathways and impaired glycolysis, limiting IL-1β production. In summary, NLRP3 variants causing CAPS form a constitutively active inflammasome inducing pyroptosis and IL-18 release without cell priming, which enables the host's innate defence against pathogens while also limiting IL-1β-dependent inflammatory episodes through immunometabolism modulation.

DOI: https://doi.org/10.1038/s41467-024-44990-0
Cell Rep. 2024 Feb 07. pii: S2211-1247(24)00074-3. [Epub ahead of print]43(2): 113746

Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation.

Weiwei Shi, Tiffany J Cassmann, Aditya Vijay Bhagwate, Taro Hitosugi, W K Eddie Ip.

  Lactic acid has emerged as an important modulator of immune cell function. It can be produced by both gut microbiota and the host metabolism at homeostasis and during disease states. The production of lactic acid in the gut microenvironment is vital for tissue homeostasis. In the present study, we examined how lactic acid integrates cellular metabolism to shape the epigenome of macrophages during pro-inflammatory response. We found that lactic acid serves as a primary fuel source to promote histone H3K27 acetylation, which allows the expression of immunosuppressive gene program including Nr4a1. Consequently, macrophage pro-inflammatory function was transcriptionally repressed. Furthermore, the histone acetylation induced by lactic acid promotes a form of long-term immunosuppression ("trained immunosuppression"). Pre-exposure to lactic acid induces lipopolysaccharide tolerance. These findings thus indicate that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment.

Keywords:  CP: Immunology; CP: Metabolism; epigenetic reprogramming; histone acetylation; immunosuppression; inflammation; inflammatory bowel disease; lactic acid; macrophage; metabolism; metabolite sensing; tissue microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2024.113746
Nature. 2024 Feb;626(7998): 271-279

A break in mitochondrial endosymbiosis as a basis for inflammatory diseases.

Michael P Murphy, Luke A J O'Neill.

Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation. This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs. Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus. Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases. A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors. Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities. Thus, whereas mitochondria can be considered 'the enemy within' the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases.

DOI: https://doi.org/10.1038/s41586-023-06866-z
Cell Metab. 2024 Jan 30. pii: S1550-4131(24)00008-1. [Epub ahead of print]

Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells.

Theresa Ramalho, Patricia A Assis, Ogooluwa Ojelabi, Lin Tan, Brener Carvalho, Luiz Gardinassi, Osvaldo Campos, Philip L Lorenzi, Katherine A Fitzgerald, Cole Haynes, Douglas T Golenbock, Ricardo T Gazzinelli.

  Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy.

Keywords:  PD-1; PD-L1; Plasmodium chabaudi; TCA cycle; cGAS-STING; immuno checkpoint markers; inate immunity; itaconate; itaconic acid; lymphocytes; malaria; metabolism; methylenesuccinic acid; mitochondria; mitochondrial DNA; monocyte-derived dendritic cells; mtDNA

DOI:  https://doi.org/10.1016/j.cmet.2024.01.008
J Innate Immun. 2024 Feb 03.

IMMUNOMETABOLIC REGULATION OF BACTERIAL INFECTION, BIOFILMS, AND ANTIBIOTIC SUSCEPTIBILITY.

Ying-Tsun Chen, Gaurav Kumar Lohia, Samantha Chen, Sebastián A Riquelme.

BACKGROUND: Upon infection, mucosal tissues activate a brisk inflammatory response to clear the pathogen: i.e., resistance to disease. Resistance to disease is orchestrated by tissue-resident macrophages, which undergo profound metabolic reprogramming after sensing the pathogen. These metabolically activated macrophages release many inflammatory factors, which promote their bactericidal function. However, in immunocompetent individuals, pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, and Salmonella evade this type of immunity, generating communities that thrive for the long term.
SUMMARY: These organisms develop features that render them less susceptible to eradication, such as biofilms and increased tolerance to antibiotics. Furthermore, after antibiotic therapy withdraw, "persister" cells rapidly upsurge, triggering inflammatory relapses that worsen host health. How these pathogens persist in inflamed tissues replete with activated macrophages remains poorly understood.
KEY MESSAGES: In this review, we discuss recent findings indicating that the ability of P. aeruginosa, S. aureus, and Salmonella to evolve biofilms and antibiotic tolerance is promoted by the similar metabolic routes that regulate macrophage metabolic reprogramming.

