bims-imicid 2024-07-28 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–07–28
27 papers selected by
Dylan Ryan, University of Cambridge

Complex roles for mitochondrial complexes in microglia.
Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
Metabolic Messengers: itaconate.
Immunometabolites in viral infections: Action mechanism and function.
Roles of Critical Amino Acids Metabolism in The Interactions Between Intracellular Bacterial Infection and Macrophage Function.
Metabolic Regulation in the Induction of Trained Immunity.
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.
Role of glucose metabolism reprogramming in keratinocytes in the link between psoriasis and metabolic syndrome.
Dysregulated cytokine and oxidative response in hyper-glycolytic monocytes in obesity.
Desaminotyrosine is a redox-active microbial metabolite that bolsters macrophage antimicrobial functions while attenuating IL-6 production.
Metabolism and HSC fate: what NADPH is made for.
Metabolic determinants of germinal center B cell formation and responses.
Immunometabolic alteration of CD4+ T cells in the pathogenesis of primary Sjögren's syndrome.
Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis.
A small intestinal bile acid modulates the gut microbiome to improve host metabolic phenotypes following bariatric surgery.
Revealing metabolic alterations in brucellosis patients by targeted metabolomics.
Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux.
An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
Iron scavenging and myeloid cell polarization.
Lactate: a missing link between metabolism and inflammation in CKD progression?
Derivation of novel metabolic pathway score identifies alanine metabolism as a targetable influencer of TNF-alpha signaling.
Dietary glutamine supports mucosal germinal center B cell lymphomas.
Host cell CRISPR genomics and modelling reveal shared metabolic vulnerabilities in the intracellular development of Plasmodium falciparum and related hemoparasites.
High Glucose Increases Lactate and Induces the Transforming Growth Factor Beta-Smad 1/5 Atherogenic Pathway in Primary Human Macrophages.
Temporal changes in plasma metabolic signatures to predict immune response of antiretroviral therapy among people living with HIV.

Nat Metab. 2024 Jul 24.

Complex roles for mitochondrial complexes in microglia.

Rosa C Paolicelli, Stefano Pluchino.

DOI: https://doi.org/10.1038/s42255-024-01095-8
Nat Metab. 2024 Jul 24.

Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.

Bella Mora-Romero, Nicolas Capelo-Carrasco, Juan J Pérez-Moreno, María I Alvarez-Vergara, Laura Trujillo-Estrada, Carmen Romero-Molina, Emilio Martinez-Marquez, Noelia Morano-Catalan, Marisa Vizuete, Jose Lopez-Barneo, Jose L Nieto-Gonzalez, Pablo Garcia-Junco-Clemente, Javier Vitorica, Antonia Gutierrez, David Macias, Alicia E Rosales-Nieves, Alberto Pascual.

Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.

DOI: https://doi.org/10.1038/s42255-024-01081-0
Nat Metab. 2024 Jul 24.

Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.

Joshua S Stoolman, Rogan A Grant, Taylor A Poor, Samuel E Weinberg, Karis B D'Alessandro, Jerica Tan, Jennifer Yuan-Shih Hu, Megan E Zerrer, Walter A Wood, Madeline C Harding, Sahil Soni, Karen M Ridge, Paul T Schumacker, G R Scott Budinger, Navdeep S Chandel.

Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer's disease and the response to demyelinating injury1-5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7-10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.

DOI: https://doi.org/10.1038/s42255-024-01080-1
Nat Metab. 2024 Jul 26.

Metabolic Messengers: itaconate.

A F McGettrick, L A Bourner, F C Dorsey, L A J O'Neill.

The metabolite itaconate has emerged as an important immunoregulator with roles in antibacterial defence, inhibition of inflammation and, more recently, as an inhibitory factor in obesity. Itaconate is one of the most upregulated metabolites in inflammatory macrophages. It is produced owing to the disturbance of the tricarboxylic acid cycle and the diversion of aconitate to itaconate via the enzyme aconitate decarboxylase 1. In immunology, initial studies concentrated on the role of itaconate in inflammatory macrophages where it was shown to be inhibitory, but this has expanded as the impact of itaconate on other cell types is starting to emerge. This review focuses on itaconate as a key immunoregulatory metabolite and describes its diverse mechanisms of action and its many impacts on the immune and inflammatory responses and in cancer. We also examine the clinical relevance of this immunometabolite and its therapeutic potential for immune and inflammatory diseases.

DOI: https://doi.org/10.1038/s42255-024-01092-x
J Med Virol. 2024 Jul;96(7): e29807

Immunometabolites in viral infections: Action mechanism and function.

Behnaz Bouzari, Uliana Y Chugaeva, Sajad Karampoor, Rasoul Mirzaei.

