bims-imicid 2024-04-28 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024‒04‒28
thirty-one papers selected by
Dylan Ryan, University of Cambridge

TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis.
Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation.
Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation.
Potential therapies targeting metabolic pathways in systemic lupus erythematosus.
Redox Regulation of Immunometabolism in Microglia Underpinning Diabetic Retinopathy.
2-Substituted-4,7-dihydro-4-ethylpyrazolo[1,5-a]pyrimidin-7-ones alleviate LPS-induced inflammation by modulating cell metabolism via CD73 upon macrophage polarization.
Mitochondrial-dependent oxidative phosphorylation is key for postnatal metabolic adaptation of alveolar macrophages in the lung.
Immunometabolic Signatures of Circulating Monocytes in Humans with Obesity and Insulin Resistance.
Lipid metabolism in tumor-infiltrating regulatory T cells: perspective to precision immunotherapy.
Investigating the role of itaconate in macrophage activation and oxidative stress injury in sepsis-associated acute kidney injury.
The causes and consequences of trained immunity in myeloid cells.
The potential role of CMC1 as an immunometabolic checkpoint in T cell immunity.
Epstein-Barr-Virus-Driven Cardiolipin Synthesis Sustains Metabolic Remodeling During B-cell Lymphomagenesis.
S100A8/9 modulates perturbation and glycolysis of macrophages in allergic asthma mice.
Lactobacillus Reuteri Vesicles Regulate Mitochondrial Function of Macrophages to Promote Mucosal and Cutaneous Wound Healing.
Hepatitis B virus and hepatitis C virus affect mitochondrial function through different metabolic pathways, explaining virus-specific clinical features of chronic hepatitis.
Short-chain fatty acids inhibit the activation of T lymphocytes and myeloid cells and induce innate immune tolerance.
Cancer cell metabolism and antitumour immunity.
The Glycolytic Metabolite Methylglyoxal Covalently Inactivates the NLRP3 Inflammasome.
Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring.
Disulfiram treatment suppresses antibody-producing reactions by inhibiting macrophage activation and B cell pyrimidine metabolism.
Short-Term Dietary Restriction Potentiates an Anti-Inflammatory Circulating Mucosal-Associated Invariant T-Cell Response.
Melatonin-induced upregulation of telomerase activity interferes with macrophage mitochondrial metabolism and suppresses NLRP3 inflammasome activation in the treatment of Pneumonia.
Commensal bacteria inhibit viral infections via a tryptophan metabolite.
A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron.
Metabolomics captures the differential metabolites in the replication pathway of snakehead vesiculovirus regulated by glutamine.
TNFRSF6 induces mitochondrial dysfunction and microglia activation in the in vivo and in vitro models of sepsis-associated encephalopathy.
Urinary metabolomic profiling of a cohort of Colombian patients with systemic lupus erythematosus.
ACOD1, rather than itaconate, facilitates p62-mediated activation of Nrf2 in microglia post spinal cord contusion.
The functional role of L-fucose on dendritic cell function and polarization.
Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease.

Sci Signal. 2024 Apr 23. 17(833): eadg5678

TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis.

Emma L Bishop, Nancy Gudgeon, Taylor Fulton-Ward, Victoria Stavrou, Jennie Roberts, Adam Boufersaoui, Daniel A Tennant, Martin Hewison, Karim Raza, Sarah Dimeloe.

Upon activation, T cells undergo metabolic reprogramming to meet the bioenergetic demands of clonal expansion and effector function. Because dysregulated T cell cytokine production and metabolic phenotypes coexist in chronic inflammatory disease, including rheumatoid arthritis (RA), we investigated whether inflammatory cytokines released by differentiating T cells amplified their metabolic changes. We found that tumor necrosis factor-α (TNF-α) released by human naïve CD4+ T cells upon activation stimulated the expression of a metabolic transcriptome and increased glycolysis, amino acid uptake, mitochondrial oxidation of glutamine, and mitochondrial biogenesis. The effects of TNF-α were mediated by activation of Akt-mTOR signaling by the kinase ITK and did not require the NF-κB pathway. TNF-α stimulated the differentiation of naïve cells into proinflammatory T helper 1 (TH1) and TH17 cells, but not that of regulatory T cells. CD4+ T cells from patients with RA showed increased TNF-α production and consequent Akt phosphorylation upon activation. These cells also exhibited increased mitochondrial mass, particularly within proinflammatory T cell subsets implicated in disease. Together, these findings suggest that T cell-derived TNF-α drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.

DOI: https://doi.org/10.1126/scisignal.adg5678
Sci Adv. 2024 Apr 26. 10(17): eadk1045

Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation.

Thiruvaimozhi Abimannan, Velayoudame Parthibane, Si-Hung Le, Nagampalli Vijaykrishna, Stephen D Fox, Baktiar Karim, Govind Kunduri, Daniel Blankenberg, Thorkell Andresson, Takeshi Bamba, Usha Acharya, Jairaj K Acharya.

T helper 17 (TH17) cells are implicated in autoimmune diseases, and several metabolic processes are shown to be important for their development and function. In this study, we report an essential role for sphingolipids synthesized through the de novo pathway in TH17 cell development. Deficiency of SPTLC1, a major subunit of serine palmitoyl transferase enzyme complex that catalyzes the first and rate-limiting step of de novo sphingolipid synthesis, impaired glycolysis in differentiating TH17 cells by increasing intracellular reactive oxygen species (ROS) through enhancement of nicotinamide adenine dinucleotide phosphate oxidase 2 activity. Increased ROS leads to impaired activation of mammalian target of rapamycin C1 and reduced expression of hypoxia-inducible factor 1-alpha and c-Myc-induced glycolytic genes. SPTLCI deficiency protected mice from developing experimental autoimmune encephalomyelitis and experimental T cell transfer colitis. Our results thus show a critical role for de novo sphingolipid biosynthetic pathway in shaping adaptive immune responses with implications in autoimmune diseases.

DOI: https://doi.org/10.1126/sciadv.adk1045
Nat Metab. 2024 Apr 24.

Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation.

Aliya Lakhani, Ximin Chen, Laurence C Chen, Mihe Hong, Mobina Khericha, Yu Chen, Yvonne Y Chen, Junyoung O Park.

Metabolism is an indispensable part of T cell proliferation, activation and exhaustion, yet the metabolism of chimeric antigen receptor (CAR)-T cells remains incompletely understood. CARs are composed of extracellular domains-often single-chain variable fragments (scFvs)-that determine ligand specificity and intracellular domains that trigger signalling following antigen binding. Here, we show that CARs differing only in the scFv variously reprogramme T cell metabolism. Even without exposure to antigens, some CARs increase proliferation and nutrient uptake in T cells. Using stable isotope tracers and mass spectrometry, we observed basal metabolic fluxes through glycolysis doubling and amino acid uptake overtaking anaplerosis in CAR-T cells harbouring a rituximab scFv, unlike other similar anti-CD20 scFvs. Disparate rituximab and 14G2a-based anti-GD2 CAR-T cells are similarly hypermetabolic and channel excess nutrients to nitrogen overflow metabolism. Modest overflow metabolism of CAR-T cells and metabolic compatibility between cancer cells and CAR-T cells are identified as features of efficacious CAR-T cell therapy.