DOI: https://doi.org/10.1159/000536649
Immunogenetics. 2024 Feb 08.

Regulation of genes involved in the metabolic adaptation of murine microglial cells in response to elevated HIF-1α mediated activation.

Ida Florance, Seenivasan Ramasubbu.

  Microglia cells are activated in response to different stress signals. Several metabolic adaptations underlie microglia activation in the brain. Among these, in conditions like ischemic stroke and, hypoxic stress stimuli activate microglia cells. Hypoxic stress is mediated by HIF-1α. Although HIF-1α has been implicated in the alteration of metabolic pathways, changes in microglia lipid metabolism during M1 activation of microglia induced by elevated HIF-1α levels are yet to be understood. This can also merit interest in the development of novel targets to mitigate chronic inflammation. Our study aims to elucidate the transcriptional regulation of metabolic pathways in microglia cells during HIF-1α mediated activation. To study the adaptations in the metabolic pathways we induced microglia activation, by activating HIF-1α. Here, we show that microglia cells activated in response to elevated HIF-1α require ongoing lipogenesis and fatty acid breakdown. Notably, autophagy is activated during the initial stages of microglia activation. Inhibition of autophagy in activated microglia affects their viability and phagocytic activity. Collectively, our study expands the understanding of the molecular link between autophagy, lipid metabolism, and inflammation during HIF-1α mediated microglial activation that can lead to the development of promising strategies for controlling maladaptive activation states of microglia responsible for neuroinflammation. Together, our findings suggest that the role of HIF-1α in regulating metabolic pathways during hypoxia in microglia is beyond optimization of glucose utilization and distinctly regulates lipid metabolism during pro-inflammatory activation.

Keywords:  Autophagy; HIF-1 alpha; Hypoxia; Lipid accumulation; Microglia; Palmitic acid

DOI:  https://doi.org/10.1007/s00251-024-01334-y
Int J Biochem Cell Biol. 2024 Feb 01. pii: S1357-2725(24)00032-3. [Epub ahead of print]169 106541

Tumor necrosis factor α-induced protein 8-like-2 controls microglia phenotype via metabolic reprogramming in BV2 microglial cells and responses to neuropathic pain.

Yeqi Li, Cui Yin, Jinhong Jiang, Huan Yang, Feifei Zhang, Yanhong Xing, Wuyang Wang, Chen Lu.

  Microglial are major players in neuroinflammation that have recently emerged as potential therapeutic targets for neuropathic pain. Glucose metabolic programming has been linked to differential activation state and function in microglia. Tumor necrosis factor α-induced protein 8-like-2 (TNFAIP8L2) is an important component in regulating the anti-inflammatory response. However, the role of TNFAIP8L2 in microglia differential state during neuropathic pain and its interplay with glucose metabolic reprogramming in microglia has not yet been determined. Thus, we aimed to investigate the role of TNFAIP8L2 in the status of microglia in vitro and in vivo. BV2 microglial cells were treated with lipopolysaccharides plus interferon-gamma (LPS/IFNγ) or interleukin-4 (IL-4) to induce the two different phenotypes of microglia in vitro. In vivo experiments were conducted by chronic constriction injury of the sciatic nerve (CCI). We investigated whether TNFAIP8L2 regulates glucose metabolic programming in BV2 microglial cells. The data in vitro showed that TNFAIP8L2 lowers glycolysis and increases mitochondrial oxidative phosphorylation (OXPHOS) in inflammatory microglia. Blockade of glycolytic pathway abolished TNFAIP8L2-mediated differential activation of microglia. TNFAIP8L2 suppresses inflammatory microglial activation and promotes restorative microglial activation in BV2 microglial cells and in spinal cord microglia after neuropathic pain. Furthermore, TNFAIP8L2 controls differential activation of microglia and glucose metabolic reprogramming through the MAPK/mTOR/HIF-1α signaling axis. This study reveals that TNFAIP8L2 plays a critical role in neuropathic pain, providing important insights into glucose metabolic reprogramming and microglial phenotypic transition, which indicates that TNFAIP8L2 may be used as a potential drug target for the prevention of neuropathic pain.

Keywords:  HIF-1α; Metabolic reprogramming; Microglia; Neuropathic pain; TNFAIP8L2

DOI:  https://doi.org/10.1016/j.biocel.2024.106541
Redox Biol. 2024 Jan 22. pii: S2213-2317(24)00030-2. [Epub ahead of print]70 103054

Targeting the ACOD1-itaconate axis stabilizes atherosclerotic plaques.

