bims-imicid 2023-04-30 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–04–30
34 papers selected by
Dylan Ryan, University of Cambridge

A druggable copper-signalling pathway that drives inflammation.
Methotrexate suppresses psoriatic skin inflammation by inhibiting muropeptide transporter SLC46A2 activity.
Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy.
SRC2 controls CD4+ T cell activation via stimulating c-Myc-mediated upregulation of amino acid transporter Slc7a5.
Metabolic alterations of the immune system in the pathogenesis of autoimmune diseases.
A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke.
Zika virus-induces metabolic alterations in fetal neuronal progenitors that could influence in neurodevelopment during early pregnancy.
Regulation of CD8 T-cell signaling, metabolism, and cytotoxic activity by extracellular lysophosphatidic acid.
Mitochondrial fusion induced by transforming growth factor-β1 serves as a switch that governs the metabolic reprogramming during differentiation of regulatory T cells.
Acidity promotes the differentiation of immunosuppressive regulatory T cells.
Deficiency of angiopoietin-like 4 enhances CD8+ T cell bioactivity via metabolic reprogramming for impairing tumour progression.
2-Deoxyglucose alleviates migraine-related behaviors by modulating microglial inflammatory factors in experimental model of migraine.
Network analysis of toxin production in Clostridioides difficile identifies key metabolic dependencies.
Salt sensitivity includes effects on immune cell signalling and metabolism.
Metabolic profiling of patients with different idiopathic inflammatory myopathy subtypes reveals potential biomarkers in plasma.
Cross-talk of inflammation and chondrocyte intracellular metabolism in osteoarthritis.
HIV-Differentiated Metabolite N-Acetyl-L-Alanine Dysregulates Human Natural Killer Cell Responses to Mycobacterium tuberculosis Infection.
Neutrophil (dys)function due to altered immuno-metabolic axis in type 2 diabetes: implications in combating infections.
Short chain fatty acids, a possible treatment option for autoimmune diseases.
Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses.
From Gasotransmitter to Immunomodulator: The Emerging Role of Hydrogen Sulfide in Macrophage Biology.
Neutrophil aging exacerbates high fat diet induced metabolic alterations.
Combined FRET-FLIM and NAD(P)H FLIM to Analyze B Cell Receptor Signaling Induced Metabolic Activity of Germinal Center B Cells In Vivo.
β-cell function is regulated by metabolic and epigenetic programming of islet-associated macrophages, involving Axl, Mertk, and TGFβ receptor signaling.
PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion.
Formaldehyde exacerbates asthma in mice through the potentiation of HIF-1α-mediated pro-inflammatory responses in pulmonary macrophages.
CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.
Sirtuin 1 activator alleviated lethal inflammatory injury via promotion of autophagic degradation of pyruvate kinase M2.
Administration of an LXR agonist promotes atherosclerotic lesion remodelling in murine inflammatory arthritis.
Gain‑of‑function of IDO in DCs inhibits T cell immunity by metabolically regulating surface molecules and cytokines.
Maternal diet supplementation with high-docosahexaenoic-acid canola oil, along with arachidonic acid, promotes immune system development in allergy-prone BALB/c mouse offspring at 3 weeks of age.
Metabololipidomic and proteomic profiling reveals aberrant macrophage activation and interrelated immunomodulatory mediator release during aging.
Weighted Gene Co-Expression Network Analysis Identifies a Functional Guild and Metabolite Cluster Mediating the Relationship between Mucosal Inflammation and Adherence to the Mediterranean Diet in Ulcerative Colitis.
A Mediterranean Diet Pattern improves intestinal inflammation concomitant with reshaping of the bacteriome in ulcerative colitis: A randomized controlled trial.

Nature. 2023 Apr 26.

A druggable copper-signalling pathway that drives inflammation.

Stéphanie Solier, Sebastian Müller, Tatiana Cañeque, Antoine Versini, Arnaud Mansart, Fabien Sindikubwabo, Leeroy Baron, Laila Emam, Pierre Gestraud, G Dan Pantoș, Vincent Gandon, Christine Gaillet, Ting-Di Wu, Florent Dingli, Damarys Loew, Sylvain Baulande, Sylvère Durand, Valentin Sencio, Cyril Robil, François Trottein, David Péricat, Emmanuelle Näser, Céline Cougoule, Etienne Meunier, Anne-Laure Bègue, Hélène Salmon, Nicolas Manel, Alain Puisieux, Sarah Watson, Mark A Dawson, Nicolas Servant, Guido Kroemer, Djillali Annane, Raphaël Rodriguez.

Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

DOI: https://doi.org/10.1038/s41586-023-06017-4
Immunity. 2023 Apr 24. pii: S1074-7613(23)00163-2. [Epub ahead of print]

Methotrexate suppresses psoriatic skin inflammation by inhibiting muropeptide transporter SLC46A2 activity.

Ravi Bharadwaj, Christina F Lusi, Siavash Mashayekh, Abhinit Nagar, Malireddi Subbarao, Griffin I Kane, Kimberly A Wodzanowski, Ashley R Brown, Kendi Okuda, Amanda Monahan, Donggi Paik, Anubhab Nandy, Madison V Anonick, William E Goldman, Thirumala-Devi Kanneganti, Megan H Orzalli, Catherine Leimkuhler Grimes, Prabhani U Atukorale, Neal Silverman.

  Cytosolic innate immune sensing is critical for protecting barrier tissues. NOD1 and NOD2 are cytosolic sensors of small peptidoglycan fragments (muropeptides) derived from the bacterial cell wall. These muropeptides enter cells, especially epithelial cells, through unclear mechanisms. We previously implicated SLC46 transporters in muropeptide transport in Drosophila immunity. Here, we focused on Slc46a2, which was highly expressed in mammalian epidermal keratinocytes, and showed that it was critical for the delivery of diaminopimelic acid (DAP)-muropeptides and activation of NOD1 in keratinocytes, whereas the related transporter Slc46a3 was critical for delivering the NOD2 ligand MDP to keratinocytes. In a mouse model, Slc46a2 and Nod1 deficiency strongly suppressed psoriatic inflammation, whereas methotrexate, a commonly used psoriasis therapeutic, inhibited Slc46a2-dependent transport of DAP-muropeptides. Collectively, these studies define SLC46A2 as a transporter of NOD1-activating muropeptides, with critical roles in the skin barrier, and identify this transporter as an important target for anti-inflammatory intervention.