  The interplay between viral pathogens and host metabolism plays a pivotal role in determining the outcome of viral infections. Upon viral detection, the metabolic landscape of the host cell undergoes significant changes, shifting from oxidative respiration via the tricarboxylic acid (TCA) cycle to increased aerobic glycolysis. This metabolic shift is accompanied by elevated nutrient accessibility, which is vital for cell function, development, and proliferation. Furthermore, depositing metabolites derived from fatty acids, TCA intermediates, and amino acid catabolism accelerates the immunometabolic transition, facilitating pro-inflammatory and antimicrobial responses. Immunometabolites refer to small molecules involved in cellular metabolism regulating the immune response. These molecules include nutrients, such as glucose and amino acids, along with metabolic intermediates and signaling molecules adenosine, lactate, itaconate, succinate, kynurenine, and prostaglandins. Emerging evidence suggests that immunometabolites released by immune cells establish a complex interaction network within local niches, orchestrating and fine-tuning immune responses during viral diseases. However, our current understanding of the immense capacity of metabolites to convey essential cell signals from one cell to another or within cellular compartments remains incomplete. Unraveling these complexities would be crucial for harnessing the potential of immunometabolites in therapeutic interventions. In this review, we discuss specific immunometabolites and their mechanisms of action in viral infections, emphasizing recent findings and future directions in this rapidly evolving field.

Keywords:  antimicrobial defense; immune responses; immunometabolites; metabolism; viral infection

DOI:  https://doi.org/10.1002/jmv.29807
Curr Microbiol. 2024 Jul 20. 81(9): 280

Roles of Critical Amino Acids Metabolism in The Interactions Between Intracellular Bacterial Infection and Macrophage Function.

Zuowei Zhang, Yurou Wang, Lin Xia, Ying Zhang.

Macrophages, as crucial participants in the innate immune system, respond to pathogenic challenges through their dynamic metabolic adjustments, demonstrating the intimate interplay between cellular metabolism and immune function. Bacterial infection of macrophages causes changes in macrophage metabolism, affecting both macrophage function and bacterial virulence and intracellular survival. This review explores the reprogramming of amino acid metabolism in macrophages in response to bacterial infection, with a particular focus on the influence of critical amino acids such as serine, glutamine, and arginine on the immune functions of macrophages; highlights the roles of these metabolic pathways in macrophage functions such as phagocytosis, inflammatory response, immune regulation, and pathogen clearance; reveals how pathogens exploit and manipulate the amino acid metabolism within macrophages to support their own growth and replication, thereby showcasing the intricate interplay between macrophages and pathogens. It provides a foundation for understanding the interactions between macrophages amino acid metabolism and pathogens, offering potential strategies and therapeutic targets for the development of novel anti-infection therapies.

DOI: https://doi.org/10.1007/s00284-024-03801-x
Semin Immunopathol. 2024 Jul 25. 46(3-4): 7

Metabolic Regulation in the Induction of Trained Immunity.

Anaisa V Ferreira, Jorge Domínguez-Andrés, Laura M Merlo Pich, Leo A B Joosten, Mihai G Netea.

  The innate immune system exhibits features of memory, termed trained immunity, which promote faster and more robust responsiveness to heterologous challenges. Innate immune memory is sustained through epigenetic modifications, affecting gene accessibility, and promoting a tailored gene transcription for an enhanced immune response. Alterations in the epigenetic landscape are intertwined with metabolic rewiring. Here, we review the metabolic pathways that underscore the induction and maintenance of trained immunity, including glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, and amino acid and lipid metabolism. The intricate interplay of these pathways is pivotal for establishing innate immune memory in distinct cellular compartments. We explore in particular the case of resident lung alveolar macrophages. We propose that leveraging the memory of the innate immune system may present therapeutic potential. Specifically, targeting the metabolic programs of innate immune cells is an emerging strategy for clinical interventions, either to boost immune responses in immunosuppressed conditions or to mitigate maladaptive activation in hyperinflammatory diseases.

Keywords:  Epigenetics; Metabolism; Therapy; Trained immunity

DOI:  https://doi.org/10.1007/s00281-024-01015-8
Adv Sci (Weinh). 2024 Jul 22. e2401077

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 Mycobacterium tuberculosis (M.tb), is a major global health concern, particularly affecting those with weakened immune systems, including the elderly. CD4+ T cell response is crucial for immunity against M.tb, but chronic infections and aging can lead to T cell exhaustion and senescence, worsening TB disease. Mitochondrial dysfunction, prevalent in aging and chronic diseases, disrupts cellular metabolism, increases oxidative stress, and impairs T-cell functions. This study investigates the effect of mitochondrial transplantation (mito-transfer) on CD4+ T cell differentiation and function in aged mouse models and human CD4+ T cells from elderly individuals. Mito-transfer in naïve CD4+ T cells is found to promote protective effector and memory T cell generation during M.tb infection in mice. Additionally, it improves elderly human T cell function by increasing mitochondrial mass and altering cytokine production, thereby reducing markers of exhaustion and senescence. These findings suggest mito-transfer as a novel approach to enhance aged CD4+ T cell functionality, potentially benefiting immune responses in the elderly and chronic TB patients. This has broader implications for diseases where mitochondrial dysfunction contributes to T-cell exhaustion and senescence.