Karl J Harber, Annette E Neele, Cindy Paa van Roomen, Marion Jj Gijbels, Linda Beckers, Myrthe den Toom, Bauke V Schomakers, Daan Af Heister, Lisa Willemsen, Guillermo R Griffith, Kyra E de Goede, Xanthe Amh van Dierendonck, Myrthe E Reiche, Aurélie Poli, Frida L-H Mogensen, Alessandro Michelucci, Sanne Gs Verberk, Helga de Vries, Michel van Weeghel, Jan Van den Bossche, Menno Pj de Winther.

  Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr-/- atherogenic mice transplanted with Acod1-/- bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1-/- mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.

Keywords:  Acod1; Atherosclerosis; IRG1; Immunometabolism; Itaconate; Macrophage

DOI:  https://doi.org/10.1016/j.redox.2024.103054
J Inflamm Res. 2024 ;17 603-616

Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases.

Yushan Xu, Miaomiao Li, Mengjiao Lin, Dawei Cui, Jue Xie.

  CD4+ T cells play a critical role in the pathogenesis of viral diseases, which are activated by the internal metabolic pathways encountering with viral antigens. Glutaminolysis converts glutamine into tricarboxylic acid (TCA) circulating metabolites by α-ketoglutaric acid, which is essential for the proliferation and differentiation of CD4+ T cells and plays a central role in providing the energy and structural components needed for viral replication after the virus hijacks the host cell. Changes in glutaminolysis in CD4+ T cells are accompanied by changes in the viral status of the host cell due to competition for glutamine between immune cells and host cells. More recently, attempts have been made to treat tumours, autoimmune diseases, and viral diseases by altering the breakdown of glutamine in T cells. In this review, we will discuss the current knowledge of glutaminolysis in the CD4+ T cell subsets from viral diseases, not only increasing our understanding of immunometabolism but also providing a new perspective for therapeutic target in viral diseases.

Keywords:  CD4+ T cells; glutamine; glutaminolysis; immune response; viral diseases

DOI:  https://doi.org/10.2147/JIR.S443482
Cancer Res. 2024 Feb 05.

Immunometabolic adaptation of CD19-targeted CAR T cells in the central nervous system microenvironment of patients promotes memory development.

Lior Goldberg, Eric R Haas, Ryan Urak, Vibhuti Vyas, Khyatiben V Pathak, Krystine Garcia-Mansfield, Patrick Pirrotte, Jyotsana Singhal, James L Figarola, Ibrahim Aldoss, Stephen J Forman, Xiuli Wang.

Metabolic reprogramming is a hallmark of T cell activation, and metabolic fitness is fundamental for T cell-mediated anti-tumor immunity. Insights into the metabolic plasticity of chimeric antigen receptor (CAR) T cells in patients could help identify approaches to improve their efficacy in treating cancer. Here, we investigated the spatiotemporal immunometabolic adaptation of CD19-targeted CAR T cells using clinical samples from CAR T cell-treated patients. Context-dependent immunometabolic adaptation of CAR T cells demonstrated the link between their metabolism, activation, differentiation, function, and local microenvironment. Specifically, compared to the peripheral blood, low lipid availability, high IL-15, and low TGFβ in the central nervous system microenvironment promoted immunometabolic adaptation of CAR T cells, including upregulation of a lipolytic signature and memory properties. Pharmacologic inhibition of lipolysis in cerebrospinal fluid led to decreased CAR T cell survival. Furthermore, manufacturing CAR T cells in cerebrospinal fluid enhanced their metabolic fitness and anti-leukemic activity. Overall, this study elucidates spatiotemporal immunometabolic rewiring of CAR T cells in patients and demonstrates that these adaptations can be exploited to maximize the therapeutic efficacy of CAR T cells.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2299
Nat Commun. 2024 Feb 05. 15(1): 975

Resolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease.

Mary E Walker, Roberta De Matteis, Mauro Perretti, Jesmond Dalli.

