bims-imicid 2024-03-31 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–03–31
twenty-one papers selected by
Dylan Ryan, University of Cambridge

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.
Defective mitochondria remodelling in B cells leads to an aged immune response.
ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition.
Oxidative phosphorylation in HIV-1 infection: impacts on cellular metabolism and immune function.
Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.
The Impact of Glycolysis and Its Inhibitors on the Immune Response to Inflammation and Autoimmunity.
Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.
Fatostatin promotes anti-tumor immunity by reducing SREBP2 mediated cholesterol metabolism in tumor-infiltrating T lymphocytes.
Pathogenesis or a response to lithium? A novel perspective for mitochondrial mass fluctuation of naïve T cells in patients with bipolar disorder.
Thioredoxin is a metabolic rheostat controlling regulatory B cells.
The Accumulation of Phenyllactic Acid Impairs Host Glutamine Metabolism and Inhibits African Swine Fever Virus Replication: A Novel Target for the Development of Anti-ASFV Drugs.
Senescence and aging differentially alter key metabolic pathways in murine brain microglia.
Amino Acid Metabolism in Leukocytes Showing In Vitro IgG Memory from SARS-CoV2-Infected Patients.
GPR41 and GPR43 regulate CD8+ T cell priming during herpes simplex virus type 1 infection.
The Role of Neutral Sphingomyelinase-2 (NSM2) in the Control of Neutral Lipid Storage in T Cells.
Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue.
The Immunomodulatory Potential of Short-Chain Fatty Acids in Multiple Sclerosis.
Mevalonate kinase-deficient THP-1 cells show a disease-characteristic pro-inflammatory phenotype.
Metabolic profiling of synovial fluid in human temporomandibular joint osteoarthritis.
Metabolomics identifies phenotypic biomarkers of amino acid metabolism in milk allergy and sensitized tolerance.
Imidazole propionate ameliorates atopic dermatitis-like skin lesions by inhibiting mitochondrial ROS and mTORC2.

Nat Neurosci. 2024 Mar 27.

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.

Edward N Wilson, Congcong Wang, Michelle S Swarovski, Kristy A Zera, Hannah E Ennerfelt, Qian Wang, Aisling Chaney, Esha Gauba, Javier A Ramos Benitez, Yann Le Guen, Paras S Minhas, Maharshi Panchal, Yuting J Tan, Eran Blacher, Chinyere A Iweka, Haley Cropper, Poorva Jain, Qingkun Liu, Swapnil S Mehta, Abigail J Zuckerman, Matthew Xin, Jacob Umans, Jolie Huang, Aarooran S Durairaj, Geidy E Serrano, Thomas G Beach, Michael D Greicius, Michelle L James, Marion S Buckwalter, Melanie R McReynolds, Joshua D Rabinowitz, Katrin I Andreasson.

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β42 oligomer-induced bioenergetic changes, suggesting that amyloid-β42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

DOI: https://doi.org/10.1038/s41593-024-01610-w
Nat Commun. 2024 Mar 22. 15(1): 2569

Defective mitochondria remodelling in B cells leads to an aged immune response.

Marta Iborra-Pernichi, Jonathan Ruiz García, María Velasco de la Esperanza, Belén S Estrada, Elena R Bovolenta, Claudia Cifuentes, Cristina Prieto Carro, Tamara González Martínez, José García-Consuegra, María Fernanda Rey-Stolle, Francisco Javier Rupérez, Milagros Guerra Rodriguez, Rafael J Argüello, Sara Cogliati, Fernando Martín-Belmonte, Nuria Martínez-Martín.

The B cell response in the germinal centre (GC) reaction requires a unique bioenergetic supply. Although mitochondria are remodelled upon antigen-mediated B cell receptor stimulation, mitochondrial function in B cells is still poorly understood. To gain a better understanding of the role of mitochondria in B cell function, here we generate mice with B cell-specific deficiency in Tfam, a transcription factor necessary for mitochondrial biogenesis. Tfam conditional knock-out (KO) mice display a blockage of the GC reaction and a bias of B cell differentiation towards memory B cells and aged-related B cells, hallmarks of an aged immune response. Unexpectedly, blocked GC reaction in Tfam KO mice is not caused by defects in the bioenergetic supply but is associated with a defect in the remodelling of the lysosomal compartment in B cells. Our results may thus describe a mitochondrial function for lysosome regulation and the downstream antigen presentation in B cells during the GC reaction, the dysruption of which is manifested as an aged immune response.