Keywords:  CD4+ T Cells; T cell exhaustion; T cell senescence; cellular reprogramming; immune aging; immunometabolism; mitochondrial dysfunction; mitochondrial reprogramming; mitochondrial transplantation; oxidative stress; tuberculosis

DOI:  https://doi.org/10.1002/advs.202401077
Int Immunopharmacol. 2024 Jul 19. pii: S1567-5769(24)01225-6. [Epub ahead of print]139 112704

Role of glucose metabolism reprogramming in keratinocytes in the link between psoriasis and metabolic syndrome.

Liang Yan, Wenqiu Wang, Yuxin Qiu, Chongli Yu, Rui Wang, Chengxin Li.

  The mechanism linking psoriasis to metabolic syndrome (MetS) remains poorly understood. Recent reports indicate upregulation of glycolysis-related proteins in psoriatic keratinocytes (KCs). However, the role of glucose metabolism reprogramming in psoriatic KCs, psoriasis, and psoriasis with MetS remains unclear. In this study, we confirmed glucose metabolism reprogramming in psoriatic KCs by examining glycolysis-related genes, proteins, and metabolites. We found that inhibiting glucose metabolism reprogramming in psoriasiform KCs led to improvements in psoriasiform features. Notably, we observed enhanced glucose metabolism reprogramming in KCs within psoriatic skin lesions of patients with MetS. In vitro, high-glucose and high-fat culture intensified glucose metabolism reprogramming in psoriasiform KCs partially via the AKT/mTOR pathway. These findings highlight a strong link between the glycolytic switch and KC function and suggest that glucose metabolism reprogramming in KCs contributes to heightened psoriatic inflammation in MetS.

Keywords:  AKT/mTOR pathway; Glucose metabolism reprogramming; Keratinocytes; Metabolic syndrome; Psoriasis

DOI:  https://doi.org/10.1016/j.intimp.2024.112704
Front Immunol. 2024 ;15 1416543

Dysregulated cytokine and oxidative response in hyper-glycolytic monocytes in obesity.

Veselina Radushev, Isabel Karkossa, Janina Berg, Martin von Bergen, Beatrice Engelmann, Ulrike Rolle-Kampczyk, Matthias Blüher, Ulf Wagner, Kristin Schubert, Manuela Rossol.

   Introduction: Obesity is associated with a plethora of health complications, including increased susceptibility to infections or decreased vaccine efficacy, partly due to dysregulated immune responses. Monocytes play a crucial role in innate immunity, yet their functional alterations in obesity remain poorly understood.
Methods: Here, we employed proteomic and metabolomic analyses to investigate monocyte characteristics in individuals with overweight, obesity, impaired glucose tolerance (IGT), and type 2 diabetes (T2D), compared to lean donors.
Results and discussion: Our results revealed distinct molecular signatures in monocytes from individuals with obesity, with significant alterations in pathways related to metabolism, cellular migration, and phagocytosis. Moreover, LPS-induced activation of monocytes unveiled heightened metabolic reprogramming towards glycolysis in subjects with obesity accompanied by dysregulated cytokine responses and elevated oxidative stress. Additionally, monocytes from donors with obesity exhibited increased lipid droplet accumulation. These findings shed light on the immunometabolic dysregulation underlying obesity-associated immune dysfunction, highlighting potential targets for therapeutic intervention.

Keywords:  IL-8; immunometabolism; monocytes; obesity; respiratory burst

DOI:  https://doi.org/10.3389/fimmu.2024.1416543
FASEB J. 2024 Jul 31. 38(14): e23844

Desaminotyrosine is a redox-active microbial metabolite that bolsters macrophage antimicrobial functions while attenuating IL-6 production.

Junyang Zhou, Jinzhi Han, Yanxia Wei, Yugang Wang.