DOI: https://doi.org/10.1038/s42255-024-01034-7
Clin Immunol. 2024 Apr 20. pii: S1521-6616(24)00115-3. [Epub ahead of print]263 110224

Potential therapies targeting metabolic pathways in systemic lupus erythematosus.

Ryo Hisada, Michihito Kono.

  The pathophysiology of systemic lupus erythematosus (SLE) is multifactorial and involves alterations in metabolic pathways, including glycolysis, lipid metabolism, amino acid metabolism, and mitochondrial dysfunction. Increased glycolysis in SLE T cells, which is associated with elevated glucose transporter 1 expression, suggests targeting glucose transporters and hexokinase as potential treatments. Abnormalities in lipid metabolism, particularly in lipid rafts and enzymes, present new therapeutic targets. This review discusses how changes in glutaminolysis and tryptophan metabolism affect T-cell function, suggesting new therapeutic interventions, as well as mitochondrial dysfunction in SLE, which increases reactive oxygen species. The review also emphasizes that modulating metabolic pathways in immune cells is a promising approach for SLE treatment, and can facilitate personalized therapies based on individual metabolic profiles of patients with SLE. The review provides novel insights into strategies for managing SLE.

Keywords:  Immune cells; Metabolome; Systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.clim.2024.110224
Antioxidants (Basel). 2024 Mar 29. pii: 423. [Epub ahead of print]13(4):

Redox Regulation of Immunometabolism in Microglia Underpinning Diabetic Retinopathy.

Luwei Cai, Mengxue Xia, Fang Zhang.

  Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among the working-age population. Microglia, resident immune cells in the retina, are recognized as crucial drivers in the DR process. Microglia activation is a tightly regulated immunometabolic process. In the early stages of DR, the M1 phenotype commonly shifts from oxidative phosphorylation to aerobic glycolysis for energy production. Emerging evidence suggests that microglia in DR not only engage specific metabolic pathways but also rearrange their oxidation-reduction (redox) system. This redox adaptation supports metabolic reprogramming and offers potential therapeutic strategies using antioxidants. Here, we provide an overview of recent insights into the involvement of reactive oxygen species and the distinct roles played by key cellular antioxidant pathways, including the NADPH oxidase 2 system, which promotes glycolysis via enhanced glucose transporter 4 translocation to the cell membrane through the AKT/mTOR pathway, as well as the involvement of the thioredoxin and nuclear factor E2-related factor 2 antioxidant systems, which maintain microglia in an anti-inflammatory state. Therefore, we highlight the potential for targeting the modulation of microglial redox metabolism to offer new concepts for DR treatment.

Keywords:  diabetic retinopathy; immunometabolism; microglia; redox

DOI:  https://doi.org/10.3390/antiox13040423
Mol Immunol. 2024 Apr 20. pii: S0161-5890(24)00074-9. [Epub ahead of print]170 99-109

2-Substituted-4,7-dihydro-4-ethylpyrazolo[1,5-a]pyrimidin-7-ones alleviate LPS-induced inflammation by modulating cell metabolism via CD73 upon macrophage polarization.

Alessia Ricci, Susi Zara, Fabrizio Carta, Valentina Di Valerio, Silvia Sancilio, Amelia Cataldi, Silvia Selleri, Claudiu T Supuran, Simone Carradori, Marialucia Gallorini.

  Macrophage polarization towards the M1 phenotype under bacterial product-related exposure (LPS) requires a rapid change in gene expression patterns and cytokine production along with a metabolic rewiring. Metabolic pathways and redox reactions are such tightly connected, giving rise to an area of research referred to as immunometabolism. A role in this context has been paid to the master redox-sensitive regulator Nuclear factor erythroid 2-related factor 2 (Nrf2) and to the 5'-ectonucleotidase CD73, a marker related to macrophage metabolism rearrangement under pro-inflammatory conditions. In this light, a cell model of LPS-stimulated macrophages has been established and nine 4,7-dihydro-4-ethylpyrazolo[l,5-a]pyrimidin-7-ones with a potential anti-inflammatory effect have been administered. Our data highlight that two selected compounds (namely, 5 and 8) inhibit the LPS-induced Nrf2 nuclear translocation and ameliorate the activity rate of the antioxidant enzyme catalase. Additionally, the pyridine-containing compound (8) promotes the shift from the pro-inflammatory immunophenotype M1 to the pro-resolving M2 one, by downregulating CD80 and iNOS and by enhancing CD163 and TGFβ1 expression. Most importantly, CD73 is modulated by these compounds as well as the lactate production. Our data demonstrate that pyrazolo[l,5-a]pyrimidine derivatives are effective as anti-inflammatory compounds. Furthermore, these pyrazolo[l,5-a]pyrimidines exert their action via CD73-related signaling and modulation of cell metabolism of activated macrophages.

Keywords:  CD73; Immunomodulation; Inflammation; LPS; Macrophages; Metabolism; Nrf2; Polarization; Pyrazolo[l,5-a]pyrimidin-7-ones

DOI:  https://doi.org/10.1016/j.molimm.2024.04.004
Int Immunopharmacol. 2024 Apr 23. pii: S1567-5769(24)00530-7. [Epub ahead of print]133 112012

Mitochondrial-dependent oxidative phosphorylation is key for postnatal metabolic adaptation of alveolar macrophages in the lung.

Jun Zhang, Yu Peng, Haosen Song, Siqi Liu, Chuanwei Li, Yi Zhang, Xiaowei Shi, Huifang Guo, Yingping Xu.

  Alveolar macrophages (AMs) seed in lung during embryogenesis and become mature in perinatal period. Establishment of acclimatization to environmental challenges is important, whereas the detailed mechanisms that drive metabolic adaptation of AMs remains to be elucidated. Here, we showed that energy metabolism of AMs was transformed from glycolysis prenatally to oxidative phosphorylation (OXPHOS) postnatally accompanied by up-regulated expression of mitochondrial transcription factor A (TFAM). TFAM deficiency disturbed mitochondrial stability and decreased OXPHOS, which finally impaired AM maintenance and function, but not AM embryonic development. Mechanistically, Tfam-deletion resulted in impaired mitochondrial respiration and decreased ATP production, which triggered endoplasmic reticulum (ER) stress to cause B cell lymphoma 2 ovarian killer (BOK) accumulation and abnormal distribution of intracellular Ca2+, eventually led to induce AM apoptotic death. Thus, our data illustrated mitochondrial-dependent OXPHOS played a key role in orchestrating AM postnatal metabolic adaptation.

Keywords:  Alveolar macrophages; Endoplasmic reticulum stress; Metabolic adaptation; mitochondrial transcription factor A

DOI:  https://doi.org/10.1016/j.intimp.2024.112012
Diabetes. 2024 Apr 24. pii: db230970. [Epub ahead of print]

Immunometabolic Signatures of Circulating Monocytes in Humans with Obesity and Insulin Resistance.

Lisa Smeehuijzen, Anouk Gijbels, Joline P Nugteren-Boogaard, Frank Vrieling, Mehdi Boutagouga Boudjadja, Inez Trouwborst, Kelly M Jardon, Gabby B Hul, Edith J M Feskens, Ellen E Blaak, Gijs H Goossens, Lydia A Afman, Rinke Stienstra.