While cardiovascular disease (CVD) is one of the major co-morbidities in patients with rheumatoid arthritis (RA), the mechanism(s) that contribute to CVD in patients with RA remain to be fully elucidated. Herein, we observe that plasma concentrations of 13-series resolvin (RvT)4 negatively correlate with vascular lipid load in mouse inflammatory arthritis. Administration of RvT4 to male arthritic mice fed an atherogenic diet significantly reduces atherosclerosis. Assessment of the mechanisms elicited by this mediator demonstrates that RvT4 activates cholesterol efflux in lipid laden macrophages via a Scavenger Receptor class B type 1 (SR-BI)-Neutral Cholesterol Ester Hydrolase-dependent pathway. This leads to the reprogramming of lipid laden macrophages yielding tissue protection. Pharmacological inhibition or knockdown of macrophage SR-BI reverses the vasculo-protective activities of RvT4 in vitro and in male mice in vivo. Together these findings elucidate a RvT4-SR-BI centered mechanism that orchestrates macrophage responses to limit atherosclerosis during inflammatory arthritis.

DOI: https://doi.org/10.1038/s41467-024-44868-1
Am J Physiol Endocrinol Metab. 2024 Feb 07.

Quantification of the Immunometabolite Protein Modifications S-2-Succinocysteine and 2,3- Dicarboxypropylcysteine.

J Hunter Cox, Richard S McCain, Emery Tran, Shoba Swaminathan, Holland H Smith, Gerardo G Piroli, Michael Shtutman, Michael D Walla, William E Cotham, Norma Frizzell.

  The tricarboxylic acid (TCA) cycle metabolite fumarate non-enzymatically reacts with the amino acid cysteine to form S-(2-succino)cysteine (2SC), referred to as protein succination. The immunometabolite itaconate accumulates during lipopolysaccharide (LPS) stimulation of macrophages and microglia. Itaconate non-enzymatically reacts with cysteine residues to generate 2,3-dicarboxypropylcysteine (2,3-DCP), referred to as protein dicarboxypropylation. Since fumarate and itaconate levels dynamically change in activated immune cells, the levels of both 2SC and 2,3-DCP reflect the abundance of these metabolites and their capacity to modify protein thiols. We generated ethyl esters of 2SC and 2,3-DCP from protein hydrolysates and used stable isotope dilution mass spectrometry to determine the abundance of these in LPS-stimulated Highly Aggressively Proliferating Immortalized (HAPI) microglia). To quantify the stoichiometry of succination and dicarboxypropylation, reduced cysteines were alkylated with iodoacetic acid to form S-carboxymethylcysteine (CMC) which was then esterified. Itaconate derived 2,3-DCP, but not fumarate derived 2SC, increased in LPS-treated HAPI microglia. Stoichiometric measurements demonstrated that 2,3-DCP increased from 1.57 to 9.07% of total cysteines upon LPS stimulation. This methodology to simultaneously distinguish and quantify both 2SC and 2,3-DCP will have broad applications in the physiology of metabolic diseases. In addition, we find that available anti-2SC antibodies also detect the structurally similar 2,3-DCP, therefore 'succinate moiety' may better describe the antigen recognized.

Keywords:  fumarate; immunometabolism; itaconate; microglia; protein modification

DOI:  https://doi.org/10.1152/ajpendo.00354.2023
J Virol. 2024 Feb 06. e0175123

PKM2 induces mitophagy through the AMPK-mTOR pathway promoting CSFV proliferation.

Xiaodi Liu, Quanhui Yan, Xueyi Liu, Wenkang Wei, Linke Zou, Feifan Zhao, Sen Zeng, Lin Yi, Hongxing Ding, Mingqiu Zhao, Jinding Chen, Shuangqi Fan.