DOI: https://doi.org/10.1038/s41467-024-46763-1
Cell Rep. 2024 Mar 23. pii: S2211-1247(24)00323-1. [Epub ahead of print]43(4): 113995

ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition.

Ziqi Zou, Qian Cheng, Jiajie Zhou, Chenyao Guo, Andreas V Hadjinicolaou, Mariolina Salio, Xinghua Liang, Cuiyu Yang, Yue Du, Weiran Yao, Dongrui Wang, Vincenzo Cerundolo, Qingqing Wang, Meng Xia.

  The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we find that the 20-μM low arginine condition, representing the levels found in the plasma of patients with cancers, confers Treg-like immunosuppressive capacities upon activated T cells. In vivo mouse tumor models and human single-cell RNA-sequencing datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low arginine-activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.

Keywords:  CP: Immunology; SLC7A11; T cells; arginine; immunosuppression; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2024.113995
Front Immunol. 2024 ;15 1360342

Oxidative phosphorylation in HIV-1 infection: impacts on cellular metabolism and immune function.

Natalia Rodriguez Rodriguez, Trinisia Fortune, Esha Hegde, Matthew Paltiel Weinstein, Aislinn M Keane, Jesse F Mangold, Talia H Swartz.

  Human Immunodeficiency Virus Type 1 (HIV-1) presents significant challenges to the immune system, predominantly characterized by CD4+ T cell depletion, leading to Acquired Immunodeficiency Syndrome (AIDS). Antiretroviral therapy (ART) effectively suppresses the viral load in people with HIV (PWH), leading to a state of chronic infection that is associated with inflammation. This review explores the complex relationship between oxidative phosphorylation, a crucial metabolic pathway for cellular energy production, and HIV-1, emphasizing the dual impact of HIV-1 infection and the metabolic and mitochondrial effects of ART. The review highlights how HIV-1 infection disrupts oxidative phosphorylation, promoting glycolysis and fatty acid synthesis to facilitate viral replication. ART can exacerbate metabolic dysregulation despite controlling viral replication, impacting mitochondrial DNA synthesis and enhancing reactive oxygen species production. These effects collectively contribute to significant changes in oxidative phosphorylation, influencing immune cell metabolism and function. Adenosine triphosphate (ATP) generated through oxidative phosphorylation can influence the metabolic landscape of infected cells through ATP-detected purinergic signaling and contributes to immunometabolic dysfunction. Future research should focus on identifying specific targets within this pathway and exploring the role of purinergic signaling in HIV-1 pathogenesis to enhance HIV-1 treatment modalities, addressing both viral infection and its metabolic consequences.

Keywords:  HIV-1; antiretroviral therapy (ART); immune metabolism; mitochondrial dysfunction; oxidative phosphorylation

DOI:  https://doi.org/10.3389/fimmu.2024.1360342
Cell Metab. 2024 Mar 26. pii: S1550-4131(24)00092-5. [Epub ahead of print]

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

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

DOI: https://doi.org/10.1016/j.cmet.2024.03.013
Molecules. 2024 Mar 14. pii: 1298. [Epub ahead of print]29(6):

The Impact of Glycolysis and Its Inhibitors on the Immune Response to Inflammation and Autoimmunity.

Beata Pająk, Rafał Zieliński, Waldemar Priebe.

  Glucose metabolism is a crucial biological pathway maintaining the activation of extra- and intracellular signaling pathways involved in the immune response. Immune cell stimulation via various environmental factors results in their activation and metabolic reprogramming to aerobic glycolysis. Different immune cells exhibit cell-type-specific metabolic patterns when performing their biological functions. Numerous published studies have shed more light on the importance of metabolic reprogramming in the immune system. Moreover, this knowledge is crucial for revealing new ways to target inflammatory pathologic states, such as autoimmunity and hyperinflammation. Here, we discuss the role of glycolysis in immune cell activity in physiological and pathological conditions, and the potential use of inhibitors of glycolysis for disease treatment.

Keywords:  2-deoxy-D-glucose; D-glucose; D-mannose; autoimmunity; glycolysis; glycolysis inhibitors; immune cells; inflammation

DOI:  https://doi.org/10.3390/molecules29061298
Nat Commun. 2024 Mar 22. 15(1): 2598

Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.