  Intestinal microbiota contributes to host defense against pathogens while avoiding the induction of inflammation in homeostatic conditions, but the mechanism is not fully understood. To investigate the potential role of the bacterial metabolite desaminotyrosine (DAT) in regulating host defense and inflammation, we pretreated mouse bone marrow-derived macrophages (BMDMs) with DAT for 12 hours and then challenged with bacterial lipopolysaccharide (LPS). We found that DAT priming-enhanced type I interferon response while selectively inhibiting proinflammatory interleukin (IL)-6 production after exposure to LPS. This is related to the fact that DAT is a natural antioxidant determined by radical scavenging assay in a cell-free system. DAT-primed cells had increased levels of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) upon LPS stimulation. Countering the increased NADPH by supplementing extra oxidized NADP+ to cells reversed DAT's effect on LPS-induced Il-6 and interferon-stimulated gene expressions. DAT-primed cells also were more resistant to oxidative stress-induced generation of reactive oxygen species and cell death. DAT promoted the production of antimicrobial effector nitric oxide in a cellular redox-dependent manner, leading to enhanced macrophage antimicrobial activity during Salmonella enterica infection. Our data suggest that DAT acts as a host-microbiota crosstalk signal in shaping host immune defense and inflammatory response.

Keywords:  antimicrobial defense; inflammation; macrophage; oxidative stress; redox‐active metabolite

DOI:  https://doi.org/10.1096/fj.202400638R
Trends Cell Biol. 2024 Jul 24. pii: S0962-8924(24)00141-7. [Epub ahead of print]

Metabolism and HSC fate: what NADPH is made for.

Claudia Morganti, Massimo Bonora, Keisuke Ito.

  Mitochondrial metabolism plays a central role in the regulation of hematopoietic stem cell (HSC) biology. Mitochondrial fatty acid oxidation (FAO) is pivotal in controlling HSC self-renewal and differentiation. Herein, we discuss recent evidence suggesting that NADPH generated in the mitochondria can influence the fate of HSCs. Although NADPH has multiple functions, HSCs show high levels of NADPH that are preferentially used for cholesterol biosynthesis. Endogenous cholesterol supports the biogenesis of extracellular vesicles (EVs), which are essential for maintaining HSC properties. We also highlight the significance of EVs in hematopoiesis through autocrine signaling. Elucidating the mitochondrial NADPH-cholesterol axis as part of the metabolic requirements of healthy HSCs will facilitate the development of new therapies for hematological disorders.

Keywords:  FAO; HSC self-renewal; cholesterol; exosome; hematopoiesis; mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.tcb.2024.07.003
Nat Chem Biol. 2024 Jul 26.

Metabolic determinants of germinal center B cell formation and responses.

Jun Wu, Jiawen Zhou, Gen Li, Xuan Sun, Chen Xiang, Haiyan Chen, Peng Jiang.

Germinal center (GC) B cells are crucial for the generation of GCs and long-lived humoral immunity. Here we report that one-carbon metabolism determines the formation and responses of GC B cells. Upon CD40 stimulation, GC B cells selectively upregulate methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression to generate purines and the antioxidant glutathione. MTHFD2 depletion reduces GC B cell frequency and antigen-specific antibody production. Moreover, supplementation with nucleotides and antioxidants suffices to promote GC B cell formation and function in vitro and in vivo through activation of the mammalian target of rapamycin complex 1 signaling pathway. Moreover, we found that antigen stimulation enhances YY1 binding to the Mthfd2 promoter and promotes MTHFD2 transcription. Interestingly, these findings can be generalized to the pentose phosphate pathway, which is another major source of reducing power and nucleotides. Therefore, these results suggest that an increased capacity for nucleotide synthesis and redox balance is required for GC B cell formation and responses, revealing a key aspect of GC B cell fate determination.

DOI: https://doi.org/10.1038/s41589-024-01690-6
Clin Exp Med. 2024 Jul 22. 24(1): 163

Immunometabolic alteration of CD4+ T cells in the pathogenesis of primary Sjögren's syndrome.

Yingying Chen, Xuan Luo, Chuiwen Deng, Lidan Zhao, Hui Gao, Jiaxin Zhou, Linyi Peng, Huaxia Yang, Mengtao Li, Wen Zhang, Yan Zhao, Yunyun Fei.

  Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disorder wherein CD4+ T cells play a pivotal role in its pathogenesis. However, the underlying mechanisms driving the hyperactivity of CD4+ T cells in pSS remain poorly understood. This study aimed to investigate the potential role of immunometabolic alterations in driving the hyperactivity of CD4+ T cells in pSS. We employed Seahorse XF assay to evaluate the metabolic phenotype of CD4+ T cells, conducted flow cytometry to assess the effector function and differentiation of CD4+ T cells and measured the level of intracellular reactive oxygen species (ROS). Additionally, transcriptome sequencing, PCR, and Western blotting were utilized to examine the expression of glycolytic genes. Our investigation revealed that activated CD4+ T cells from pSS patients exhibited elevated aerobic glycolysis, rather than oxidative phosphorylation, resulting in excessive production of IFN-γ and IL-17A. Inhibition of glycolysis by 2-Deoxy-D-glucose reduced the expression of IFN-γ and IL-17A in activated CD4+ T cells and mitigated the differentiation of Th1 and Th17 cells. Furthermore, the expression of glycolytic genes, including CD3E, CD28, PIK3CA, AKT1, mTOR, MYC, LDHA, PFKL, PFKFB3, and PFKFB4, was upregulated in activated CD4+ T cells from pSS patients. Specifically, the expression and activity of LDHA were enhanced, contributing to an increased level of intracellular ROS. Targeting LDHA with FX-11 or inhibiting ROS with N-acetyl-cysteine had a similar effect on reversing the dysfunction of activated CD4+ T cells from pSS patients. Our study unveils heightened aerobic glycolysis in activated CD4+ T cells from pSS patients, and inhibition of glycolysis or its metabolite normalizes the dysfunction of activated CD4+ T cells. These findings suggest that aerobic glycolysis may be a promising therapeutic target for the treatment of pSS.