  Viruses exploit the host cell's energy metabolism system to support their replication. Mitochondria, known as the powerhouse of the cell, play a critical role in regulating cell survival and virus replication. Our prior research indicated that the classical swine fever virus (CSFV) alters mitochondrial dynamics and triggers glycolytic metabolic reprogramming. However, the role and mechanism of PKM2, a key regulatory enzyme of glycolytic metabolism, in CSFV replication remain unclear. In this study, we discovered that CSFV enhances PKM2 expression and utilizes PKM2 to inhibit pyruvate production. Using an affinity purification coupled mass spectrometry system, we successfully identified PKM as a novel interaction partner of the CSFV non-structural protein NS4A. Furthermore, we validated the interaction between PKM2 and both CSFV NS4A and NS5A through co-immunoprecipitation and confocal analysis. PKM2 was found to promote the expression of both NS4A and NS5A. Moreover, we observed that PKM2 induces mitophagy by activating the AMPK-mTOR signaling pathway, thereby facilitating CSFV proliferation. In summary, our data reveal a novel mechanism whereby PKM2, a metabolic enzyme, promotes CSFV proliferation by inducing mitophagy. These findings offer a new avenue for developing antiviral strategies.IMPORTANCEViruses rely on the host cell's material-energy metabolic system for replication, inducing host metabolic disorders and subsequent immunosuppression-a major contributor to persistent viral infections. Classical swine fever virus (CSFV) is no exception. Classical swine fever is a severe acute infectious disease caused by CSFV, resulting in significant economic losses to the global pig industry. While the role of the metabolic enzyme PKM2 (pyruvate dehydrogenase) in the glycolytic pathway of tumor cells has been extensively studied, its involvement in viral infection remains relatively unknown. Our data unveil a new mechanism by which the metabolic enzyme PKM2 mediates CSFV infection, offering novel avenues for the development of antiviral strategies.

Keywords:  AMPK-mTOR; cellular metabolism; classical swine fever virus; mitophagy; pyruvate kinase M2; viral infection

DOI:  https://doi.org/10.1128/jvi.01751-23
bioRxiv. 2024 Jan 27. pii: 2024.01.24.577036. [Epub ahead of print]

Mitochondrial Transplantation promotes protective effector and memory CD4 + T cell response during Mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4 + T cells.

Colwyn A Headley, Shalini Gautam, Angelica Olmo-Fontanez, Andreu Garcia-Vilanova, Varun Dwivedi, Alyssa Schami, Susan Weintraub, Philip S Tsao, Jordi B Torrelles, Joanne Turner.

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis ( M.tb ), remains a significant health concern worldwide, especially in populations with weakened or compromised immune systems, such as the elderly. Proper adaptive immune function, particularly a CD4 + T cell response, is central to host immunity against M.tb . Chronic infections, such as M.tb , as well as aging promote T cell exhaustion and senescence, which can impair immune control and promote progression to TB disease. Mitochondrial dysfunction contributes to T cell dysfunction, both in aging and chronic infections and diseases. Mitochondrial perturbations can disrupt cellular metabolism, enhance oxidative stress, and impair T-cell signaling and effector functions. This study examined the impact of mitochondrial transplantation (mito-transfer) on CD4 + T cell differentiation and function using aged mouse models and human CD4 + T cells from elderly individuals. Our study revealed that mito-transfer in naïve CD4 + T cells promoted the generation of protective effector and memory CD4 + T cells during M.tb infection in mice. Further, mito-transfer enhanced the function of elderly human T cells by increasing their mitochondrial mass and modulating cytokine production, which in turn reduced exhaustion and senescence cell markers. Our results suggest that mito-transfer could be a novel strategy to reestablish aged CD4 + T cell function, potentially improving immune responses in the elderly and chronic TB patients, with a broader implication for other diseases where mitochondrial dysfunction is linked to T cell exhaustion and senescence.

DOI: https://doi.org/10.1101/2024.01.24.577036
Cell Commun Signal. 2024 Feb 08. 22(1): 101

1-Pyrroline-5-carboxylate inhibit T cell glycolysis in prostate cancer microenvironment by SHP1/PKM2/LDHB axis.

Lei Chang, Guohao Li, Shan Jiang, Jie Li, Jin Yang, Kavita Shah, Le Zhou, Hanrui Song, Leyuan Deng, Zhiguo Luo, Yonglian Guo, Yutao Yan.

   BACKGROUND: Our previous studies demonstrated that 1-Pyrroline-5-carboxylate (P5C) released by prostate cancer cells inhibits T cell proliferation and function by increasing SHP1 expression. We designed this study to further explore the influence of P5C on T cell metabolism, and produced an antibody for targeting P5C to restore the functions of T cells.
METHOD: We co-immunoprecipated SHP1 from T cells and analyzed the proteins that were bound to it using liquid chromatography mass spectrometry (LC/MS-MS). The influence of P5C on T cells metabolism was also detected by LC/MS-MS. Seahorse XF96 analyzer was further used to identify the effect of P5C on T cells glycolysis. We subsequently designed and produced an antibody for targeting P5C by monoclonal technique and verified its effectiveness to restore the function of T cells in vitro and in vivo.
RESULT: PKM2 and LDHB bind SHP1 in T cells, and P5C could increase the levels of p-PKM2 while having no effect on the levels of PKM2 and LDHB. We further found that P5C influences T cell energy metabolism and carbohydrate metabolism. P5C also inhibits the activity of PKM2 and decreases the content of intracellular lactic acid while increasing the activity of LDH. Using seahorse XF96 analyzer, we confirmed that P5C remarkably inhibits glycolysis in T cells. We produced an antibody for targeting P5C by monoclonal technique and verified that the antibody could oppose the influence of P5C to restore the process of glycolysis and function in T cells. Meanwhile, the antibody also inhibits the growth of prostate tumors in an animal model.
CONCLUSION: Our study revealed that P5C inhibits the process of glycolysis in T cells by targeting SHP1/PKM2/LDHB complexes. Moreover, it is important that the antibody for targeting P5C could restore the function of T cells and inhibit the growth of prostate tumors.