Nick Huang, Thomas Winans, Brandon Wyman, Zachary Oaks, Tamas Faludi, Gourav Choudhary, Zhi-Wei Lai, Joshua Lewis, Miguel Beckford, Manuel Duarte, Daniel Krakko, Akshay Patel, Joy Park, Tiffany Caza, Mahsa Sadeghzadeh, Laurence Morel, Mark Haas, Frank Middleton, Katalin Banki, Andras Perl.

Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4-CD8- double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.

DOI: https://doi.org/10.1038/s41467-024-46441-2
Eur J Pharmacol. 2024 Mar 22. pii: S0014-2999(24)00207-3. [Epub ahead of print] 176519

Fatostatin promotes anti-tumor immunity by reducing SREBP2 mediated cholesterol metabolism in tumor-infiltrating T lymphocytes.

Lei Zhu, Yilin Shi, Zhelong Feng, Dingyi Yuan, Shiduo Guo, Yuxia Wang, Haowen Shen, Yan Li, Fang Yan, Yajing Wang.

  Aberrant lipid metabolism impacts intratumoral T cell-mediated immune response and tumor growth. Fatostatin functions as an inhibitor of sterol regulatory element binding protein (SREBP) activation. However, the complex effects of fatostatin on cholesterol metabolism in the tumor microenvironment (TME) and its influence on T cell anti-tumor immunity remain unclear. In this study, fatostatin effectively suppressed B16 melanoma, MC38 colon cancer, and Lewis lung cancer (LLC) transplanted tumor growth in immunocompetent mice by reducing SREBPs-mediated lipid metabolism, especially cholesterol levels. Mechanistically, fatostatin decreased intracellular cholesterol accumulation and inhibited X-box binding protein 1 (XBP1)-mediated endoplasmic reticulum (ER) stress, reducing Treg cells and alleviating CD8+ T cell exhaustion in the TME, exerting anti-tumor activity. Nevertheless， this effect was impaired in immunodeficient nude mice, suggesting fatostatin's anti-tumor efficacy in transplanted tumors partly relies on T cell-mediated anti-tumor immunity. Our study highlights SREBP2-mediated cholesterol metabolism as a potential strategy for anti-tumor immunotherapy, and confirms fatostatin's promise in tumor immunotherapy.

Keywords:  CD8(+) T cell exhaustion; Cholesterol; Endoplasmic reticulum stress; Fatostatin; Regulatory T cells; XBP1

DOI:  https://doi.org/10.1016/j.ejphar.2024.176519
J Affect Disord. 2024 Mar 21. pii: S0165-0327(24)00518-4. [Epub ahead of print]

Pathogenesis or a response to lithium? A novel perspective for mitochondrial mass fluctuation of naïve T cells in patients with bipolar disorder.

Zhenni Chen, Bingqi Wang, Yiran Huang, Xiaofan Wang, Wanzhen Li, Min Wang.

   BACKGROUND: Immune imbalances are associated with the pathogenesis and pharmacological efficacy of bipolar disorder (BD). The underlying mechanisms remain largely obscure but may involve immunometabolic dysfunctions of T-lymphocytes.
METHODS: We investigated if inflammatory cytokines and the immunometabolic function of T-lymphocytes, including frequencies of subsets, mitochondrial mass (MM), and low mitochondrial membrane potential (MMPLow) differed between BD patients (n = 47) and healthy controls (HC, n = 43). During lithium treatment of hospitalized patients (n = 33), the association between weekly T-lymphocyte immune metabolism and clinical symptoms was analyzed, and preliminary explorations on possible mechanisms were conducted.
RESULTS: In comparison to HC, BD patients predominantly showed a trend toward CD4+ naïve T (Tn) activation and exhibited mitochondrial metabolic disturbances such as decreased MM and increased MMPLow. Lower CD4+ Tn-MM correlated with elevated IL-6, IL-8, and decreased IL-17 A in BD patients. With lithium treatment effective, MM of CD4+ T/Tn was negatively correlated with depression score HAMD. When lithium intolerance was present, MM of CD4+ T/Tn was positively correlated with depression score HAMD and mania score BRMS. Lithium does not mediate through the inositol depletion hypothesis, but the mRNA level of IMPA2 in peripheral blood is associated with mitochondrial function in CD8+ T cells.
LIMITATIONS: The cross-sectional design and short-term follow-up meant that we could not directly examine the causality of BD and immune dysregulation.
CONCLUSION: The altered metabolism of CD4+ Tn was strongly associated with remodeling of the inflammatory landscape in BD patients and can also be used to reflect the short-term therapeutic effects of lithium.