Keywords:  Aerobic glycolysis; CD4+ T cells; Lactate dehydrogenase A; Primary Sjögren’s syndrome; Reactive oxygen species

DOI:  https://doi.org/10.1007/s10238-024-01429-6
Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00825-8. [Epub ahead of print] 114496

Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.

Kan Etoh, Hirotaka Araki, Tomoaki Koga, Yuko Hino, Kanji Kuribayashi, Shinjiro Hino, Mitsuyoshi Nakao.

  The senescent microenvironment and aged cells per se contribute to tissue remodeling, chronic inflammation, and age-associated dysfunction. However, the metabolic and epigenomic bases of the senescence-associated secretory phenotype (SASP) remain largely unknown. Here, we show that ATP-citrate lyase (ACLY), a key enzyme in acetyl-coenzyme A (CoA) synthesis, is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.

Keywords:  ACLY; CP: Cell biology; CP: Metabolism; H3K27 acetylation; SASP; acetyl-CoA; citrate metabolism; senescence; senostatics

DOI:  https://doi.org/10.1016/j.celrep.2024.114496
Sci Adv. 2024 Jul 26. 10(30): eado3141

Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis.

Shuwei Hu, Rui Li, Dongxu Gong, Pei Hu, Jitu Xu, Yingjie Ai, Xiaojie Zhao, Chencheng Hu, Minghuan Xu, Chenxi Liu, Shuyu Chen, Jie Fan, Zhonghua Zhao, Zhigang Zhang, Huijuan Wu, Yanyong Xu.

Metabolic dysfunction-associated steatohepatitis (MASH) is regulated by complex interplay between the macrophages and surrounding cells in the liver. Here, we show that Atf3 regulates glucose-fatty acid cycle in macrophages attenuates hepatocyte steatosis, and fibrogenesis in hepatic stellate cells (HSCs). Overexpression of Atf3 in macrophages protects against the development of MASH in Western diet-fed mice, whereas Atf3 ablation has the opposite effect. Mechanistically, Atf3 improves the reduction of fatty acid oxidation induced by glucose via forkhead box O1 (FoxO1) and Cd36. Atf3 inhibits FoxO1 activity via blocking Hdac1-mediated FoxO1 deacetylation at K242, K245, and K262 and increases Zdhhc4/5-mediated CD36 palmitoylation at C3, C7, C464, and C466; furthermore, macrophage Atf3 decreases hepatocytes lipogenesis and HSCs activation via retinol binding protein 4 (Rbp4). Anti-Rbp4 can prevent MASH progression that is induced by Atf3 deficiency in macrophages. This study identifies Atf3 as a regulator of glucose-fatty acid cycle. Targeting macrophage Atf3 or Rbp4 may be a plausible therapeutic strategy for MASH.

DOI: https://doi.org/10.1126/sciadv.ado3141
Cell Host Microbe. 2024 Jul 17. pii: S1931-3128(24)00232-4. [Epub ahead of print]

A small intestinal bile acid modulates the gut microbiome to improve host metabolic phenotypes following bariatric surgery.

Yingjia Chen, Snehal N Chaudhari, David A Harris, Cullen F Roberts, Andrei Moscalu, Vasundhara Mathur, Lei Zhao, Ali Tavakkoli, A Sloan Devlin, Eric G Sheu.

  Bariatric surgical procedures such as sleeve gastrectomy (SG) provide effective type 2 diabetes (T2D) remission in human patients. Previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we show that LCA worsens glucose tolerance and impairs whole-body metabolism. We also show that taurodeoxycholic acid (TDCA), which is the only bile acid whose concentration increases in the murine small intestine post-SG, suppresses the bacterial bile acid-inducible (bai) operon and production of LCA both in vitro and in vivo. Treatment of diet-induced obese mice with TDCA reduces LCA levels and leads to microbiome-dependent improvements in glucose handling. Moreover, TDCA abundance is decreased in small intestinal tissue from T2D patients. This work reveals that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery.