Keywords:  Glycolysis; P5C; Prostate cancer; SHP1; T cell

DOI:  https://doi.org/10.1186/s12964-024-01493-1
EBioMedicine. 2024 Feb 06. pii: S2352-3964(24)00028-8. [Epub ahead of print]101 104993

Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis.

Zhaoli Luo, Ziyang Sheng, Liye Hu, Lei Shi, Yichen Tian, Xiaochu Zhao, Wei Yang, Zhongnan Xiao, Danmin Shen, Weihua Wu, Ting Lan, Boqian Zhao, Xiaogang Wang, Nan Zhuang, Jian-Nan Zhang, Yamei Wang, Yabin Lu, Liyong Wang, Chenguang Zhang, Peipei Wang, Jing An, Fei Yang, Qian Li.

   BACKGROUND: Macrophages are innate immune cells whose phagocytosis function is critical to the prognosis of stroke and peritonitis. cis-aconitic decarboxylase immune-responsive gene 1 (Irg1) and its metabolic product itaconate inhibit bacterial infection, intracellular viral replication, and inflammation in macrophages. Here we explore whether itaconate regulates phagocytosis.
METHODS: Phagocytosis of macrophages was investigated by time-lapse video recording, flow cytometry, and immunofluorescence staining in macrophage/microglia cultures isolated from mouse tissue. Unbiased RNA-sequencing and ChIP-sequencing assays were used to explore the underlying mechanisms. The effects of Irg1/itaconate axis on the prognosis of intracerebral hemorrhagic stroke (ICH) and peritonitis was observed in transgenic (Irg1flox/flox; Cx3cr1creERT/+, cKO) mice or control mice in vivo.
FINDINGS: In a mouse model of ICH, depletion of Irg1 in macrophage/microglia decreased its phagocytosis of erythrocytes, thereby exacerbating outcomes (n = 10 animals/group, p < 0.05). Administration of sodium itaconate/4-octyl itaconate (4-OI) promoted macrophage phagocytosis (n = 7 animals/group, p < 0.05). In addition, in a mouse model of peritonitis, Irg1 deficiency in macrophages also inhibited phagocytosis of Staphylococcus aureus (n = 5 animals/group, p < 0.05) and aggravated outcomes (n = 9 animals/group, p < 0.05). Mechanistically, 4-OI alkylated cysteine 155 on the Kelch-like ECH-associated protein 1 (Keap1), consequent in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and transcriptional activation of Cd36 gene. Blocking the function of CD36 completely abolished the phagocytosis-promoting effects of Irg1/itaconate axis in vitro and in vivo.
INTERPRETATION: Our findings provide a potential therapeutic target for phagocytosis-deficiency disorders, supporting further development towards clinical application for the benefit of stroke and peritonitis patients.
FUNDING: The National Natural Science Foundation of China (32070735, 82371321 to Q. Li, 82271240 to F. Yang) and the Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ202010025033 to Q. Li).

Keywords:  Intracerebral hemorrhagic stroke; Irg1; Itaconate; Macrophage; Peritonitis; Phagocytosis

DOI:  https://doi.org/10.1016/j.ebiom.2024.104993
Free Radic Biol Med. 2024 Feb 07. pii: S0891-5849(24)00054-6. [Epub ahead of print]

Supplementation of nicotinamide mononucleotide diminishes COX-2 associated inflammatory responses in macrophages by activating kynurenine/AhR signaling.

Jing Liu, Wenxuan Hou, Zhaoyun Zong, Yuling Chen, Xiaohui Liu, Ran Zhang, Haiteng Deng.