Keywords:  NOD1; SLC transporters; inflammation; innate immunity; methotrexate; muropeptide; psoriasis

DOI:  https://doi.org/10.1016/j.immuni.2023.04.001
Sci Adv. 2023 Apr 28. 9(17): eadg0654

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy.

Yu-Jia Chen, Guan-Nan Li, Xian-Jing Li, Lin-Xing Wei, Min-Jie Fu, Zhou-Li Cheng, Zhen Yang, Gui-Qi Zhu, Xu-Dong Wang, Cheng Zhang, Jin-Ye Zhang, Yi-Ping Sun, Hexige Saiyin, Jin Zhang, Wei-Ren Liu, Wen-Wei Zhu, Kun-Liang Guan, Yue Xiong, Yong Yang, Dan Ye, Lei-Lei Chen.

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8+ T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti-PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1-deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell-based immunotherapy.

DOI: https://doi.org/10.1126/sciadv.adg0654
Proc Natl Acad Sci U S A. 2023 May 02. 120(18): e2221352120

SRC2 controls CD4+ T cell activation via stimulating c-Myc-mediated upregulation of amino acid transporter Slc7a5.

Wencan Zhang, Xu Cao, Xiancai Zhong, Hongmin Wu, Yun Shi, Mingye Feng, Yi-Chang Wang, David Ann, Yousang Gwack, Yate-Ching Yuan, Weirong Shang, Zuoming Sun.

  T cell activation stimulates substantially increased protein synthesis activity to accumulate sufficient biomass for cell proliferation. The protein synthesis is fueled by the amino acids transported from the environment. Steroid nuclear receptor coactivator 2 (SRC2) is a member of a family of transcription coactivators. Here, we show that SRC2 recruited by c-Myc enhances CD4+ T cell activation to stimulate immune responses via upregulation of amino acid transporter Slc7a5. Mice deficient of SRC2 in T cells (SRC2fl/fl/CD4Cre) are resistant to the induction of experimental autoimmune encephalomyelitis (EAE) and susceptible to Citrobacter rodentium (C. rodentium) infection. Adoptive transfer of naive CD4+ T cells from SRC2fl/fl/CD4Cre mice fails to elicit EAE and colitis in Rag1/ recipients. Further, CD4+ T cells from SRC2fl/fl/CD4Cre mice display defective T cell proliferation, cytokine production, and differentiation both in vitro and in vivo. Mechanically, SRC2 functions as a coactivator to work together with c-Myc to stimulate the expression of amino acid transporter Slc7a5 required for T cell activation. Slc7a5 fails to be up-regulated in CD4+ T cells from SRC2fl/fl/CD4Cre mice, and forced expression of Slc7a5 rescues proliferation, cytokine production, and the ability of SRC2fl/fl/CD4Cre CD4+ T cells to induce EAE. Therefore, SRC2 is essential for CD4+ T cell activation and, thus, a potential drug target for controlling CD4+ T cell-mediated autoimmunity.

Keywords:  CD4+ T cell; T cell activation; autoimmunity; c-Myc

DOI:  https://doi.org/10.1073/pnas.2221352120
PLoS Biol. 2023 Apr;21(4): e3002084

Metabolic alterations of the immune system in the pathogenesis of autoimmune diseases.

Luz P Blanco, Mariana J Kaplan.

Systemic autoimmune diseases are characteristically associated with aberrant autoreactive innate and adaptive immune responses that lead to tissue damage and increased morbidity and mortality. Autoimmunity has been linked to alterations in the metabolic functions of immune cells (immunometabolism) and, more specifically, to mitochondrial dysfunction. Much has been written about immunometabolism in autoimmunity in general, so this Essay focuses on recent research into the role of mitochondrial dysfunction in the dysregulation of innate and adaptive immunity that is characteristic of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Enhancing the understanding of mitochondrial dysregulation in autoimmunity will hopefully contribute to accelerating the development of immunomodulatory treatments for these challenging diseases.

DOI: https://doi.org/10.1371/journal.pbio.3002084
J Neuroinflammation. 2023 Apr 25. 20(1): 97

A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke.

Wen-Yu Ma, Qing-Lin Wu, Sha-Sha Wang, Hong-Yun Wang, Jun-Rui Ye, Hong-Shuo Sun, Zhong-Ping Feng, Wen-Bin He, Shi-Feng Chu, Zhao Zhang, Nai-Hong Chen.

  Ischemic stroke is characterized by the presence of reactive microglia. However, its precise involvement in stroke etiology is still unknown. We used metabolic profiling and showed that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative phosphorylation to glycolysis, which was reliant on the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-hypoxia inducible factor 1α (HIF-1α) signaling pathway. Once activated, microglia enter a chronic tolerant state as a result of widespread energy metabolism abnormalities, which reduces immunological responses, including cytokine release and phagocytosis. Metabolically dysfunctional microglia were also found in mice using genome-wide RNA sequencing after chronic administration of CKLF1, and there was a decrease in the inflammatory response. Finally, we showed that the loss of CKLF1 reversed the defective immune response of microglia, as indicated by the maintenance its phagocytosis to neutrophils, thereby mitigating the long-term outcomes of ischemic stroke. Overall, CKLF1 plays a crucial role in the relationship between microglial metabolic status and immune function in stroke, which prepares a potential therapeutic strategy for ischemic stroke.

Keywords:  CKLF1; Immune tolerance; Ischemic stroke; Metabolic reprogramming; Microglia; Phagocytosis

DOI:  https://doi.org/10.1186/s12974-023-02779-w
Biol Open. 2023 Apr 15. pii: bio059889. [Epub ahead of print]12(4):

Zika virus-induces metabolic alterations in fetal neuronal progenitors that could influence in neurodevelopment during early pregnancy.

Javier Gilbert-Jaramillo, Ujang Purnama, Zoltán Molnár, William S James.