Keywords:  bariatric surgery; bile acid-inducible operon; bile acids; lithocholic acid; metabolism; small intestine; taurodeoxycholic acid; type 2 diabetes

DOI:  https://doi.org/10.1016/j.chom.2024.06.014
J Pharm Biomed Anal. 2024 Jul 15. pii: S0731-7085(24)00410-2. [Epub ahead of print]249 116370

Revealing metabolic alterations in brucellosis patients by targeted metabolomics.

Lei Fu, Hao Zhang, Yingyi Dai, Hongfeng Zhang, Xinhong Pan, Shouyi Chen, Lei Tan.

  Brucellosis, a zoonotic disease caused by brucella infection, presents metabolic profile changes in patients that have not been extensively explored. This study utilized an ultra-high performance liquid chromatography tandem mass spectrometry based targeted metabolomic approach to comprehensively investigated metabolic changes in Brucella patients. Serum samples of brucellosis 50 patients and 50 well-matched healthy controls were analyzed for 228 metabolites, revealing significant alterations in 83 metabolites in brucellosis patients. Notably, disruptions were observed in key metabolite pathways, such as amino acid metabolism, urea cycle, tricarboxylic acid cycle (TCA), and fatty acid metabolism. Patients diagnosed with Brucellosis exhibited distinct differences in the levels of aspartate, glutamate, β-alanine, and asparagine when compared to controls. Within the urea cycle, a significant downregulation of arginine was observed, whereas ornithine levels were considerably upregulated. In the TCA cycle, concentrations of 2-oxoglutarate, succinate, and malate were significantly elevated, while citrate levels demonstrated a notable decrease. Due to the interruption of the TCA cycle, glycolysis was accelerated to compensate for the resultant energy deficit in Brucella patients. Concurrently, there was a significant increase in the levels of short and medium-chain fatty acids, while long-chain fatty acids showed a marked decrease. The study systematically revealed significant metabolic alterations in Brucellosis patients and further explored the potential correlation between these changes and clinic symptoms, including fatigue, muscle soreness and prolonged fever. The results enhanced our understanding of Brucellosis, offering valuable insights potentially beneficial in formulating more effective treatment strategies and improving prognostic approaches.

Keywords:  Brucellosis; Infectious disease; Metabolic abnormalities; Metabolomics; UHPLC-MS/MS

DOI:  https://doi.org/10.1016/j.jpba.2024.116370
Nat Commun. 2024 Jul 26. 15(1): 6311

Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux.

Lifeng Chen, Jingjing Zhang, Weibin Xu, Jiayi Chen, Yujun Tang, Si Xiong, Yaolan Li, Hong Zhang, Manmei Li, Zhong Liu.

Respiratory syncytial virus (RSV) hijacks cholesterol or autophagy pathways to facilitate optimal replication. However, our understanding of the associated molecular mechanisms remains limited. Here, we show that RSV infection blocks cholesterol transport from lysosomes to the endoplasmic reticulum by downregulating the activity of lysosomal acid lipase, activates the SREBP2-LDLR axis, and promotes uptake and accumulation of exogenous cholesterol in lysosomes. High cholesterol levels impair the VAP-A-binding activity of ORP1L and promote the recruitment of dynein-dynactin, PLEKHM1, or HOPS VPS39 to Rab7-RILP, thereby facilitating minus-end transport of autophagosomes and autolysosome formation. Acidification inhibition and dysfunction of cholesterol-rich lysosomes impair autophagy flux by inhibiting autolysosome degradation, which promotes the accumulation of RSV fusion protein. RSV-F storage is nearly abolished after cholesterol depletion or knockdown of LDLR. Most importantly, the knockout of LDLR effectively inhibits RSV infection in vivo. These findings elucidate the molecular mechanism of how RSV co-regulates lysosomal cholesterol reprogramming and autophagy and reveal LDLR as a novel target for anti-RSV drug development.

DOI: https://doi.org/10.1038/s41467-024-50711-4
Nat Aging. 2024 Jul 23.

An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.

Zehan Song, Sang Hee Park, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang, Anita Wong Lin, Kartoosh Heydari, Claudia C S Chini, Eduardo N Chini, Cholsoon Jang, Danica Chen.

How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.

DOI: https://doi.org/10.1038/s43587-024-00670-8
Trends Immunol. 2024 Jul 24. pii: S1471-4906(24)00155-8. [Epub ahead of print]

Iron scavenging and myeloid cell polarization.

Natalie Ludwig, Stefania Cucinelli, Simon Hametner, Martina U Muckenthaler, Lucas Schirmer.