Obesity is associated with chronic inflammation and metabolic complications, including insulin resistance (IR). Immune cells drive inflammation through the rewiring of intracellular metabolism. However, the impact of obesity-related IR on the metabolism and functionality of circulating immune cells, like monocytes, remains poorly understood. To increase insight into the inter-individual variation of immunometabolic signatures among individuals and their role in the development of IR, we assessed systemic and tissue-specific IR and circulating immune markers, and we characterized metabolic signatures and cytokine secretion of circulating monocytes from 194 individuals with a BMI≥25kg/m2. Monocyte metabolic signatures were defined using extracellular acidification rates (ECAR) to estimate glycolysis and oxygen consumption rates (OCR) for oxidative metabolism. Although monocyte metabolic signatures and function based on cytokine secretion varied greatly among subjects, they were strongly associated with each other. The ECAR/OCR ratio, representing the balance between glycolysis and oxidative metabolism, was negatively associated with fasting insulin, systemic IR, and liver-specific IR. These results indicate that monocytes from individuals with IR were relatively more dependent on oxidative metabolism, while monocytes from more insulinsensitive individuals were more dependent on glycolysis. Additionally, circulating CXCL11 was negatively associated with the degree of systemic IR and positively with the ECAR/OCR ratio in monocytes, suggesting that individuals with high IR and a monocyte metabolic dependence on oxidative metabolism also have lower levels of circulating CXCL11. Our findings suggest that monocyte metabolism is related to obesity-associated IR progression and deepen insights into the interplay between innate immune cell metabolism and IR development in humans.

DOI: https://doi.org/10.2337/db23-0970
Biomark Res. 2024 Apr 22. 12(1): 41

Lipid metabolism in tumor-infiltrating regulatory T cells: perspective to precision immunotherapy.

Yukai Shan, Tianao Xie, Yuchao Sun, Ziyi Lu, Win Topatana, Sarun Juengpanich, Tianen Chen, Yina Han, Jiasheng Cao, Jiahao Hu, Shijie Li, Xiujun Cai, Mingyu Chen.

  Regulatory T cells (Tregs) are essential to the negative regulation of the immune system, as they avoid excessive inflammation and mediate tumor development. The abundance of Tregs in tumor tissues suggests that Tregs may be eliminated or functionally inhibited to stimulate antitumor immunity. However, immunotherapy targeting Tregs has been severely hampered by autoimmune diseases due to the systemic elimination of Tregs. Recently, emerging studies have shown that metabolic regulation can specifically target tumor-infiltrating immune cells, and lipid accumulation in TME is associated with immunosuppression. Nevertheless, how Tregs actively regulate metabolic reprogramming to outcompete effector T cells (Teffs), and how lipid metabolic reprogramming contributes to the immunomodulatory capacity of Tregs have not been fully discussed. This review will discuss the physiological processes by which lipid accumulation confers a metabolic advantage to tumor-infiltrating Tregs (TI-Tregs) and amplifies their immunosuppressive functions. Furthermore, we will provide a summary of the driving effects of various metabolic regulators on the metabolic reprogramming of Tregs. Finally, we propose that targeting the lipid metabolism of TI-Tregs could be efficacious either alone or in conjunction with immune checkpoint therapy.

Keywords:  Immunosuppression; Lipid metabolism; Metabolic competition; Metabolic regulatory switches; Tregs; Tumor therapies

DOI:  https://doi.org/10.1186/s40364-024-00588-8
Mol Biol Rep. 2024 Apr 20. 51(1): 533

Investigating the role of itaconate in macrophage activation and oxidative stress injury in sepsis-associated acute kidney injury.

Lei Yang, Pei Zhou, Ruidong Li, Yuping Yin, Gengchen Xie, Liang Shi, Peng Zhang, Kaixiong Tao.

  BACKGROUND: Sepsis may be linked to oxidative stress and can be controlled by itaconate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nevertheless, the itaconate impact on sepsis-associated acute kidney injury (SA-AKI) has yet to be definitively established.METHODS: We employed SA-AKI mouse model through a cecal ligation and puncture (CLP) procedure for the in vivo investigation of the potential nephroprotective effect of itaconate in this study. A plasmid was transfected into RAW264.7 cells to examine the Nrf2 pathway function after itaconate administration. Finally, the immune-responsive gene 1-knockout (IRG1-/-) mice were used to study the itaconate impacts on oxidative stress-induced SA-AKI.
RESULTS: We have shown that 4-octyl itaconate (OI) significantly reduced CD11b-positive macrophage aggregation and activated the Nrf2 pathway in the bone marrow-derived macrophages (BMDM). The impacts of Nrf2 inhibitor ML385 on the anti-inflammatory and antioxidant properties of itaconate were found to be partial. OI inhibited lipopolysaccharide-induced oxidative stress injury in RAW264.7 macrophages and activated Nrf2 in the nucleus to hinder the expression of nuclear factor kappa B p65, thereby suppressing oxidative stress injury in the macrophages. Additionally, the introduction of the transfected plasmid resulted in a partial inhibition of the anti-inflammatory impact of itaconate. The kidney injury caused by sepsis exhibited greater severity in the IRG1-/- mice than in the wild type mice. Exogenous OI partially attenuated the kidney injury induced by sepsis in the IRG1-/- mice and suppressed the oxidative stress injury in macrophages.
CONCLUSIONS: This investigation offers new proof to support the itaconate function in the development and progression of SA-AKI and shows a new possible therapeutic agent for the SA-AKI treatment.

Keywords:  Acute kidney injury; Itaconate; Nrf2; Oxidative stress; Sepsis

DOI:  https://doi.org/10.1007/s11033-024-09462-0
Front Immunol. 2024 ;15 1365127

The causes and consequences of trained immunity in myeloid cells.

Gunapati Bhargavi, Selvakumar Subbian.

  Conventionally, immunity in humans has been classified as innate and adaptive, with the concept that only the latter type has an immunological memory/recall response against specific antigens or pathogens. Recently, a new concept of trained immunity (a.k.a. innate memory response) has emerged. According to this concept, innate immune cells can exhibit enhanced responsiveness to subsequent challenges, after initial stimulation with antigen/pathogen. Thus, trained immunity enables the innate immune cells to respond robustly and non-specifically through exposure or re-exposure to antigens/infections or vaccines, providing enhanced resistance to unrelated pathogens or reduced infection severity. For example, individuals vaccinated with BCG to protect against tuberculosis were also protected from malaria and SARS-CoV-2 infections. Epigenetic modifications such as histone acetylation and metabolic reprogramming (e.g. shift towards glycolysis) and their inter-linked regulations are the key factors underpinning the immune activation of trained cells. The integrated metabolic and epigenetic rewiring generates sufficient metabolic intermediates, which is crucial to meet the energy demand required to produce proinflammatory and antimicrobial responses by the trained cells. These factors also determine the efficacy and durability of trained immunity. Importantly, the signaling pathways and regulatory molecules of trained immunity can be harnessed as potential targets for developing novel intervention strategies, such as better vaccines and immunotherapies against infectious (e.g., sepsis) and non-infectious (e.g., cancer) diseases. However, aberrant inflammation caused by inappropriate onset of trained immunity can lead to severe autoimmune pathological consequences, (e.g., systemic sclerosis and granulomatosis). In this review, we provide an overview of conventional innate and adaptive immunity and summarize various mechanistic factors associated with the onset and regulation of trained immunity, focusing on immunologic, metabolic, and epigenetic changes in myeloid cells. This review underscores the transformative potential of trained immunity in immunology, paving the way for developing novel therapeutic strategies for various infectious and non-infectious diseases that leverage innate immune memory.