Keywords:  Bipolar disorder; Immune metabolism; Lithium; Mitochondrial abnormality

DOI:  https://doi.org/10.1016/j.jad.2024.03.095
Nat Immunol. 2024 Mar 29.

Thioredoxin is a metabolic rheostat controlling regulatory B cells.

Hannah F Bradford, Thomas C R McDonnell, Alexander Stewart, Andrew Skelton, Joseph Ng, Zara Baig, Franca Fraternali, Deborah Dunn-Walters, David A Isenberg, Adnan R Khan, Claudio Mauro, Claudia Mauri.

Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (Breg) cell differentiation and function is unknown. Here we show that Breg cell differentiation, unlike non-Breg cells, relies on mitochondrial electron transport and homeostatic levels of reactive oxygen species (ROS). Single-cell RNA sequencing analysis revealed that TXN, encoding the metabolic redox protein thioredoxin (Trx), is highly expressed by Breg cells, unlike Trx inhibitor TXNIP which was downregulated. Pharmacological inhibition or gene silencing of TXN resulted in mitochondrial membrane depolarization and increased ROS levels, selectively suppressing Breg cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by Breg cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx+ B cells. Exogenous Trx stimulation restored Breg cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies Breg cell impairment in patients with SLE.

DOI: https://doi.org/10.1038/s41590-024-01798-w
Viruses. 2024 Mar 13. pii: 449. [Epub ahead of print]16(3):

The Accumulation of Phenyllactic Acid Impairs Host Glutamine Metabolism and Inhibits African Swine Fever Virus Replication: A Novel Target for the Development of Anti-ASFV Drugs.

Junfei Dai, Xusheng Ma, Ashenafi Kiros Wubshet, Qian Li, Xiaofen Shang, Zhikuan Luo, Jianan Liu, Zhiyu Li, Mingxia Li, Yujie Song, Lijun Guo, Jie Zhang, Haixue Zheng.

  African swine fever (ASF) is a highly contagious and hemorrhagic disease caused by infection with the African swine fever virus (ASFV), resulting in a mortality rate of up to 100%. Currently, there are no effective treatments and commercially available vaccines for ASF. Therefore, it is crucial to identify biochemicals derived from host cells that can impede ASFV replication, with the aim of preventing and controlling ASF. The ASFV is an acellular organism that promotes self-replication by hijacking the metabolic machinery and biochemical resources of host cells. ASFV specifically alters the utilization of glucose and glutamine, which are the primary metabolic sources in mammalian cells. This study aimed to investigate the impact of glucose and glutamine metabolic dynamics on the rate of ASFV replication. Our findings demonstrate that ASFV infection favors using glutamine as a metabolic fuel to facilitate self-replication. ASFV replication can be substantially inhibited by blocking glutamine metabolism. The metabolomics analysis of the host cell after late-stage ASFV infection revealed a significant disruption of normal glutamine metabolic pathways due to the abundant expression of PLA (phenyllactic acid). Pretreatment with PLA also inhibited ASFV proliferation and glutamine consumption following infection. The metabolomic analysis also showed that PLA pretreatment greatly slowed down the metabolism of amino acids and nucleotides that depend on glutamine. The depletion of these building blocks directly hindered the replication of ASFV by decreasing the biosynthetic precursors produced during the replication of ASFV's progeny virus. These findings provide valuable insight into the possibility of pursuing the development of antiviral drugs against ASFV that selectively target metabolic pathways.

Keywords:  ASFV; glutamine; inhibition; metabolics; phenyllactic acid

DOI:  https://doi.org/10.3390/v16030449
Neurosci Lett. 2024 Mar 26. pii: S0304-3940(24)00128-9. [Epub ahead of print] 137751

Senescence and aging differentially alter key metabolic pathways in murine brain microglia.

Milan R Stojiljkovic, Christian Schmeer, Otto W Witte.