  Cortical development consists of an orchestrated process in which progenitor cells exhibit distinct fate restrictions regulated by time-dependent activation of energetic pathways. Thus, the hijacking of cellular metabolism by Zika virus (ZIKV) to support its replication may contribute to damage in the developing fetal brain. Here, we showed that ZIKV replicates differently in two glycolytically distinct pools of cortical progenitors derived from human induced pluripotent stem cells (hiPSCs), which resemble the metabolic patterns of quiescence (early hi-NPCs) and immature brain cells (late hi-NPCs) in the forebrain. This differential replication alters the transcription of metabolic genes in both pools of cortical progenitors but solely upregulates the glycolytic capacity of early hi-NPCs. Analysis using Imagestream® revealed that, during early stages of ZIKV replication, in early hi-NPCs there is an increase in lipid droplet abundance and size. This stage of ZIKV replication significantly reduced the mitochondrial distribution in both early and late hi-NPCs. During later stages of ZIKV replication, late hi-NPCs show reduced mitochondrial size and abundance. The finding that there are alterations of cellular metabolism during ZIKV infection which are specific to pools of cortical progenitors at different stages of maturation may help to explain the differences in brain damage over each trimester.

Keywords:  Fetal neurodevelopment; Metabolism; Neurometabolism; Neuronal progenitors; ZIKV; Zika virus

DOI:  https://doi.org/10.1242/bio.059889
Immunol Rev. 2023 Apr 25.

Regulation of CD8 T-cell signaling, metabolism, and cytotoxic activity by extracellular lysophosphatidic acid.

Raul M Torres, Jacqueline A Turner, Marc D'Antonio, Roberta Pelanda, Kimberly N Kremer.

  Lysophosphatidic acid (LPA) is an endogenous bioactive lipid that is produced extracellularly and signals to cells via cognate LPA receptors, which are G-protein coupled receptors (GPCRs). Mature lymphocytes in mice and humans express three LPA receptors, LPA2 , LPA5, and LPA6 , and work from our group has determined that LPA5 signaling by T lymphocytes inhibits specific antigen-receptor signaling pathways that ultimately impair lymphocyte activation, proliferation, and function. In this review, we discuss previous and ongoing work characterizing the ability of an LPA-LPA5 axis to serve as a peripheral immunological tolerance mechanism that restrains adaptive immunity but is subverted during settings of chronic inflammation. Specifically, LPA-LPA5 signaling is found to regulate effector cytotoxic CD8 T cells by (at least) two mechanisms: (i) regulating the actin-microtubule cytoskeleton in a manner that impairs immunological synapse formation between an effector CD8 T cell and antigen-specific target cell, thus directly impairing cytotoxic activity, and (ii) shifting T-cell metabolism to depend on fatty-acid oxidation for mitochondrial respiration and reducing metabolic efficiency. The in vivo outcome of LPA5 inhibitory activity impairs CD8 T-cell killing and tumor immunity in mouse models providing impetus to consider LPA5 antagonism for the treatment of malignancies and chronic infections.

Keywords:  T cells; cytotoxic; cytotoxicity; lipid mediators; signal transduction cancer

DOI:  https://doi.org/10.1111/imr.13208
Redox Biol. 2023 Apr 23. pii: S2213-2317(23)00110-6. [Epub ahead of print]62 102709

Mitochondrial fusion induced by transforming growth factor-β1 serves as a switch that governs the metabolic reprogramming during differentiation of regulatory T cells.

Yulai Fang, Qin Zhang, Changjun Lv, Yilei Guo, Yue He, Pengxiang Guo, Zhifeng Wei, Yufeng Xia, Yue Dai.

  Although metabolic reprogramming during the differentiation of regulatory T cells (Treg cells) has been extensively studied, the molecular switch to alter energy metabolism remains undefined. The present study explores the critical role of mitochondrial dynamics in the reprogramming and consequent generation of Treg cells. The results showed that during Treg cell differentiation, mitochondrial fusion but not fission led to elevation of oxygen consumption rate values, facilitation of metabolic reprogramming, and increase of number of Treg cells and expression of Foxp3 in vitro and in vivo. Mechanistically, mitochondrial fusion favored fatty acid oxidation but restricted glycolysis in Treg cells through down-regulating the expression of HIF-1α. Transforming growth factor-β1 (TGF-β1) played a crucial role in the induction of mitochondrial fusion, which activated Smad2/3, promoted the expression of PGC-1α and therefore facilitated the expression of mitochondrial fusion proteins. In conclusion, during Treg cell differentiation, TGF-β1 promotes PGC-1α-mediated mitochondrial fusion, which drives metabolic reprogramming from glycolysis to fatty acid oxidation via suppressing HIF-1α expression, and therefore favors the generation of Treg cells. The signals and proteins involved in mitochondrial fusion are potential therapeutic targets for Treg cell-related diseases.

Keywords:  Differentiation; Metabolic reprogramming; Mitochondrial fusion; TGF-β1; Treg cells

DOI:  https://doi.org/10.1016/j.redox.2023.102709
Eur J Immunol. 2023 Apr 25. e2350511

Acidity promotes the differentiation of immunosuppressive regulatory T cells.

Karoliina Tuomela, Megan K Levings.

  The metabolic milieu is emerging as a major contributing factor in the maintenance of the immunosuppressive microenvironment within tumours. In particular, the presence of lactic acid produced by highly glycolytic cancer cells is known to suppress antitumour immune cell subsets while promoting immunosuppressive cell populations, such as regulatory T cells (Tregs). Unlike conventional T cells, Tregs have a uniquely potent ability to take up lactic acid to fuel both mitochondrial metabolism and gluconeogenesis, supporting suppressive function and proliferation. In this issue of the European Journal of [Immunology [Eur. J. Immunol. 2023.53:2250258], Rao et al. uncover a novel mechanism by which lactic acid can support Treg accumulation within tumours in mice. This study shows that lactic acid, through a pH-dependent mechanism rather than lactate itself, promotes TGFβ-induced differentiation of Tregs from conventional CD4+ T cells. These findings build on the already multifaceted role of lactic acid in maintaining an immunosuppressive tumour microenvironment. This article is protected by copyright. All rights reserved.

Keywords:  Lactic acid; Regulatory T cells; Treg metabolism; immunosuppressive microenvironment

DOI:  https://doi.org/10.1002/eji.202350511
Immunology. 2023 Apr 24.

Deficiency of angiopoietin-like 4 enhances CD8+ T cell bioactivity via metabolic reprogramming for impairing tumour progression.

Shizhen Ding, Zhijie Lin, Xiaoyuan Zhang, Xiaoqing Jia, Hualing Li, Yi Fu, Xuefeng Wang, Guoqiang Zhu, Guotao Lu, Weiming Xiao, Weijuan Gong.