Keywords:  animal models; cell signaling; epigenetics; inflammation; innate immunity; macrophage; metabolism; neutrophil

DOI:  https://doi.org/10.3389/fimmu.2024.1365127
Oncoimmunology. 2024 ;13(1): 2344905

The potential role of CMC1 as an immunometabolic checkpoint in T cell immunity.

Yuwen Chen, Jie Gao, Mingyue Ma, Ke Wang, Fangming Liu, Feiyu Yang, Xin Zou, Zhouli Cheng, Duojiao Wu.

  T cell immunity is critical for human defensive immune response. Exploring the key molecules during the process provides new targets for T cell-based immunotherapies. CMC1 is a mitochondrial electron transport chain (ETC) complex IV chaperon protein. By establishing in-vitro cell culture system and Cmc1 gene knock out mice, we evaluated the role of CMC1 in T cell activation and differentiation. The B16-OVA tumor model was used to test the possibility of targeting CMC1 for improving T cell anti-tumor immunity. We identified CMC1 as a positive regulator in CD8+T cells activation and terminal differentiation. Meanwhile, we found that CMC1 increasingly expressed in exhausted T (Tex) cells. Genetic lost of Cmc1 inhibits the development of CD8+T cell exhaustion in mice. Instead, deletion of Cmc1 in T cells prompts cells to differentiate into metabolically and functionally quiescent cells with increased memory-like features and tolerance to cell death upon repetitive or prolonged T cell receptor (TCR) stimulation. Further, the in-vitro mechanistic study revealed that environmental lactate enhances CMC1 expression by inducing USP7, mediated stabilization and de-ubiquitination of CMC1 protein, in which a mechanism we propose here that the lactate-enriched tumor microenvironment (TME) drives CD8+TILs dysfunction through CMC1 regulatory effects on T cells. Taken together, our study unraveled the novel role of CMC1 as a T cell regulator and its possibility to be utilized for anti-tumor immunotherapy.

Keywords:  CMC1; T cell; USP7; lactate; tumor microenvironment

DOI:  https://doi.org/10.1080/2162402X.2024.2344905
Res Sq. 2024 Apr 08. pii: rs.3.rs-4013392. [Epub ahead of print]

Epstein-Barr-Virus-Driven Cardiolipin Synthesis Sustains Metabolic Remodeling During B-cell Lymphomagenesis.

Haixi You, Larissa Havey, Zhixuan Li, John Asara, Rui Guo.

Epstein-Barr Virus (EBV) is associated with a range of B-cell malignancies, including Burkitt, Hodgkin, post-transplant, and AIDS-related lymphomas. Studies highlight EBV's transformative capability to induce oncometabolism in B-cells to support energy, biosynthetic precursors, and redox equivalents necessary for transition from quiescent to proliferation. Mitochondrial dysfunction presents an intrinsic barrier to EBV B-cell immortalization. Yet, how EBV maintains B-cell mitochondrial function and metabolic fluxes remains unclear. Here we show that EBV boosts cardiolipin(CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBNA2-induced CL enzyme transactivation. Pharmaceutical and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B-cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis, all vital for EBV-transformed B-cells. Targeting CL biosynthesis destabilizes mitochondrial one-carbon enzymes, causing synthetic lethality when coupled with a SHMT1/2 inhibitor. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering new strategies against EBV-associated B-cell malignancies.

DOI: https://doi.org/10.21203/rs.3.rs-4013392/v1
PeerJ. 2024 ;12 e17106

S100A8/9 modulates perturbation and glycolysis of macrophages in allergic asthma mice.

Xiaoyi Ji, Chunhua Nie, Yuan Yao, Yu Ma, Huafei Huang, Chuangli Hao.

  Background: Allergic asthma is the most prevalent asthma phenotype and is associated with the disorders of immune cells and glycolysis. Macrophages are the most common type of immune cells in the lungs. Calprotectin (S100A8 and S100A9) are two pro-inflammatory molecules that target the Toll-like receptor 4 (TLR4) and are substantially increased in the serum of patients with severe asthma. This study aimed to determine the effects of S100A8/A9 on macrophage polarization and glycolysis associated with allergic asthma.Methods: To better understand the roles of S100A8 and S100A9 in the pathogenesis of allergic asthma, we used ovalbumin (OVA)-induced MH-S cells, and OVA-sensitized and challenged mouse models (wild-type male BALB/c mice). Enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, flow cytometry, hematoxylin-eosin staining, and western blotting were performed. The glycolysis inhibitor 3-bromopyruvate (3-BP) was used to observe changes in glycolysis in mice.
Results: We found knockdown of S100A8 or S100A9 in OVA-induced MH-S cells inhibited inflammatory cytokines, macrophage polarization biomarker expression, and pyroptosis cell proportion, but increased anti-inflammatory cytokine interleukin (IL)-10 mRNA; also, glycolysis was inhibited, as evidenced by decreased lactate and key enzyme expression; especially, knockdown of S100A8 or S100A9 inhibited the activity of TLR4/myeloid differentiation primary response gene 88 (MyD88)/Nuclear factor kappa-B (NF-κB) signaling pathway. Intervention with lipopolysaccharides (LPS) abolished the beneficial effects of S100A8 and S100A9 knockdown. The observation of OVA-sensitized and challenged mice showed that S100A8 or S100A9 knockdown promoted respiratory function, improved lung injury, and inhibited inflammation; knockdown of S100A8 or S100A9 also suppressed macrophage polarization, glycolysis levels, and activation of the TLR4/MyD88/NF-κB signaling pathway in the lung. Conversely, S100A9 overexpression exacerbated lung injury and inflammation, promoting macrophage polarization and glycolysis, which were antagonized by the glycolysis inhibitor 3-BP.
Conclusion: S100A8 and S100A9 play critical roles in allergic asthma pathogenesis by promoting macrophage perturbation and glycolysis through the TLR4/MyD88/NF-κB signaling pathway. Inhibition of S100A8 and S100A9 may be a potential therapeutic strategy for allergic asthma.

Keywords:  Allergic asthma; Glycolysis; Macrophages perturbation; S100A8/9; TLR4/MyD88/NF-κB

DOI:  https://doi.org/10.7717/peerj.17106
Adv Sci (Weinh). 2024 Apr 22. e2309725

Lactobacillus Reuteri Vesicles Regulate Mitochondrial Function of Macrophages to Promote Mucosal and Cutaneous Wound Healing.

Yuan Chen, Xiaoyao Huang, Anqi Liu, Siyuan Fan, Shiyu Liu, Zihan Li, Xiaoxue Yang, Hao Guo, Meiling Wu, Meng Liu, Peisheng Liu, Fei Fu, Siying Liu, Kun Xuan.