  Microglia, the resident immune cells of the central nervous system, are critically involved in maintaining brain homeostasis. With age, microglia display morphological and functional alterations that have been associated with cognitive decline and neurodegeneration. Although microglia seem to participate in an increasing number of biological processes which require a high energy demand, little is known about their metabolic regulation under physiological and pathophysiological conditions and during aging/senescence. Here, we determined mRNA expression levels of critical rate limiting enzymes in several key metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis in association with oxidative phosphorylation in microglia, both under aging and senescent conditions. We found strong evidence for different metabolic changes occuring in senescent vs. aged microglia cells. While senescent microglia display a hypermetabolic state as indicated by increased expression of key enzymes involved in glycolysis and pentose phosphate pathway, aging microglia are rather in a state of hypometabolism. Our findings indicate that studies involving aging and senescent microglia require a clear differentiation between these microglial states due to profound metabolic differences observed here. Understanding metabolic changes in senescent and aged microglia may lead to novel strategies to decrease over-activation of these cells due to aging, which is associated to the process of inflamm-aging and neurodegeneration.

Keywords:  Aging; Immune system; Metabolism; Microglia; Senescence

DOI:  https://doi.org/10.1016/j.neulet.2024.137751
Diseases. 2024 Feb 23. pii: 43. [Epub ahead of print]12(3):

Amino Acid Metabolism in Leukocytes Showing In Vitro IgG Memory from SARS-CoV2-Infected Patients.

Giuseppina Fanelli, Veronica Lelli, Sara Rinalducci, Anna Maria Timperio.

  The immune response to infectious diseases is directly influenced by metabolic activities. COVID-19 is a disease that affects the entire body and can significantly impact cellular metabolism. Recent studies have focused their analysis on the potential connections between post-infection stages of SARS-CoV2 and different metabolic pathways. The spike S1 antigen was found to have in vitro IgG antibody memory for PBMCs when obtaining PBMC cultures 60-90 days post infection, and a significant increase in S-adenosyl homocysteine, sarcosine, and arginine was detected by mass spectrometric analysis. The involvement of these metabolites in physiological recovery from viral infections and immune activity is well documented, and they may provide a new and simple method to better comprehend the impact of SARS-CoV2 on leukocytes. Moreover, there was a significant change in the metabolism of the tryptophan and urea cycle pathways in leukocytes with IgG memory. With these data, together with results from the literature, it seems that leukocyte metabolism is reprogrammed after viral pathogenesis by activating certain amino acid pathways, which may be related to protective immunity against SARS-CoV2.

Keywords:  COVID-19; SARS-CoV2; cell ELISA; mass spectrometry; metabolomics

DOI:  https://doi.org/10.3390/diseases12030043
Front Immunol. 2024 ;15 1332588

GPR41 and GPR43 regulate CD8+ T cell priming during herpes simplex virus type 1 infection.

Ariane Renita Lee, Kayla Roberta Wilson, Michele Clarke, Sven Engel, David C Tscharke, Thomas Gebhardt, Sammy Bedoui, Annabell Bachem.

  Naïve CD8+ T cells need to undergo a complex and coordinated differentiation program to gain the capacity to control virus infections. This not only involves the acquisition of effector functions, but also regulates the development of a subset of effector CD8+ T cells into long-lived and protective memory cells. Microbiota-derived metabolites have recently gained interest for their influence on T cells, but much remains unclear about their role in CD8+ T cell differentiation. In this study, we investigated the role of the G protein-coupled receptors (GPR)41 and GPR43 that can bind microbiota-derived short chain fatty acids (SCFAs) in CD8+ T cell priming following epicutaneous herpes simplex virus type 1 (HSV-1) infection. We found that HSV-specific CD8+ T cells in GPR41/43-deficient mice were impaired in the antigen-elicited production of interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), granzyme B and perforin, and failed to differentiate effectively into memory precursors. The defect in controlling HSV-1 at the site of infection could be restored when GPR41 and GPR43 were expressed exclusively by HSV-specific CD8+ T cells. Our findings therefore highlight roles for GPR41 and GPR43 in CD8+ T cell differentiation, emphasising the importance of metabolite sensing in fine-tuning anti-viral CD8+ T cell priming.

Keywords:  CD8+ T cells; GPR41; GPR43; MPEC; SCFA; differentiation; microbiota

DOI:  https://doi.org/10.3389/fimmu.2024.1332588
Int J Mol Sci. 2024 Mar 13. pii: 3247. [Epub ahead of print]25(6):

The Role of Neutral Sphingomyelinase-2 (NSM2) in the Control of Neutral Lipid Storage in T Cells.

Rebekka Schempp, Janna Eilts, Marie Schöl, Maria Fernanda Grijalva Yépez, Agnes Fekete, Dominik Wigger, Fabian Schumacher, Burkhard Kleuser, Marco van Ham, Lothar Jänsch, Markus Sauer, Elita Avota.