  Angiopoietin-like 4 (ANGPTL4) is a secreted metabolism-modulating glycoprotein involved in the progression of tumours, cardiovascular diseases, metabolic syndrome and infectious diseases. In this study, more CD8+ T cells were activated to be effector T cells in ANGPTL4-/- mice. Impaired growth of tumours implanted in 3LL, B16BL6 or MC38 cells and reduced metastasis by B16F10 cells were observed in ANGPTL4-/- mice. Bone marrow (BM) transplantation experiments displayed that deficiency of ANGPTL4 in either host or BM cells promoted CD8+ T cell activation. However, ANGPTL4 deficiency in CD8+ T cells themselves showed more efficient anti-tumour activities. Recombinant ANGPTL4 protein promoted tumour growth in vivo with the less CD8+ T cell infiltration and it directly downregulated CD8+ T cell activation ex vivo. Transcriptome sequencing and metabolism analysis identified that ANGPTL4-/- CD8+ T cells increased glycolysis and decreased oxidative phosphorylation, which was dependent on the PKCζ-LKB1-AMPK-mTOR signalling axis. Reverse correlation of elevated ANGPTL4 levels in sera and tumour tissues with activated CD8+ T cells in the peripheral blood was displayed in patients with colorectal cancer. These results demonstrated that ANGPTL4 decreased immune surveillance in tumour progression by playing an immune-modulatory role on CD8+ T cells via metabolic reprogramming. Efficient blockade of ANGPTL4 expression in tumour patients would generate an effective anti-tumour effect mediated by CD8+ T cells.

Keywords:  ANGPTL4; CD8; T cell; metabolism; tumour

DOI:  https://doi.org/10.1111/imm.13650
Front Neurol. 2023 ;14 1115318

2-Deoxyglucose alleviates migraine-related behaviors by modulating microglial inflammatory factors in experimental model of migraine.

Tao Qiu, Yanjie Zhou, Luyu Hu, Zhengming Shan, Yu Zhang, Yuting Fang, Wanbin Huang, Lily Zhang, Shanghua Fan, Zheman Xiao.

   Background: Targeting metabolic pathways has emerged as a new migraine treatment strategy as researchers realize the critical role metabolism plays in migraine. Activated inflammatory cells undergo metabolic reprogramming and rely on glycolysis to function. The objective of this study was to investigate the glycolysis changes in the experimental model of migraine and the effect of glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) in the pathophysiology of migraine.
Methods: We used a rat model of migraine that triggered migraine attacks by applying inflammatory soup (IS) to the dura and examined changes in glycolysis. 2-DG was used to inhibit glycolysis, and the effects of 2-DG on mechanical ectopic pain, microglial cell activation, calcitonin gene-related peptides (CGRP), c-Fos, and inflammatory factors induced by inflammatory soup were observed. LPS stimulated BV2 cells to establish a model in vitro to observe the effects of 2-DG on brain-derived neurotrophic factor (BDNF) after microglia activation.
Results: In the experimental model of migraine, key enzymes involved in glycolysis such as phosphofructokinase platelet (PFKP), hexokinase (HK2), hypoxia inducible factor-1α (HIF-1α), lactate dehydrogenase (LDH) and pyruvate kinase (PKM2) were expressed in the medullary dorsal horn. While the expression of electronic respiratory transport chain complex IV (COXIV) decreased. There were no significant changes in glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway. The glycolysis inhibitor 2-DG alleviated migraine-like symptoms in an experimental model of migraine, reduced the release of proinflammatory cytokines caused by microglia activation, and decreased the expression of CGRP and c-Fos. Further experiments in vitro demonstrated that glycolysis inhibition can reduce the release of Iba-1/proBDNF/BDNF and inhibit the activation of microglia.
Conclusion: The migraine rat model showed enhanced glycolysis. This study suggests that glycolytic inhibitor 2-DG is an effective strategy for alleviating migraine-like symptoms. Glycolysis inhibition may be a new target for migraine treatment.

Keywords:  2-Deoxy-D-glucose; energy metabolism; glycolysis; inflammation; migraine

DOI:  https://doi.org/10.3389/fneur.2023.1115318
PLoS Comput Biol. 2023 Apr 26. 19(4): e1011076

Network analysis of toxin production in Clostridioides difficile identifies key metabolic dependencies.

Deborah A Powers, Matthew L Jenior, Glynis L Kolling, Jason A Papin.

Clostridioides difficile pathogenesis is mediated through its two toxin proteins, TcdA and TcdB, which induce intestinal epithelial cell death and inflammation. It is possible to alter C. difficile toxin production by changing various metabolite concentrations within the extracellular environment. However, it is unknown which intracellular metabolic pathways are involved and how they regulate toxin production. To investigate the response of intracellular metabolic pathways to diverse nutritional environments and toxin production states, we use previously published genome-scale metabolic models of C. difficile strains CD630 and CDR20291 (iCdG709 and iCdR703). We integrated publicly available transcriptomic data with the models using the RIPTiDe algorithm to create 16 unique contextualized C. difficile models representing a range of nutritional environments and toxin states. We used Random Forest with flux sampling and shadow pricing analyses to identify metabolic patterns correlated with toxin states and environment. Specifically, we found that arginine and ornithine uptake is particularly active in low toxin states. Additionally, uptake of arginine and ornithine is highly dependent on intracellular fatty acid and large polymer metabolite pools. We also applied the metabolic transformation algorithm (MTA) to identify model perturbations that shift metabolism from a high toxin state to a low toxin state. This analysis expands our understanding of toxin production in C. difficile and identifies metabolic dependencies that could be leveraged to mitigate disease severity.

DOI: https://doi.org/10.1371/journal.pcbi.1011076
Nat Rev Immunol. 2023 Apr 24.

Salt sensitivity includes effects on immune cell signalling and metabolism.

Dominik N Müller, Sabrina Geisberger, Markus Kleinewietfeld, Jonathan Jantsch.

DOI: https://doi.org/10.1038/s41577-023-00881-x
Clin Exp Med. 2023 Apr 27.

Metabolic profiling of patients with different idiopathic inflammatory myopathy subtypes reveals potential biomarkers in plasma.

Qianqian Zhao, Qiu Hu, Shuhui Meng, Qinguo Zhang, Tingting Wang, Cuilian Liu, Dongzhou Liu, Zhenyou Jiang, Xiaoping Hong.