  The interplay between bacteria and their host influences the homeostasis of the human immune microenvironment, and this reciprocal interaction also affects the process of tissue damage repair. A variety of immunomodulatory commensal bacteria reside in the body, capable of delivering membrane vesicles (MVs) to host cells to regulate the local immune microenvironment. This research revealed, for the initial time, the significant enhancement of mucosal and cutaneous wound healing by MVs secreted by the human commensal Lactobacillus reuteri (RMVs) through modulation of the inflammatory environment in wound tissue. Local administration of RMVs reduces the proportion of pro-inflammatory macrophages in inflamed tissues and mitigates the level of local inflammation, thereby facilitating the healing of oral mucosa and cutaneous wounds. The elevated oxidative stress levels in activated pro-inflammatory macrophages can be modulated by RMVs, resulting in phenotypic transformation of macrophages. Furthermore, 3-hydroxypropionaldehyde present in RMVs can decrease the mitochondrial permeability of macrophages and stabilize the mitochondrial membrane potential, thereby promoting the conversion of macrophages to an anti-inflammatory phenotype. This study pioneers the significance of commensal bacterial MVs in tissue injury repair and presents a novel concept for the repair of tissue damage.

Keywords:  Lactobacillus reuteri DSM 20016; extracellular vesicles; macrophages; mitochondria; wound healing

DOI:  https://doi.org/10.1002/advs.202309725
J Infect Dis. 2024 Apr 24. pii: jiae210. [Epub ahead of print]

Hepatitis B virus and hepatitis C virus affect mitochondrial function through different metabolic pathways, explaining virus-specific clinical features of chronic hepatitis.

Sakthi Priya Selvamani, Anis Khan, Enoch S E Tay, Matthew Garvey, Harout Ajoyan, Eve Diefenbach, Brian S Gloss, Thomas Tu, Jacob George, Mark W Douglas.

  BACKGROUND: Hepatitis C virus (HCV) and hepatitis B virus (HBV) cause chronic hepatitis with important clinical differences. HCV causes hepatic steatosis and insulin resistance, while HBV confers increased risk of liver cancer. We hypothesised these differences may be due to virus-specific effects on mitochondrial function.METHODS: Seahorse technology was utilised to investigate effects of virus infection on mitochondrial function. Cell based assays were used to measure mitochondrial membrane potential and quantify pyruvate and lactate. Mass spectrometry was performed on mitochondria isolated from HBV expressing, HCV infected and control cells cultured with isotope-labelled amino acids, to identify proteins with different abundance. Altered expression of key mitochondrial proteins was confirmed by real time PCR and western blot.
RESULTS: Reduced mitochondrial function and ATP production were observed with HCV infection and HBV expression. HCV impairs glycolysis and reduces expression of genes regulating fatty acid oxidation, promoting lipid accumulation. HBV causes lactate accumulation by increasing expression of lactate dehydrogenase A, which converts pyruvate to lactate. In HBV expressing cells there was marked enrichment of pyruvate dehydrogenase kinase, inhibiting conversion of pyruvate to acetyl-CoA and thereby reducing its availability for mitochondrial oxidative phosphorylation.
CONCLUSIONS: HCV and HBV impair mitochondrial function and reduce ATP production. HCV reduces acetyl-CoA availability for energy production by impairing fatty acid oxidation, causing lipid accumulation and hepatic steatosis. HBV has no effect on fatty oxidation but reduces acetyl-CoA availability by disrupting pyruvate metabolism. This promotes lactic acidosis and oxidative stress, increasing the risk of disease progression and liver cancer.

Keywords:  hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; liver cancer; metabolism; mitochondria; steatosis

DOI:  https://doi.org/10.1093/infdis/jiae210
Benef Microbes. 2023 Sep 01. 14(4): 401-419

Short-chain fatty acids inhibit the activation of T lymphocytes and myeloid cells and induce innate immune tolerance.

M Porbahaie, A Hummel, H Saouadogo, R M L Coelho, H F J Savelkoul, M Teodorowicz, R J J van Neerven.

The intestinal microbiota contributes to gut immune homeostasis, where short-chain fatty acids (SCFAs) function as the major mediators. We aimed to elucidate the immunomodulatory effects of acetate, propionate, and butyrate. With that in mind, we sought to characterise the expression of SCFA receptors and transporters as well as SCFAs' impact on the activation of different immune cells. Whereas all three SCFAs decreased tumour necrosis factor (TNF)-α production in activated T cells, only butyrate and propionate inhibited interferon (IFN)-γ, interleukin (IL)-17, IL-13, and IL-10 production. Butyrate and propionate inhibited the expression of the chemokine receptors CCR9 and CCR10 in activated T- and B-cells, respectively. Similarly, butyrate and propionate were effective inhibitors of IL-1β, IL-6, TNF-α, and IL-10 production in myeloid cells upon lipopolysaccharide and R848 stimulation. Acetate was less efficient at inhibiting cytokine production except for IFN-α. Moreover, SCFAs inhibited the production of IL-6 and TNF-α in monocytes, myeloid dendritic cells (mDC), and plasmacytoid dendritic cells (pDC), whereas acetate effects were relatively more prominent in pDCs. In monocytes and mDCs, acetate was a less efficient inhibitor, but it was equally effective in inhibiting pDCs activation. We also studied the ability of SCFAs to induce trained immunity or tolerance. Butyrate and propionate - but not acetate - prevented Toll-like receptor-mediated activation in SCFA-trained cells, as demonstrated by a reduced production of IL-6 and TNF-α. Our findings indicate that butyrate and propionate are equally efficient in inhibiting the adaptive and innate immune response and did not induce trained immunity. The findings may be explained by differential SCFA receptor and transporter expression profiles of the immune cells.

DOI: https://doi.org/10.1163/18762891-20220113
Nat Rev Immunol. 2024 Apr 22.

Cancer cell metabolism and antitumour immunity.

Mara De Martino, Jeffrey C Rathmell, Lorenzo Galluzzi, Claire Vanpouille-Box.

Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancer cell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.

DOI: https://doi.org/10.1038/s41577-024-01026-4
bioRxiv. 2024 Apr 20. pii: 2024.04.19.589802. [Epub ahead of print]

The Glycolytic Metabolite Methylglyoxal Covalently Inactivates the NLRP3 Inflammasome.

Caroline Stanton, Chavin Buasakdi, Jie Sun, Ian Levitan, Prerona Bora, Sergei Kutseikin, R Luke Wiseman, Michael J Bollong.

The NLRP3 inflammasome promotes inflammation in disease, yet the full repertoire of mechanisms regulating its activity are not well delineated. Among established regulatory mechanisms, covalent modification of NLRP3 has emerged as a common route for pharmacological inactivation of this protein. Here, we show that inhibition of the glycolytic enzyme PGK1 results in the accumulation of methylglyoxal, a reactive metabolite whose increased levels decrease NLRP3 assembly and inflammatory signaling in cells. We find that methylglyoxal inactivates NLRP3 via a non-enzymatic, covalent crosslinking-based mechanism, promoting inter- and intra-protein MICA posttranslational linkages within NLRP3. This work establishes NLRP3 as capable of sensing a host of electrophilic chemicals, both exogenous small molecules and endogenous reactive metabolites, and suggests a mechanism by which glycolytic flux can moderate the activation status of a central inflammatory signaling pathway.