  Myeloid cells that populate all human organs and blood are a versatile class of innate immune cells. They are crucial for sensing and regulating processes as diverse as tissue homeostasis and inflammation and are frequently characterized by their roles in either regulating or promoting inflammation. Recent studies in cultured cells and mouse models highlight the role of iron in skewing the functional properties of myeloid cells in tissue damage and repair. Here, we review certain emerging concepts on how iron influences and determines myeloid cell polarization in the context of its uptake, storage, and metabolism, including in conditions such as multiple sclerosis (MS), sickle cell disease, and tumors.

Keywords:  hemolysis; macrophages; multiple sclerosis; neuroinflammation; sickle cell disease; tumor microenvironment

DOI:  https://doi.org/10.1016/j.it.2024.06.006
Kidney Int. 2024 Aug;pii: S0085-2538(24)00390-9. [Epub ahead of print]106(2): 183-185

Lactate: a missing link between metabolism and inflammation in CKD progression?

Nobuaki Nishima, Shinji Tanaka.

Persistent enhancement of glycolysis in kidney tubular epithelial cells has been linked to the progression of chronic kidney disease, although the underlying mechanisms are largely unknown. In this issue of Kidney International, Wang et al. report that the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 plays a crucial role in kidney fibrosis by enhancing histone H4 lysine 12 lactylation through lactate accumulation. This increases the transcription of nuclear factor-κB-related genes and promotes inflammation and fibrosis. Inhibiting 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 reduces these effects, indicating therapeutic potential for kidney fibrosis.

DOI: https://doi.org/10.1016/j.kint.2024.05.016
Heliyon. 2024 Jul 15. 10(13): e33502

Derivation of novel metabolic pathway score identifies alanine metabolism as a targetable influencer of TNF-alpha signaling.

Brandon N D'Souza, Manoj Yadav, Prem Prashant Chaudhary, Grace Ratley, Max Yang Lu, Derron A Alves, Ian A Myles.

Background: Better understanding of the interaction between metabolism and immune response will be key to understanding physiology and disease. Tumor Necrosis Factor-alpha (TNFα) has been studied widely. However, despite the extensive knowledge about TNFα, the cytokine appears to induce not only variable, but often contradictory, effects on inflammation and cell proliferation. Despite advancements in the metabolomics field, it is still difficult to analyze the types of multi-dose, multi-time point studies needed for elucidating the varied immunologic responses induced by TNFα.
Results: We studied the dose and time course effects of TNFα on murine fibroblast cultures and further elucidated these connections using selective blockade of the TNF receptors (TNFR1 and TNFR2). To streamline analysis, we developed a method to collate the metabolic pathway output from MetaboAnalyst into a single value for the Index of pathway significance (IPS). Using this metric, we tested dose-, time-, and receptor-dependent effects of TNFα signaling on cell metabolism. Guided by these results, we then demonstrate that alanine supplementation enriched TNFR1-related responses in both cell and mouse models.
Conclusions: Our results suggest that TNFα, particularly when signaling through TNFR1, may preferentially use alanine metabolism for energy. These results are limited in by cell type used and immune outputs measured. However, we anticipate that our novel method may assist other researchers in identifying metabolic targets that influence their disease or model of interest through simplifying the analysis of multi-condition experiments. Furthermore, our results endorse the consideration of follow up studies in immunometabolism to improve outcomes in TNF-mediated diseases.

DOI: https://doi.org/10.1016/j.heliyon.2024.e33502
Nat Immunol. 2024 Jul 22.

Dietary glutamine supports mucosal germinal center B cell lymphomas.

DOI: https://doi.org/10.1038/s41590-024-01911-z
Nat Commun. 2024 Jul 21. 15(1): 6145

Host cell CRISPR genomics and modelling reveal shared metabolic vulnerabilities in the intracellular development of Plasmodium falciparum and related hemoparasites.

Marina Maurizio, Maria Masid, Kerry Woods, Reto Caldelari, John G Doench, Arunasalam Naguleswaran, Denis Joly, Martín González-Fernández, Jonas Zemp, Mélanie Borteele, Vassily Hatzimanikatis, Volker Heussler, Sven Rottenberg, Philipp Olias.

Parasitic diseases, particularly malaria (caused by Plasmodium falciparum) and theileriosis (caused by Theileria spp.), profoundly impact global health and the socioeconomic well-being of lower-income countries. Despite recent advances, identifying host metabolic proteins essential for these auxotrophic pathogens remains challenging. Here, we generate a novel metabolic model of human hepatocytes infected with P. falciparum and integrate it with a genome-wide CRISPR knockout screen targeting Theileria-infected cells to pinpoint shared vulnerabilities. We identify key host metabolic enzymes critical for the intracellular survival of both of these lethal hemoparasites. Remarkably, among the metabolic proteins identified by our synergistic approach, we find that host purine and heme biosynthetic enzymes are essential for the intracellular survival of P. falciparum and Theileria, while other host enzymes are only essential under certain metabolic conditions, highlighting P. falciparum's adaptability and ability to scavenge nutrients selectively. Unexpectedly, host porphyrins emerge as being essential for both parasites. The shared vulnerabilities open new avenues for developing more effective therapies against these debilitating diseases, with the potential for broader applicability in combating apicomplexan infections.