  Idiopathic inflammatory myopathy (IIM) are heterogeneous autoimmune diseases that primarily affect the proximal muscles. IIM subtypes include dermatomyositis (DM), polymyositis (PM), and anti-synthetase syndrome (ASS). Metabolic disturbances may cause irreversible structural damage to muscle fibers in patients with IIM. However, the metabolite profile of patients with different IIM subtypes remains elusive. To investigate metabolic alterations and identify patients with different IIM subtypes, we comprehensively profiled plasma metabolomics of 46 DM, 13 PM, 12 ASS patients, and 30 healthy controls (HCs) using UHPLC-Q Exactive HF mass spectrometer. Multiple statistical analyses and random forest were used to discover differential metabolites and potential biomarkers. We found that tryptophan metabolism, phenylalanine and tyrosine metabolism, fatty acid biosynthesis, beta-oxidation of very long chain fatty acids, alpha-linolenic acid and linoleic acid metabolism, steroidogenesis, bile acid biosynthesis, purine metabolism, and caffeine metabolism are all enriched in the DM, PM, and ASS groups. We also found that different subtypes of IIM have their unique metabolic pathways. We constructed three models (five metabolites) to identify DM, PM, ASS from HC in the discovery and validation sets. Five to seven metabolites can distinguish DM from PM, DM from ASS, and PM from ASS. A panel of seven metabolites can identify anti-melanoma differentiation-associated gene 5 positive (MDA5 +) DM with high accuracy in the discovery and validation sets. Our results provide potential biomarkers for diagnosing different subtypes of IIM and a better understanding of the underlying mechanisms of IIM.

Keywords:  Anti-MDA5 positive dermatomyositis; Biomarker; Idiopathic inflammatory myopathy; Metabolomics

DOI:  https://doi.org/10.1007/s10238-023-01073-6
Osteoarthritis Cartilage. 2023 Apr 22. pii: S1063-4584(23)00756-2. [Epub ahead of print]

Cross-talk of inflammation and chondrocyte intracellular metabolism in osteoarthritis.

Manoj Arra, Yousef Abu-Amer.

  Osteoarthritis is a disease that impacts millions around the world, leading to significant financial and medical burden for patients and the healthcare system. However, no effective biomarkers or disease modifying therapeutics exist for the early identification and management of the disease. Inflammation drives chondrocytes to express ECM degrading enzymes and interruption of this pathway is a viable target to prevent degradation of cartilage. It has been demonstrated that inflammation can alter the intracellular metabolism of chondrocytes, a process known as metabolic reprogramming. This metabolic reprogramming is critical for cartilage breakdown by shifting chondrocytes to an ECM-catabolic state and likely as a potential therapeutic target for osteoarthritis. Metabolic modulators hold the potential to reduce chondrocyte inflammatory responses and protect cartilage. In this narrative review, we explore some of the existing examples of interactions between metabolism and inflammatory pathways in chondrocytes. We summarize the impact of inflammatory stimulation on various metabolic pathways and describe several examples by which targeting of metabolism is able to modulate ECM-degrading activity of chondrocytes to protect against cartilage damage.

Keywords:  Chondrocytes; Inflammation; Intracellular metabolism; IκBζ; Osteoarthritis

DOI:  https://doi.org/10.1016/j.joca.2023.04.003
Int J Mol Sci. 2023 Apr 14. pii: 7267. [Epub ahead of print]24(8):

HIV-Differentiated Metabolite N-Acetyl-L-Alanine Dysregulates Human Natural Killer Cell Responses to Mycobacterium tuberculosis Infection.

Baojun Yang, Tanmoy Mukherjee, Rajesh Radhakrishnan, Padmaja Paidipally, Danish Ansari, Sahana John, Ramakrishna Vankayalapati, Deepak Tripathi, Guohua Yi.

  Mycobacterium tuberculosis (Mtb) has latently infected over two billion people worldwide (LTBI) and caused ~1.6 million deaths in 2021. Human immunodeficiency virus (HIV) co-infection with Mtb will affect the Mtb progression and increase the risk of developing active tuberculosis by 10-20 times compared with HIV- LTBI+ patients. It is crucial to understand how HIV can dysregulate immune responses in LTBI+ individuals. Plasma samples collected from healthy and HIV-infected individuals were investigated using liquid chromatography-mass spectrometry (LC-MS), and the metabolic data were analyzed using the online platform Metabo-Analyst. ELISA, surface and intracellular staining, flow cytometry, and quantitative reverse-transcription PCR (qRT-PCR) were performed using standard procedures to determine the surface markers, cytokines, and other signaling molecule expressions. Seahorse extra-cellular flux assays were used to measure mitochondrial oxidative phosphorylation and glycolysis. Six metabolites were significantly less abundant, and two were significantly higher in abundance in HIV+ individuals compared with healthy donors. One of the HIV-upregulated metabolites, N-acetyl-L-alanine (ALA), inhibits pro-inflammatory cytokine IFN-γ production by the NK cells of LTBI+ individuals. ALA inhibits the glycolysis of LTBI+ individuals' NK cells in response to Mtb. Our findings demonstrate that HIV infection enhances plasma ALA levels to inhibit NK-cell-mediated immune responses to Mtb infection, offering a new understanding of the HIV-Mtb interaction and providing insights into the implication of nutrition intervention and therapy for HIV-Mtb co-infected patients.

Keywords:  HIV–Mtb co-infection; Mtb latent infection (LTBI); N-acetyl-L-alanine; interferon-γ; metabolite; natural killer cells

DOI:  https://doi.org/10.3390/ijms24087267
Hum Cell. 2023 Apr 28.

Neutrophil (dys)function due to altered immuno-metabolic axis in type 2 diabetes: implications in combating infections.

Pooja Yedehalli Thimmappa, Sampara Vasishta, Kailash Ganesh, Aswathy S Nair, Manjunath B Joshi.

  Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated inflammatory signaling networks, aberrant cytokine production and increased acute phase reactants which leads to a pro-inflammatory 'feed forward loop'. Nutrient 'excess' conditions in T2D with hyperglycemia, elevated lipids and branched-chain amino acids significantly alter the functions of immune cells including neutrophils. Neutrophils are metabolically active cells and utilizes energy from glycolysis, stored glycogen and β-oxidation while depending on the pentose phosphate pathway for NADPH for performing effector functions such as chemotaxis, phagocytosis and forming extracellular traps. Metabolic changes in T2D result in constitutive activation and impeded acquisition of effector or regulatory activities of neutrophils and render T2D subjects for recurrent infections. Increased flux through the polyol and hexosamine pathways, elevated production of advanced glycation end products (AGEs), and activation of protein kinase C isoforms lead to (a) an enhancement in superoxide generation; (b) the stimulation of inflammatory pathways and subsequently to (c) abnormal host responses. Neutrophil dysfunction diminishes the effectiveness of wound healing, successful tissue regeneration and immune surveillance against offending pathogens. Hence, Metabolic reprogramming in neutrophils determines frequency, severity and duration of infections in T2D. The present review discusses the influence of the altered immuno-metabolic axis on neutrophil dysfunction along with challenges and therapeutic opportunities for clinical management of T2D-associated infections.

Keywords:  Immuno-metabolism; Infections; Metabolism; Neutrophil extracellular traps; Neutrophils; Type 2 diabetes

DOI:  https://doi.org/10.1007/s13577-023-00905-7
Biomed Pharmacother. 2023 Apr 25. pii: S0753-3322(23)00552-8. [Epub ahead of print]163 114763

Short chain fatty acids, a possible treatment option for autoimmune diseases.

Faezeh Golpour, Mehrsa Abbasi-Alaei, Fatemeh Babaei, Mohammadreza Mirzababaei, Siavash Parvardeh, Ghazaleh Mohammadi, Marjan Nassiri-Asl.

  Gut microbiota can interact with the immune system through its metabolites. Short-chain fatty acids (SCFAs), as one of the most abundant metabolites of the resident gut microbiota play an important role in this crosstalk. SCFAs (acetate, propionate, and butyrate) regulate nearly every type of immune cell in the gut's immune cell repertoire regarding their development and function. SCFAs work through several pathways to impose protection towards colonic health and against local or systemic inflammation. Additionally, SCFAs play a role in the regulation of immune or non-immune pathways that can slow the development of autoimmunity either systematically or in situ. The present study aims to summarize the current knowledge on the immunomodulatory roles of SCFAs and the association between the SCFAs and autoimmune disorders such as celiac disease (CD), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), type 1 diabetes (T1D) and other immune-mediated diseases, uncovering a brand-new therapeutic possibility to prevent or treat autoimmunity.

Keywords:  Acetate; Autoimmune disease; Autoimmunity; Butyrate; Propionate; Short-chain fatty acid

DOI:  https://doi.org/10.1016/j.biopha.2023.114763
Int J Mol Sci. 2023 Apr 18. pii: 7463. [Epub ahead of print]24(8):

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses.

Beatrice Foglia, Marc Beltrà, Salvatore Sutti, Stefania Cannito.

  Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC's metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.

Keywords:  HCC; TCA cycle; amino acid metabolism; fatty acid metabolism; glucose metabolism; glutamine; immune response; metabolic reprogramming; tumor microenvironment; urea cycle

DOI:  https://doi.org/10.3390/ijms24087463
Antioxidants (Basel). 2023 Apr 15. pii: 935. [Epub ahead of print]12(4):

From Gasotransmitter to Immunomodulator: The Emerging Role of Hydrogen Sulfide in Macrophage Biology.

Alex Cornwell, Alireza Badiei.

  Hydrogen sulfide (H2S) has been increasingly recognized as a crucial inflammatory mediator in immune cells, particularly macrophages, due to its direct and indirect effects on cellular signaling, redox homeostasis, and energy metabolism. The intricate regulation of endogenous H2S production and metabolism involves the coordination of transsulfuration pathway (TSP) enzymes and sulfide oxidizing enzymes, with TSP's role at the intersection of the methionine pathway and glutathione synthesis reactions. Additionally, H2S oxidation mediated by sulfide quinone oxidoreductase (SQR) in mammalian cells may partially control cellular concentrations of this gasotransmitter to induce signaling. H2S is hypothesized to signal through the posttranslational modification known as persulfidation, with recent research highlighting the significance of reactive polysulfides, a derivative of sulfide metabolism. Overall, sulfides have been identified as having promising therapeutic potential to alleviate proinflammatory macrophage phenotypes, which are linked to the exacerbation of disease outcomes in various inflammatory conditions. H2S is now acknowledged to have a significant influence on cellular energy metabolism by affecting the redox environment, gene expression, and transcription factor activity, resulting in changes to both mitochondrial and cytosolic energy metabolism processes. This review covers recent discoveries pertaining to the involvement of H2S in macrophage cellular energy metabolism and redox regulation, and the potential implications for the inflammatory response of these cells in the broader framework of inflammatory diseases.

Keywords:  cellular metabolism; hydrogen sulfide; inflammation; macrophage; redox

DOI:  https://doi.org/10.3390/antiox12040935
Metabolism. 2023 Apr 26. pii: S0026-0495(23)00179-8. [Epub ahead of print] 155576

Neutrophil aging exacerbates high fat diet induced metabolic alterations.

Andrea Baragetti, Lorenzo Da Dalt, Annalisa Moregola, Monika Svecla, Ottavia Terenghi, Elisa Mattavelli, Lucia Nicolini De Gaetano, Patrizia Uboldi, Alberico Luigi Catapano, Giuseppe Danilo Norata.

   BACKGROUND: High fat diet (HFD) chronically hyper-activate the myeloid cell precursors, but whether it affects the neutrophil aging is unknown.
PURPOSE: We characterized how HFD impacts neutrophil aging, infiltration in metabolic tissues and if this aging, in turn, modulates the development of metabolic alterations. We immunophenotyped neutrophils and characterized the metabolic responses in physiology (wild-type mice, WT) and in mice with constitutively aged neutrophils (MRP8 driven conditional deletion of CXCR4; herein CXCR4fl/flCre+) or with constitutively fresh neutrophils (MRP8 driven conditional deletion of CXCR2; CXCR2fl/flCre+), following 20 weeks of HFD feeding (45 % kcal from fat).
FINDINGS: After 20 weeks HFD, the gluco-metabolic profile of CXCR4fl/flCre+ mice was comparable to that of WT mice, while CXCR2fl/flCre+ mice were protected from metabolic alterations. CXCR4fl/flCre+ infiltrated more, but CXCR2fl/flCre+ neutrophils infiltrated less, in liver and visceral adipose tissue (VAT). As consequence, while CXCR4fl/flCre+ resulted into hepatic "suicidal" neutrophils extracellular traps (NETs) and altered immune cell architecture in VAT, CXCR2fl/flCre+ promoted proresolutive hepatic NETs and reduced accumulation of pro-inflammatory macrophages in VAT. In humans, higher Cxcl12 (CXCR4 ligand) plasma levels correlated with visceral adiposity while higher levels of Cxcl1, the ligand of CXCR2, correlated with indexes of hepatic steatosis, adiposity and metabolic syndrome.
CONCLUSIONS: Neutrophil aging might contribute to the development of HFD induced metabolic disorders.