DOI: https://doi.org/10.1101/2024.04.19.589802
Nat Metab. 2024 Apr;6(4): 741-763

Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring.

Jonathan Sun, Enric Esplugues, Alicia Bort, Magdalena P Cardelo, Inmaculada Ruz-Maldonado, Pablo Fernández-Tussy, Clara Wong, Hehe Wang, Iwao Ojima, Martin Kaczocha, Rachel Perry, Yajaira Suárez, Carlos Fernández-Hernando.

Due to the rise in overnutrition, the incidence of obesity-induced hepatocellular carcinoma (HCC) will continue to escalate; however, our understanding of the obesity to HCC developmental axis is limited. We constructed a single-cell atlas to interrogate the dynamic transcriptomic changes during hepatocarcinogenesis in mice. Here we identify fatty acid binding protein 5 (FABP5) as a driver of obesity-induced HCC. Analysis of transformed cells reveals that FABP5 inhibition and silencing predispose cancer cells to lipid peroxidation and ferroptosis-induced cell death. Pharmacological inhibition and genetic ablation of FABP5 ameliorates the HCC burden in male mice, corresponding to enhanced ferroptosis in the tumour. Moreover, FABP5 inhibition induces a pro-inflammatory tumour microenvironment characterized by tumour-associated macrophages with increased expression of the co-stimulatory molecules CD80 and CD86 and increased CD8+ T cell activation. Our work unravels the dual functional role of FABP5 in diet-induced HCC, inducing the transformation of hepatocytes and an immunosuppressive phenotype of tumour-associated macrophages and illustrates FABP5 inhibition as a potential therapeutic approach.

DOI: https://doi.org/10.1038/s42255-024-01019-6
Commun Biol. 2024 Apr 22. 7(1): 488

Disulfiram treatment suppresses antibody-producing reactions by inhibiting macrophage activation and B cell pyrimidine metabolism.

Weili Chen, Etsuko Toda, Kazuhiro Takeuchi, Yurika Sawa, Kyoko Wakamatsu, Naomi Kuwahara, Arimi Ishikawa, Yuri Igarashi, Mika Terasaki, Shinobu Kunugi, Yasuhiro Terasaki, Kazuhiko Yamada, Yuya Terashima, Akira Shimizu.

Antibody responses, involving B cells, CD4 + T cells, and macrophages, are implicated in autoimmune diseases and organ transplant rejection. We have previously shown that inhibiting FROUNT with disulfiram (DSF) suppresses macrophage activation and migration, effectively treating inflammatory diseases. In this study, we investigated the effectiveness of DSF in antibody-producing reactions. Using a heart transplantation mouse model with antibody-mediated rejection, we administered anti-CD8 antibody to exclude cellular rejection. DSF directly inhibited B cell responses in vitro and significantly reduced plasma donor-specific antibodies and graft antibody deposition in vivo, resulting in prolonged survival of the heart graft. DSF also mediated various effects, including decreased macrophage infiltration and increased Foxp3+ regulatory T-cells in the grafts. Additionally, DSF inhibited pyrimidine metabolism-related gene expression induced by B-cell stimulation. These findings demonstrate that DSF modulates antibody production in the immune response complexity by regulating B-cell and macrophage responses.

DOI: https://doi.org/10.1038/s42003-024-06183-9
Nutrients. 2024 Apr 22. pii: 1245. [Epub ahead of print]16(8):

Short-Term Dietary Restriction Potentiates an Anti-Inflammatory Circulating Mucosal-Associated Invariant T-Cell Response.

Brian Fazzone, Erik M Anderson, Jared M Rozowsky, Xuanxuan Yu, Kerri A O'Malley, Scott Robinson, Salvatore T Scali, Guoshuai Cai, Scott A Berceli.

  Short-term protein-calorie dietary restriction (StDR) is a promising preoperative strategy for modulating postoperative inflammation. We have previously shown marked gut microbial activity during StDR, but relationships between StDR, the gut microbiome, and systemic immunity remain poorly understood. Mucosal-associated invariant T-cells (MAITs) are enriched on mucosal surfaces and in circulation, bridge innate and adaptive immunity, are sensitive to gut microbial changes, and may mediate systemic responses to StDR. Herein, we characterized the MAIT transcriptomic response to StDR using single-cell RNA sequencing of human PBMCs and evaluated gut microbial species-level changes through sequencing of stool samples. Healthy volunteers underwent 4 days of DR during which blood and stool samples were collected before, during, and after DR. MAITs composed 2.4% of PBMCs. More MAIT genes were differentially downregulated during DR, particularly genes associated with MAIT activation (CD69), regulation of pro-inflammatory signaling (IL1, IL6, IL10, TNFα), and T-cell co-stimulation (CD40/CD40L, CD28), whereas genes associated with anti-inflammatory IL10 signaling were upregulated. Stool analysis showed a decreased abundance of multiple MAIT-stimulating Bacteroides species during DR. The analyses suggest that StDR potentiates an anti-inflammatory MAIT immunophenotype through modulation of TCR-dependent signaling, potentially secondary to gut microbial species-level changes.

Keywords:  MAITs; immune response; inflammation; mucosal-associated invariant T-cells; short-term dietary restriction

DOI:  https://doi.org/10.3390/nu16081245
Heliyon. 2024 Apr 30. 10(8): e29681

Melatonin-induced upregulation of telomerase activity interferes with macrophage mitochondrial metabolism and suppresses NLRP3 inflammasome activation in the treatment of Pneumonia.

Wei Jiang, Jun Liu, Xuequn Zhao, Wenjie Yang.

  Objective: This study aims to investigate the effects of melatonin-induced upregulation of telomerase activity on mitochondrial metabolism and NLRP3 inflammasome activation in macrophages, with the ultimate goal of elucidating potential therapeutic implications for pneumonia treatment.Materials and methods: Macrophages were treated with melatonin to assess its impact on telomerase activity. Mitochondrial function was evaluated through the measurement of reactive oxygen species (ROS) levels and cellular energy production. NLRP3 inflammasome activation was assessed by examining the production of inflammatory cytokines, such as interleukin-1β (IL-1β). The expression levels of key proteins involved in mitochondrial metabolism and NLRP3 inflammasome signaling were also analyzed.
Results: Our findings demonstrated that melatonin treatment significantly upregulated telomerase activity in macrophages. This was associated with a reduction in ROS levels and enhanced cellular energy production, indicating improved mitochondrial function. Moreover, melatonin treatment suppressed NLRP3 inflammasome activation, resulting in reduced secretion of IL-1β. The expression levels of proteins involved in mitochondrial metabolism and NLRP3 inflammasome signaling were modulated by melatonin.
Conclusion: These results suggest that melatonin-induced upregulation of telomerase activity can interfere with mitochondrial metabolism and inhibit NLRP3 inflammasome activation in macrophages. This indicates a potential therapeutic role for melatonin in the treatment of pneumonia. Understanding the molecular mechanisms underlying these effects may lead to the development of novel therapeutic strategies targeting mitochondria and NLRP3 inflammasome activation for the management of pneumonia. Further investigations are warranted to fully uncover the therapeutic potential of melatonin and its implications for pneumonia treatment.