  The accumulation of lipid droplets (LDs) and ceramides (Cer) is linked to non-alcoholic fatty liver disease (NAFLD), regularly co-existing with type 2 diabetes and decreased immune function. Chronic inflammation and increased disease severity in viral infections are the hallmarks of the obesity-related immunopathology. The upregulation of neutral sphingomyelinase-2 (NSM2) has shown to be associated with the pathology of obesity in tissues. Nevertheless, the role of sphingolipids and specifically of NSM2 in the regulation of immune cell response to a fatty acid (FA) rich environment is poorly studied. Here, we identified the presence of the LD marker protein perilipin 3 (PLIN3) in the intracellular nano-environment of NSM2 using the ascorbate peroxidase APEX2-catalyzed proximity-dependent biotin labeling method. In line with this, super-resolution structured illumination microscopy (SIM) shows NSM2 and PLIN3 co-localization in LD organelles in the presence of increased extracellular concentrations of oleic acid (OA). Furthermore, the association of enzymatically active NSM2 with isolated LDs correlates with increased Cer levels in these lipid storage organelles. NSM2 enzymatic activity is not required for NSM2 association with LDs, but negatively affects the LD numbers and cellular accumulation of long-chain unsaturated triacylglycerol (TAG) species. Concurrently, NSM2 expression promotes mitochondrial respiration and fatty acid oxidation (FAO) in response to increased OA levels, thereby shifting cells to a high energetic state. Importantly, endogenous NSM2 activity is crucial for primary human CD4+ T cell survival and proliferation in a FA rich environment. To conclude, our study shows a novel NSM2 intracellular localization to LDs and the role of enzymatically active NSM2 in metabolic response to enhanced FA concentrations in T cells.

Keywords:  cholesteryl ester (CE); diacylglycerol (DAG); fatty acid oxidation (FAO); lipid droplet (LD); monounsaturated fatty acid (MUFA); neutral sphingomyelinase-2 (NSM2); plasma membrane (PM); triacylglycerol (TAG)

DOI:  https://doi.org/10.3390/ijms25063247
Elife. 2024 Mar 27. pii: RP91060. [Epub ahead of print]12

Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue.

Hong Chen, Lijun Sun, Lu Feng, Xue Han, Yunhua Zhang, Wenbo Zhai, Zehe Zhang, Michael Mulholland, Weizhen Zhang, Yue Yin.

  Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted interleukin-22 (IL-22) production by type 3 innate lymphoid cells (ILC3s) and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor (IL-22R) attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell-cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.

Keywords:  adipocytes; adipose tissue; immune; innate lymphoid cells; intestine; medicine; metabolism; mouse

DOI:  https://doi.org/10.7554/eLife.91060
Int J Mol Sci. 2024 Mar 11. pii: 3198. [Epub ahead of print]25(6):

The Immunomodulatory Potential of Short-Chain Fatty Acids in Multiple Sclerosis.

Laura Barcutean, Smaranda Maier, Mihai Burai-Patrascu, Lenard Farczadi, Rodica Balasa.

  Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative central nervous system (CNS) disorder, characterized by focal inflammation, demyelination, irreversible axonal loss and neurodegeneration. The proposed mechanism involves auto-reactive T lymphocytes crossing the blood-brain barrier (BBB), contributing to inflammation and demyelination. Pro-inflammatory Th1 and Th17 lymphocytes are pivotal in MS pathogenesis, highlighting an imbalanced interaction with regulatory T cells. Dysbiosis in the gut microbiota, characterized by microbial imbalance is implicated in systemic inflammation, yet its exact role in MS remains elusive. Short-chain fatty acids (SCFAs), including valerate, butyrate, propionate, and acetate, produced through dietary fiber fermentation by the gut microbiota, modulate inflammation and immune responses. Particularly, butyrate and propionate exhibit pronounced anti-inflammatory effects in both the gut and CNS. These SCFAs influence regulatory T lymphocyte expression and BBB permeability. This review discusses the potential therapeutic implications of SCFA in MS, highlighting their ability to modulate the gut-brain axis and restore immune balance.

Keywords:  acetate; butyrate; microbiome; microbiota; multiple sclerosis; propionate; short-chain fatty acids; valerate

DOI:  https://doi.org/10.3390/ijms25063198
Front Immunol. 2024 ;15 1379220

Mevalonate kinase-deficient THP-1 cells show a disease-characteristic pro-inflammatory phenotype.