  Cyclooxygenase-2 (COX-2) is an inducible enzyme responsible for prostaglandin synthesis during inflammation and immune responses. Our previous results show that NAD+ level decreased in activated macrophages while nicotinamide mononucleotide (NMN) supplementation suppressed the inflammatory responses via restoring NAD+ level and downregulating COX-2. However, whether NMN downregulates COX-2 in mouse model of inflammation, and its underlying mechanism needs to be further explored. In the present study, we established LPS- and alum-induced inflammation model and demonstrated that NMN suppressed the inflammatory responses in vivo. Quantitative proteomics in mouse peritoneal macrophages identified that NMN activated AhR signaling pathway in activated macrophages. Furthermore, we revealed that NMN supplementation led to IDO1 activation and kynurenine accumulation, which caused AhR nuclear translocation and activation. On the other hand, AhR or IDO1 knockout abolished the effects of NMN on suppressing COX-2 expression and inflammatory responses in macrophages. In summary, our results demonstrated that NMN suppresses inflammatory responses by activating IDO-kynurenine-AhR pathway, and suggested that administration of NMN in early-stage immuno-activation may cause an adverse health effect.

Keywords:  AhR; COX-2; Inflammation; Kynurenine; Mouse peritoneal macrophage; Nicotinamide mononucleotide

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.046
Res Sq. 2024 Jan 16. pii: rs.3.rs-3830161. [Epub ahead of print]

Metabolic abnormalities in the bone marrow cells of young offspring born to obese mothers.

Maloyan Alina, Elysse Phillips, Yem Alharithi, Leena Kadam, Lisa Coussens, Sushil Kumar.

Intrauterine metabolic reprogramming occurs in obese mothers during gestation, putting the offspring at high risk of developing obesity and associated metabolic disorders even before birth. We have generated a mouse model of maternal high-fat diet-induced obesity that recapitulates the metabolic changes seen in humans born to obese women. Here, we profiled and compared the metabolic characteristics of bone marrow cells of newly weaned 3-week-old offspring of dams fed either a high-fat (Off-HFD) or a regular diet (Off-RD). We utilized a state-of-the-art targeted metabolomics approach coupled with a Seahorse metabolic analyzer. We revealed significant metabolic perturbation in the offspring of HFD-fed vs. RD-fed dams, including utilization of glucose primarily via oxidative phosphorylation. We also found a reduction in levels of amino acids, a phenomenon previously linked to bone marrow aging. Using flow cytometry, we identified a unique B cell population expressing CD19 and CD11b in the bone marrow of three-week-old offspring of high-fat diet-fed mothers, and found increased expression of Cyclooxygenase-2 (COX-2) on myeloid CD11b, and on CD11b hi B cells. Altogether, we demonstrate that the offspring of obese mothers show metabolic and immune changes in the bone marrow at a very young age and prior to any symptomatic metabolic disease.

DOI: https://doi.org/10.21203/rs.3.rs-3830161/v1
iScience. 2024 Feb 16. 27(2): 108962

Newcastle disease virus infection remodels plasma phospholipid metabolism in chickens.

Jun Dai, Xusheng Qiu, Xinyuan Cui, Yiyi Feng, Yuechi Hou, Yingjie Sun, Ying Liao, Lei Tan, Cuiping Song, Weiwei Liu, Yongyi Shen, Chan Ding.

  Newcastle disease is a global problem that causes huge economic losses and threatens the health and welfare of poultry. Despite the knowledge gained on the metabolic impact of NDV on cells, the extent to which infection modifies the plasma metabolic network in chickens remains unknown. Herein, we performed targeted metabolomic and lipidomic to create a plasma metabolic network map during NDV infection. Meanwhile, we used single-cell RNA sequencing to explore the heterogeneity of lung tissue cells in response to NDV infection in vivo. The results showed that NDV remodeled the plasma phospholipid metabolism network. NDV preferentially targets infected blood endothelial cells, antigen-presenting cells, fibroblasts, and neutrophils in lung tissue. Importantly, NDV may directly regulate ribosome protein transcription to facilitate efficient viral protein translation. In conclusion, NDV infection remodels the plasma phospholipid metabolism network in chickens. This work provides valuable insights to further understand the pathogenesis of NDV.

Keywords:  Cell biology; Virology

DOI:  https://doi.org/10.1016/j.isci.2024.108962