Keywords:  Melatonin; Mitochondrial metabolism; NLRP3 inflammasome; Pneumonia; Telomerase

DOI:  https://doi.org/10.1016/j.heliyon.2024.e29681
bioRxiv. 2024 Apr 21. pii: 2024.04.21.589969. [Epub ahead of print]

Commensal bacteria inhibit viral infections via a tryptophan metabolite.

Danting Jiang, Nicole Soo, Chin Yee Tan, Sedem Dankwa, Hsuan-Yuan Wang, Barbara S Theriot, Amir Ardeshir, Nazema Y Siddiqui, Koen K A Van Rompay, Kristina De Paris, Sallie R Permar, Ria Goswami, Neeraj K Surana.

There is growing appreciation that commensal bacteria impact the outcome of viral infections, though the specific bacteria and their underlying mechanisms remain poorly understood. Studying a simian-human immunodeficiency virus (SHIV)-challenged cohort of pediatric nonhuman primates, we bioinformatically associated Lactobacillus gasseri and the bacterial family Lachnospiraceae with enhanced resistance to infection. We experimentally validated these findings by demonstrating two different Lachnospiraceae isolates, Clostridium immunis and Ruminococcus gnavus, inhibited HIV replication in vitro and ex vivo. Given the link between tryptophan catabolism and HIV disease severity, we found that an isogenic mutant of C. immunis that lacks the aromatic amino acid aminotransferase (ArAT) gene, which is key to metabolizing tryptophan into 3-indolelactic acid (ILA), no longer inhibits HIV infection. Intriguingly, we confirmed that a second commensal bacterium also inhibited HIV in an ArAT-dependent manner, thus establishing the generalizability of this finding. In addition, we found that purified ILA inhibited HIV infection by agonizing the aryl hydrocarbon receptor (AhR). Given that the AhR has been implicated in the control of multiple viral infections, we demonstrated that C. immunis also inhibited human cytomegalovirus (HCMV) infection in an ArAT-dependent manner. Importantly, metagenomic analysis of individuals at-risk for HIV revealed that those who ultimately acquired HIV had a lower fecal abundance of the bacterial ArAT gene compared to individuals who did not, which indicates our findings translate to humans. Taken together, our results provide mechanistic insights into how commensal bacteria decrease susceptibility to viral infections. Moreover, we have defined a microbiota-driven antiviral pathway that offers the potential for novel therapeutic strategies targeting a broad spectrum of viral pathogens.

DOI: https://doi.org/10.1101/2024.04.21.589969
Nat Immunol. 2024 Apr 25.

A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron.

Garima Sharma, Amit Sharma, Inhae Kim, Dong Gon Cha, Somi Kim, Eun Seo Park, Jae Gyun Noh, Juhee Lee, Ja Hyeon Ku, Yoon Ha Choi, JungHo Kong, Haena Lee, Haeun Ko, Juhun Lee, Anna Notaro, Seol Hee Hong, Joon Haeng Rhee, Sang Geon Kim, Cristina De Castro, Antonio Molinaro, Kunyoo Shin, Sanguk Kim, Jong Kyoung Kim, Dipayan Rudra, Sin-Hyeog Im.

Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8+ T cell response, and triggers macrophage 'nutritional immunity' to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into 'oncobiotics' for a multi-layered approach to cancer therapy.

DOI: https://doi.org/10.1038/s41590-024-01816-x
Dis Aquat Organ. 2024 Apr 25. 158 101-114

Metabolomics captures the differential metabolites in the replication pathway of snakehead vesiculovirus regulated by glutamine.

Binbin Sun, Yulei Zhang, Keping Chen, Lindan Sun.

  Snakehead vesiculovirus (SHVV) is a negative-sense single-stranded RNA virus that infects snakehead fish. This virus leads to illness and mortality, causing significant economic losses in the snakehead aquaculture industry. The replication and spread of SHVV in cells, which requires glutamine as a nitrogen source, is accompanied by alterations in intracellular metabolites. However, the metabolic mechanisms underlying the inhibition of viral replication by glutamine deficiency are poorly understood. This study utilized liquid chromatography-mass spectrometry to measure the differential metabolites between the channel catfish Parasilurus asotus ovary cell line infected with SHVV under glutamine-containing and glutamine-deprived conditions. Results showed that the absence of glutamine regulated 4 distinct metabolic pathways and influenced 9 differential metabolites. The differential metabolites PS(16:0/16:0), 5,10-methylene-THF, and PS(18:0/18:1(9Z)) were involved in amino acid metabolism. In the nuclear metabolism functional pathway, differential metabolites of guanosine were observed. In the carbohydrate metabolism pathway, differential metabolites of UDP-d-galacturonate were detected. In the signal transduction pathway, differential metabolites of SM(d18:1/20:0), SM(d18:1/22:1(13Z)), SM(d18:1/24:1(15 Z)), and sphinganine were found. Among them, PS(18:0/18:1(9Z)), PS(16:0/16:0), and UDP-d-galacturonate were involved in the synthesis of phosphatidylserine and glycoprotein. The compound 5,10-methylene-THF provided raw materials for virus replication, and guanosine and sphingosine are related to virus virulence. The differential metabolites may collectively participate in the replication, packaging, and proliferation of SHVV under glutamine deficiency. This study provides new insights and potential metabolic targets for combating SHVV infection in aquaculture through metabolomics approaches.

Keywords:  Glutamine-deprived; Metabolomics; Snakehead fish; Snakehead vesiculovirus; Ultra-high-performance liquid chromatography

DOI:  https://doi.org/10.3354/dao03786
Cell Mol Biol (Noisy-le-grand). 2024 Mar 31. 70(3): 102-109

TNFRSF6 induces mitochondrial dysfunction and microglia activation in the in vivo and in vitro models of sepsis-associated encephalopathy.

Danfeng Yu, Yanmei Ji, Jing Zhang, Xiaochuan Huang.

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis. The tumour necrosis factor receptor superfamily member 6 (TNFRSF6) gene encodes the Fas protein, and it participates in apoptosis induced in different cell types. This study aimed to explore TNFRSF6 function in SAE. The SAE mouse model was established by intraperitoneal injection of LPS in TNFRSF6-/- mice and C57BL/6J mice. Microglia were treated with LPS to establish the cell model. The learning, memory and cognitive functions in mice were tested by behavioral tests. Nissl staining was utilized for determining neuronal injury. Microglial activation was tested by immunofluorescence assay. ELISA was utilized for determining TNF-α, IL-1β, IL-6, and IL-10 contents. Mitochondrial dysfunction was measured by mitochondrial oxygen consumption, ATP content, ROS production, and JC-1 assay. TNFRSF6 was upregulated in the LPS-induced mouse model and cell model. TNFRSF6 deficiency notably alleviated the impaired learning, memory and cognitive functions in SAE mice. Furthermore, we found that TNFRSF6 deficiency could alleviate neuronal injury, microglial activation, and inflammation in SAE mice. Additionally, mitochondrial dysfunction in the SAE mice was improved by TNFRSF6 depletion. In the LPS-induced microglia, we also proved that TNFRSF6 knockdown reduced inflammatory response inhibited ROS production, and alleviated mitochondrial dysfunction. TNFRSF6 induced mitochondrial dysfunction and microglia activation in the in vivo and in vitro models of SAE.