Keywords:  Adiposity; CXCR2; CXCR4; Metabolic syndrome; Neutrophils

DOI:  https://doi.org/10.1016/j.metabol.2023.155576
Methods Mol Biol. 2023 ;2654 91-111

Combined FRET-FLIM and NAD(P)H FLIM to Analyze B Cell Receptor Signaling Induced Metabolic Activity of Germinal Center B Cells In Vivo.

Carolin Ulbricht, Ruth Leben, Yu Cao, Raluca A Niesner, Anja E Hauser.

  Affinity maturation of B cell clones within germinal centers constitutes an important mechanism for immune memory. During this process, B cell receptor signaling capacity is tested in multiple rounds of positive selection. Antigen stimulation and co-stimulatory signals mobilize calcium to switch on gene expression leading to proliferation and survival and to differentiation into memory B cells and plasma cells. Additionally, all these processes require adaption of B cell metabolism, and calcium signaling and metabolic pathways are closely interlinked. Mitochondrial adaption, ROS production, and NADPH oxidase activation are involved in cell fate decisions, but it remains elusive to what extent, especially because the analysis of these dynamic processes in germinal centers has to take place in vivo. Here, we introduce a quantitative intravital imaging method for combined measurement of cytoplasmic calcium concentration and enzymatic fingerprinting in germinal center B cells as a possible tool in order to further examine the relationship of calcium signaling and immunometabolism.

Keywords:  B cell receptor signaling; B cells; Fluorescence lifetime microscopy; Germinal center; Intravital microscopy; Metabolic reprogramming; NADPH oxidase

DOI:  https://doi.org/10.1007/978-1-0716-3135-5_6
iScience. 2023 Apr 21. 26(4): 106477

β-cell function is regulated by metabolic and epigenetic programming of islet-associated macrophages, involving Axl, Mertk, and TGFβ receptor signaling.

Le May Thai, Liam O'Reilly, Saskia Reibe-Pal, Nancy Sue, Holly Holliday, Lewin Small, Carsten Schmitz-Peiffer, Rama Dhenni, Vicky Wang-Wei Tsai, Nicholas Norris, Belinda Yau, Xuan Zhang, Kailun Lee, Chenxu Yan, Yan-Chuan Shi, Melkam A Kebede, Robert Brink, Gregory J Cooney, Katharine M Irvine, Samuel N Breit, Tri G Phan, Alexander Swarbrick, Trevor J Biden.

  We have exploited islet-associated macrophages (IAMs) as a model of resident macrophage function, focusing on more physiological conditions than the commonly used extremes of M1 (inflammation) versus M2 (tissue remodeling) polarization. Under steady state, murine IAMs are metabolically poised between aerobic glycolysis and oxidative phosphorylation, and thereby exert a brake on glucose-stimulated insulin secretion (GSIS). This is underpinned by epigenetic remodeling via the metabolically regulated histone demethylase Kdm5a. Conversely, GSIS is enhanced by engaging Axl receptors on IAMs, or by augmenting their oxidation of glucose. Following high-fat feeding, efferocytosis is stimulated in IAMs in conjunction with Mertk and TGFβ receptor signaling. This impairs GSIS and potentially contributes to β-cell failure in pre-diabetes. Thus, IAMs serve as relays in many more settings than currently appreciated, fine-tuning insulin secretion in response to dynamic changes in the external environment. Intervening in this nexus might represent a means of preserving β-cell function during metabolic disease.

Keywords:  Cell biology; Immunology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2023.106477
Cell Rep. 2023 Apr 26. pii: S2211-1247(23)00447-3. [Epub ahead of print]42(5): 112436

PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion.

Jennifer L Hope, Dennis C Otero, Eun-Ah Bae, Christopher J Stairiker, Ashley B Palete, Hannah A Faso, Michelle Lin, Monique L Henriquez, Sreeja Roy, Hyungseok Seo, Xue Lei, Eric S Wang, Savio Chow, Roberto Tinoco, Gregory A Daniels, Kevin Yip, Alexandre Rosa Campos, Jun Yin, Peter D Adams, Anjana Rao, Linda M Bradley.

  PSGL-1 (P-selectin glycoprotein-1) is a T cell-intrinsic checkpoint regulator of exhaustion with an unknown mechanism of action. Here, we show that PSGL-1 acts upstream of PD-1 and requires co-ligation with the T cell receptor (TCR) to attenuate activation of mouse and human CD8+ T cells and drive terminal T cell exhaustion. PSGL-1 directly restrains TCR signaling via Zap70 and maintains expression of the Zap70 inhibitor Sts-1. PSGL-1 deficiency empowers CD8+ T cells to respond to low-affinity TCR ligands and inhibit growth of PD-1-blockade-resistant melanoma by enabling tumor-infiltrating T cells to sustain an elevated metabolic gene signature supportive of increased glycolysis and glucose uptake to promote effector function. This outcome is coupled to an increased abundance of CD8+ T cell stem cell-like progenitors that maintain effector functions. Additionally, pharmacologic blockade of PSGL-1 curtails T cell exhaustion, indicating that PSGL-1 represents an immunotherapeutic target for PD-1-blockade-resistant tumors.

Keywords:  CD8 T cells; CP: Immunology; T cell exhaustion; T cell metabolism; T cell signaling; chronic infection; melanoma; tumor immunity

DOI:  https://doi.org/10.1016/j.celrep.2023.112436
Chem Biol Interact. 2023 Apr 25. pii: S0009-2797(23)00181-3. [Epub ahead of print] 110514

Formaldehyde exacerbates asthma in mice through the potentiation of HIF-1α-mediated pro-inflammatory responses in pulmonary macrophages.

Huijuan Ma, Qi Shu, Peiyao Wang, Ruilin Qin, Sijia Li, Huan Xu.