Frouwkje A Politiek, Marjolein Turkenburg, Rob Ofman, Hans R Waterham.

   Objective: Bi-allelic pathogenic variants in the MVK gene, which encodes mevalonate kinase (MK), an essential enzyme in isoprenoid biosynthesis, cause the autoinflammatory metabolic disorder mevalonate kinase deficiency (MKD). We generated and characterized MK-deficient monocytic THP-1 cells to identify molecular and cellular mechanisms that contribute to the pro-inflammatory phenotype of MKD.
Methods: Using CRISPR/Cas9 genome editing, we generated THP-1 cells with different MK deficiencies mimicking the severe (MKD-MA) and mild end (MKD-HIDS) of the MKD disease spectrum. Following confirmation of previously established disease-specific biochemical hallmarks, we studied the consequences of the different MK deficiencies on LPS-stimulated cytokine release, glycolysis versus oxidative phosphorylation rates, cellular chemotaxis and protein kinase activity.
Results: Similar to MKD patients' cells, MK deficiency in the THP-1 cells caused a pro-inflammatory phenotype with a severity correlating with the residual MK protein levels. In the MKD-MA THP-1 cells, MK protein levels were barely detectable, which affected protein prenylation and was accompanied by a profound pro-inflammatory phenotype. This included a markedly increased LPS-stimulated release of pro-inflammatory cytokines and a metabolic switch from oxidative phosphorylation towards glycolysis. We also observed increased activity of protein kinases that are involved in cell migration and proliferation, and in innate and adaptive immune responses. The MKD-HIDS THP-1 cells had approximately 20% residual MK activity and showed a milder phenotype, which manifested mainly upon LPS stimulation or exposure to elevated temperatures.
Conclusion: MK-deficient THP-1 cells show the biochemical and pro-inflammatory phenotype of MKD and are a good model to study underlying disease mechanisms and therapeutic options of this autoinflammatory disorder.

Keywords:  autoinflammatory disorders; cytokines; hyper IgD syndrome; innate immune response; isoprenoid biosynthesis; mevalonate kinase deficiency

DOI:  https://doi.org/10.3389/fimmu.2024.1379220
Front Immunol. 2024 ;15 1335181

Metabolic profiling of synovial fluid in human temporomandibular joint osteoarthritis.

Dahe Zhang, Yuxin Zhang, Simo Xia, Pei Shen, Chi Yang.

   Introduction: Temporomandibular joint (TMJ) osteoarthritis (OA) is a common TMJ degenerative disease with an unclear mechanism. Synovial fluid (SF), an important component of TMJ, contains various proteins and metabolites that may directly contribute to OA. The present study aimed to investigate the influence of SF in TMJOA at the metabolite level.
Methods: Untargeted and widely targeted metabolic profiling were employed to identify metabolic changes in SF of 90 patients with different TMJOA grades according to TMJ magnetic resonance imaging.
Results: A total 1498 metabolites were detected. Most of the metabolites were amino acids and associated metabolites, benzene and substituted derivatives, and lipids. Among patients with mild, moderate and severe TMJOA, 164 gradually increasing and 176 gradually decreasing metabolites were identified, indicating that biosynthesis of cofactors, choline metabolism, mineral absorption and selenocompound metabolism are closely related to TMJOA grade. Combined metabolomics and clinical examination revealed 37 upregulated metabolites and 16 downregulated metabolites in patients with pain, of which 19 and 26 metabolites were positively and negatively correlated, respectively, with maximum interincisal opening. A model was constructed to diagnose TMJOA grade and nine biomarkers were identified. The identified metabolites are key to exploring the mechanism of TMJOA.
Discussion: In the present study, a metabolic profile was constructed and assessed using a much larger number of human SF samples from patients with TMJOA, and a model was established to contribute to the diagnosis of TMJOA grade. The findings expand our knowledge of metabolites in human SF of TMJOA patients, and provide an important basis for further research on the pathogenesis and treatment of TMJOA.

Keywords:  biomarkers; bone resorption; condyle; metabolism; metabolome; pain

DOI:  https://doi.org/10.3389/fimmu.2024.1335181
J Allergy Clin Immunol. 2024 Mar 22. pii: S0091-6749(24)00293-8. [Epub ahead of print]

Metabolomics identifies phenotypic biomarkers of amino acid metabolism in milk allergy and sensitized tolerance.