DOI: https://doi.org/10.14715/cmb/2024.70.3.15
Sci Rep. 2024 04 25. 14(1): 9555

Urinary metabolomic profiling of a cohort of Colombian patients with systemic lupus erythematosus.

Alejandra Rojo-Sánchez, Ada Carmona-Martes, Yirys Díaz-Olmos, Mary Santamaría-Torres, Mónica P Cala, Erick Orozco-Acosta, Gustavo Aroca-Martínez, Leonardo Pacheco-Londoño, Elkin Navarro-Quiroz, Lisandro A Pacheco-Lugo.

Systemic lupus erythematosus (SLE) is an autoimmune and multisystem disease with a high public health impact. Lupus nephritis (LN), commonly known as renal involvement in SLE, is associated with a poorer prognosis and increased rates of morbidity and mortality in patients with SLE. Identifying new urinary biomarkers that can be used for LN prognosis or diagnosis is essential and is part of current active research. In this study, we applied an untargeted metabolomics approach involving liquid and gas chromatography coupled with mass spectrometry to urine samples collected from 17 individuals with SLE and no kidney damage, 23 individuals with LN, and 10 clinically healthy controls (HCs) to identify differential metabolic profiles for SLE and LN. The data analysis revealed a differentially abundant metabolite expression profile for each study group, and those metabolites may act as potential differential biomarkers of SLE and LN. The differential metabolic pathways found between the LN and SLE patients with no kidney involvement included primary bile acid biosynthesis, branched-chain amino acid synthesis and degradation, pantothenate and coenzyme A biosynthesis, lysine degradation, and tryptophan metabolism. Receiver operating characteristic curve analysis revealed that monopalmitin, glycolic acid, and glutamic acid allowed for the differentiation of individuals with SLE and no kidney involvement and individuals with LN considering high confidence levels. While the results offer promise, it is important to recognize the significant influence of medications and other external factors on metabolomics studies. This impact has the potential to obscure differences in metabolic profiles, presenting a considerable challenge in the identification of disease biomarkers. Therefore, experimental validation should be conducted with a larger sample size to explore the diagnostic potential of the metabolites found as well as to examine how treatment and disease activity influence the identified chemical compounds. This will be crucial for refining the accuracy and effectiveness of using urine metabolomics for diagnosing and monitoring lupus and lupus nephritis.

DOI: https://doi.org/10.1038/s41598-024-60217-0
Clin Transl Med. 2024 Apr;14(4): e1661

ACOD1, rather than itaconate, facilitates p62-mediated activation of Nrf2 in microglia post spinal cord contusion.

Zhanyang Qian, Mingjie Xia, Tianyu Zhao, You Li, Guangshen Li, Yanan Zhang, Haijun Li, Lei Yang.

  BACKGROUND: Spinal cord injury (SCI)-induced neuroinflammation and oxidative stress (OS) are crucial events causing neurological dysfunction. Aconitate decarboxylase 1 (ACOD1) and its metabolite itaconate (Ita) inhibit inflammation and OS by promoting alkylation of Keap1 to induce Nrf2 expression; however, it is unclear whether there is another pathway regulating their effects in inflammation-activated microglia after SCI.METHODS: Adult male C57BL/6 ACOD1-/- mice and their wild-type (WT) littermates were subjected to a moderate thoracic spinal cord contusion. The degree of neuroinflammation and OS in the injured spinal cord were assessed using qPCR, western blot, flow cytometry, immunofluorescence, and trans-well assay. We then employed immunoprecipitation-western blot, chromatin immunoprecipitation (ChIP)-PCR, dual-luciferase assay, and immunofluorescence-confocal imaging to examine the molecular mechanisms of ACOD1. Finally, the locomotor function was evaluated with the Basso Mouse Scale and footprint assay.
RESULTS: Both in vitro and in vivo, microglia with transcriptional blockage of ACOD1 exhibited more severe levels of neuroinflammation and OS, in which the expression of p62/Keap1/Nrf2 was down-regulated. Furthermore, silencing ACOD1 exacerbated neurological dysfunction in SCI mice. Administration of exogenous Ita or 4-octyl itaconate reduced p62 phosphorylation. Besides, ACOD1 was capable of interacting with phosphorylated p62 to enhance Nrf2 activation, which in turn further promoted transcription of ACOD1.
CONCLUSIONS: Here, we identified an unreported ACOD1-p62-Nrf2-ACOD1 feedback loop exerting anti-inflammatory and anti-OS in inflammatory microglia, and demonstrated the neuroprotective role of ACOD1 after SCI, which was different from that of endogenous and exogenous Ita. The present study extends the functions of ACOD1 and uncovers marked property differences between endogenous and exogenous Ita.
KEY POINTS: ACOD1 attenuated neuroinflammation and oxidative stress after spinal cord injury. ACOD1, not itaconate, interacted with p-p62 to facilitate Nrf2 expression and nuclear translocation. Nrf2 was capable of promoting ACOD1 transcription in microglia.

Keywords:  Nrf2; aconitate decarboxylase 1; itaconate; neuroinflammation; p62; spinal cord injury

DOI:  https://doi.org/10.1002/ctm2.1661
Front Immunol. 2024 ;15 1353570

The functional role of L-fucose on dendritic cell function and polarization.

Chase Burton, Amirreza Bitaraf, Kara Snyder, Chaomei Zhang, Sean J Yoder, Dorina Avram, Dongliang Du, Xiaoqing Yu, Eric K Lau.

  Despite significant advances in the development and refinement of immunotherapies administered to combat cancer over the past decades, a number of barriers continue to limit their efficacy. One significant clinical barrier is the inability to mount initial immune responses towards the tumor. As dendritic cells are central initiators of immune responses in the body, the elucidation of mechanisms that can be therapeutically leveraged to enhance their functions to drive anti-tumor immune responses is urgently needed. Here, we report that the dietary sugar L-fucose can be used to enhance the immunostimulatory activity of dendritic cells (DCs). L-fucose polarizes immature myeloid cells towards specific DC subsets, specifically cDC1 and moDC subsets. In vitro, L-fucose treatment enhances antigen uptake and processing of DCs. Furthermore, our data suggests that L-fucose-treated DCs increase stimulation of T cell populations. Consistent with our functional assays, single-cell RNA sequencing of intratumoral DCs from melanoma- and breast tumor-bearing mice confirmed transcriptional regulation and antigen processing as pathways that are significantly altered by dietary L-fucose. Together, this study provides the first evidence of the ability of L-fucose to bolster DC functionality and provides rational to further investigate how L-fucose can be used to leverage DC function in order to enhance current immunotherapy.

Keywords:  L-fucose; antigen presentation; dendritic cells; myeloid cells; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1353570
Neurobiol Dis. 2024 Apr 24. pii: S0969-9961(24)00110-4. [Epub ahead of print] 106511

Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease.

Maria Elizabeth De Sousa Rodrigues, MacKenzie L Bolen, Lisa Blackmer-Raynolds, Noah Schwartz, Jianjun Chang, Malú Gámez Tansey, Timothy Robert Sampson.

  Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.

Keywords:  Alzheimer's; Insulin; Metabolic inflammation; Soluble TNF

DOI:  https://doi.org/10.1016/j.nbd.2024.106511