DOI: https://doi.org/10.1038/s41467-024-50405-x
Biomedicines. 2024 Jul 16. pii: 1575. [Epub ahead of print]12(7):

High Glucose Increases Lactate and Induces the Transforming Growth Factor Beta-Smad 1/5 Atherogenic Pathway in Primary Human Macrophages.

Kareem Awad, Laura Kakkola, Ilkka Julkunen.

  Hundreds of millions of people worldwide are expected to suffer from diabetes mellitus. Diabetes is characterized as a dynamic and heterogeneous disease that requires deeper understanding of the pathophysiology, genetics, and metabolic shaping of this disease and its macro/microvascular complications. Macrophages play an essential role in regulating local immune responses, tissue homeostasis, and disease pathogenesis. Here, we have analyzed transforming growth factor beta 1 (TGFβ1)/Smad signaling in primary human macrophages grown in normal (NG) and high-glucose (HG; +25 mM glucose) conditions. Cell culture lactate concentration and cellular phosphofructokinase (PFK) activity were increased in HG concentrations. High glucose levels in the growth media led to increased macrophage mRNA expression of TGFβ1, and TGFβ-regulated HAMP and PLAUR mRNA levels, while the expression of TGFβ receptor II remained unchanged. Stimulation of cells with TGFβ1 protein lead to Smad2 phosphorylation in both NG and HG conditions, while the phosphorylation of Smad1/5 was detected only in response to TGFβ1 stimulation in HG conditions. The use of the specific Alk1/2 inhibitor dorsomorphin and the Alk5 inhibitor SB431542, respectively, revealed that HG conditions led TGFβ1 to activation of Smad1/5 signaling and its downstream target genes. Thus, high-glucose activates TGFβ1 signaling to the Smad1/5 pathway in primary human macrophages, which may contribute to cellular homeostasis in a harmful manner, priming the tissues for diabetic complications.

Keywords:  Smad; TGFβ1; atherosclerosis; diabetes; high glucose; macrophage

DOI:  https://doi.org/10.3390/biomedicines12071575
J Med Virol. 2024 Aug;96(8): e29798

Temporal changes in plasma metabolic signatures to predict immune response of antiretroviral therapy among people living with HIV.

Junnan Li, Jiali Lv, Fengting Yu, Yu Zhang, Yuqi Wang, Liting Yan, Qing Xiao, Qun Li, Cheng Wang, Xi Wang, Yan Hou, Fujie Zhang, Tao Zhang.

  Antiretroviral therapy (ART) is an effective treatment for people living with HIV (PLHIVs), requiring an extended period to achieve immune reconstitution. Metabolic alterations induced by ART are crucial for predicting long-term therapeutic responses, yet comprehensive investigation through large-scale clinical studies is still lacking. Here, we collected plasma samples from 108 PLHIVs to the untargeted plasma metabolomics study, based on the longitudinal metabolomics design. Cross-sectional analyzes were performed at pre- and post-ART to explore the metabolic transformation induced by the therapy. Subsequently, delta values between pre- and post-ART measurements were calculated to quantify metabolic alterations. Then, the optimal set of metabolic traits and clinical signatures were further identified and applied to construct random forest model for predicting the future therapeutic responses to ART. We found distinct ART-induced metabolic transformation among PLHIVs. After confounder-adjustments, five metabolites exhibited significant associations with future immune response: tetracosatetraenoic acid (24:4n-6) (pre-ART) (odds ratio [OR]: 0.978, 95% confidence interval [CI]: 0.955~0.997), 1-(3,4-dihydroxyphenyl)-5-hydroxy-3-decanone (pre-ART) (OR: 1.298, 95% CI: 1.061~1.727), beta-PC-M6 (change) (OR: 0.967, 95% CI: 0.938~0.993), d-Galactaro-1,4-lactone (change) (OR: 1.032, 95% CI: 1.007~1.063), Annuionone C (change) (OR: 1.100, 95% CI: 1.030~1.190). The addition of plasma metabolites to clinical markers accurately predicted immune response to ART with an area under curve of 0.91. Notably, most disrupted metabolites were significantly correlated with blood lipids, suggesting that metabolic transformation might contribute to dyslipidemia among PLHIVs. This study highlights the distinct metabolic transformation post-ART among PLHIVs and reveals the potential role of metabolic transformation as key determinants of ART efficacy.

Keywords:  HIV; UPLC‐QTOF‐MS; antiretroviral therapy; immune response; untargeted metabolomics study

DOI:  https://doi.org/10.1002/jmv.29798