Qiaozhi Zhang, Hui Wang, Shenyu Zhang, Mingwu Chen, Zhongshan Gao, Jinlyu Sun, Jizhou Wang, Linglin Fu.

   BACKGROUND: A substantial proportion of sensitized individuals tolerate suspected foods without developing allergic symptoms; this phenomenon is known as sensitized tolerance. The immunogenic and metabolic features underlying the sensitized-tolerant phenotype remain largely unknown.
OBJECTIVE: In this study, we aimed to uncover the metabolic signatures associated with clinical milk allergy and sensitized tolerance using metabolomics.
METHODS: We characterized the serum metabolic and immunological profiles of children with clinical IgE-mediated milk allergy (MA; n = 30) or milk-sensitized tolerance (MST; n = 20) and healthy controls (n = 21). A comparative analysis was performed to identify dysregulated pathways associated with the clinical manifestations of food allergy. We also analyzed specific biomarkers indicative of different sensitization phenotypes in children with MA. The candidate metabolites were validated in an independent quantification cohort (n = 41).
RESULTS: Metabolomic profiling confirmed the presence of a distinct metabolic signature that discriminated children with MA from those with MST. Amino acid metabolites generated via arginine, proline, and glutathione metabolism were uniquely altered in children with sensitized tolerance. Arginine depletion and metabolism through the polyamine pathway to fuel glutamate synthesis were closely associated with the suppression of clinical symptoms in the presence of allergen-specific IgE. In children with MA, the polysensitized state was characterized by disturbances in tryptophan metabolism.
CONCLUSIONS: By combining untargeted metabolomics with targeted validation in an independent quantification cohort, we identified candidate metabolites as phenotypic and diagnostic biomarkers of food allergy. Our results provide insights into the pathological mechanisms underlying childhood allergy and suggest potential therapeutic targets.

Keywords:  Amino acid metabolism; biomarker; food allergy; metabolomics; sensitized tolerance

DOI:  https://doi.org/10.1016/j.jaci.2024.02.023
Front Immunol. 2024 ;15 1324026

Imidazole propionate ameliorates atopic dermatitis-like skin lesions by inhibiting mitochondrial ROS and mTORC2.

Ha Eun Kim, Jong Yeong Lee, Dong-Hoon Yoo, Hyo-Hyun Park, Eun-Ju Choi, Kyung-Hwa Nam, Jin Park, Jin Kyeong Choi.

   Background: Imidazole propionate (IMP) is a histidine metabolite produced by some gut microorganisms in the human colon. Increased levels of IMP are associated with intestinal inflammation and the development and progression of cardiovascular disease and diabetes. However, the anti-inflammatory activity of IMP has not been investigated. This study aimed to elucidate the role of IMP in treating atopic dermatitis (AD).
Methods: To understand how IMP mediates immunosuppression in AD, IMP was intraperitoneally injected into a Dermatophagoides farinae extract (DFE)/1-chloro-2,4 dinitrochlorobenzene (DNCB)-induced AD-like skin lesions mouse model. We also characterized the anti-inflammatory mechanism of IMP by inducing an AD response in keratinocytes through TNF-α/IFN-γ or IL-4 stimulation.
Results: Contrary to the prevailing view that IMP is an unhealthy microbial metabolite, we found that IMP-treated AD-like skin lesions mice showed significant improvement in their clinical symptoms, including ear thickness, epidermal and dermal thickness, and IgE levels. Furthermore, IMP antagonized the expansion of myeloid (neutrophils, macrophages, eosinophils, and mast cells) and Th cells (Th1, Th2, and Th17) in mouse skin and prevented mitochondrial reactive oxygen species production by inhibiting mitochondrial energy production. Interestingly, we found that IMP inhibited AD by reducing glucose uptake in cells to suppress proinflammatory cytokines and chemokines in an AD-like in vitro model, sequentially downregulating the PI3K and mTORC2 signaling pathways centered on Akt, and upregulating DDIT4 and AMPK.
Discussion: Our results suggest that IMP exerts anti-inflammatory effects through the metabolic reprogramming of skin inflammation, making it a promising therapeutic candidate for AD and related skin diseases.

Keywords:  AMPK; DDIT4; atopic dermatitis; imidazole propionate; mTORC2; mitochondria ROS

DOI:  https://doi.org/10.3389/fimmu.2024.1324026