  Exposure to formaldehyde (FA) has been indicated to be positively correlated with increased incidence of allergic asthma in many epidemiological and experimental studies. However, few studies have ever addressed the molecular basis of the correlation. In the present study, it was found that inhaling 2.0 mg/m3 FA for 2 weeks could exacerbate the pulmonary inflammation and mucus over-accumulation in OVA-induced murine asthmatic model. The pro-inflammatory cytokines, such as IL-1β, TNF-α, IL-6 and IL-8, were increased in lung and serum of FA-exposed asthmatic mice. The contribution of HIF-1α signaling in FA-exacerbated allergic asthma was confirmed by bioinformatic analysis. HIF-1α and its downstream proteins, which are known as mediators of glycolysis, were found to be upregulated by 50 μM FA, and the FA-enhanced of glycolysis was reversed by inhibition of HIF-1α with PX-478 in vitro and YC-1 in vivo. Furthermore, it was confirmed that inhibition of HIF-1α signaling could restrain the macrophagic inflammatory responses and asthma exacerbation induced by FA. Collectively, these results revealed that FA could exacerbate asthma through the potentiation of HIF-1α-mediated inflammatory responses in macrophages, which also indicated the universal roles of FA-triggered macrophage metabolic and functional alterations in inflammatory or allergic diseases.

Keywords:  Asthma; Formaldehyde; Glycolysis; HIF-1α; Macrophage; Pro-inflammatory responses

DOI:  https://doi.org/10.1016/j.cbi.2023.110514
Nat Aging. 2023 Apr 17.

CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.

Jun Jin, Yunmei Mu, Huimin Zhang, Ines Sturmlechner, Chenyao Wang, Rohit R Jadhav, Qiong Xia, Cornelia M Weyand, Jorg J Goronzy.

Chronic systemic inflammation is one of the hallmarks of the aging immune system. Here we show that activated T cells from older adults contribute to inflammaging by releasing mitochondrial DNA (mtDNA) into their environment due to an increased expression of the cytokine-inducible SH2-containing protein (CISH). CISH targets ATP6V1A, an essential component of the proton pump V-ATPase, for proteasomal degradation, thereby impairing lysosomal function. Impaired lysosomal activity caused intracellular accumulation of multivesicular bodies and amphisomes and the export of their cargos, including mtDNA. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal release. In antigen-specific responses in vivo, CISH-deficient CD4+ T cells released less mtDNA and induced fewer inflammatory cytokines. Attenuating CISH expression may present a promising strategy to reduce inflammation in an immune response of older individuals.

DOI: https://doi.org/10.1038/s43587-023-00399-w
Front Pharmacol. 2023 ;14 1092943

Sirtuin 1 activator alleviated lethal inflammatory injury via promotion of autophagic degradation of pyruvate kinase M2.

Shuang Zhao, Yili Sun, Xicheng Wu, Yongqiang Yang, Kerui Fan, Kai Hu, Yasha Qin, Kexin Li, Ling Lin, Kun Chen, Yuhua Ma, Min Zhu, Gang Liu, Li Zhang.

  Upregulation of pyruvate kinase M2 (PKM2) is critical for the orchestration of metabolism and inflammation in critical illness, while autophagic degradation is a recently revealed mechanism that counter-regulates PKM2. Accumulating evidence suggests that sirtuin 1 (SIRT1) function as a crucial regulator in autophagy. The present study investigated whether SIRT1 activator would downregulate PKM2 in lethal endotoxemia via promotion of its autophagic degradation. The results indicated that lethal dose of lipopolysaccharide (LPS) exposure decreased the level of SIRT1. Treatment with SRT2104, a SIRT1 activator, reversed LPS-induced downregulation of LC3B-II and upregulation of p62, which was associated with reduced level of PKM2. Activation of autophagy by rapamycin also resulted in reduction of PKM2. The decline of PKM2 in SRT2104-treated mice was accompanied with compromised inflammatory response, alleviated lung injury, suppressed elevation of blood urea nitrogen (BUN) and brain natriuretic peptide (BNP), and improved survival of the experimental animals. In addition, co-administration of 3-methyladenine, an autophagy inhibitor, or Bafilomycin A1, a lysosome inhibitor, abolished the suppressive effects of SRT2104 on PKM2 abundance, inflammatory response and multiple organ injury. Therefore, promotion of autophagic degradation of PKM2 might be a novel mechanism underlying the anti-inflammatory benefits of SIRT1 activator.

Keywords:  autophagy; deacetylase; endotoxemia; pyruvate kinase M2; sirtuin 1

DOI:  https://doi.org/10.3389/fphar.2023.1092943
Clin Transl Immunology. 2023 ;12(4): e1446

Administration of an LXR agonist promotes atherosclerotic lesion remodelling in murine inflammatory arthritis.

Dragana Dragoljevic, Man Kit Sam Lee, Gerard Pernes, Pooranee K Morgan, Cynthia Louis, Waled Shihata, Kevin Huynh, Arina A Kochetkova, Patrick W Bell, Natalie A Mellett, Peter J Meikle, Graeme I Lancaster, Michael J Kraakman, Prabhakara R Nagareddy, Beatriz Y Hanaoka, Ian P Wicks, Andrew J Murphy.

   Objectives: The leading cause of mortality in patients with rheumatoid arthritis is atherosclerotic cardiovascular disease (CVD). We have shown that murine arthritis impairs atherosclerotic lesion regression, because of cellular cholesterol efflux defects in haematopoietic stem and progenitor cells (HSPCs), causing monocytosis and impaired atherosclerotic regression. Therefore, we hypothesised that improving cholesterol efflux using a Liver X Receptor (LXR) agonist would improve cholesterol efflux and improve atherosclerotic lesion regression in arthritis.
Methods: Ldlr-/- mice were fed a western-type diet for 14 weeks to initiate atherogenesis, then switched to a chow diet to induce lesion regression and divided into three groups; (1) control, (2) K/BxN serum transfer inflammatory arthritis (K/BxN) or (3) K/BxN arthritis and LXR agonist T0901317 daily for 2 weeks.
Results: LXR activation during murine inflammatory arthritis completely restored atherosclerotic lesion regression in arthritic mice, evidenced by reduced lesion size, macrophage abundance and lipid content. Mechanistically, serum from arthritic mice promoted foam cell formation, demonstrated by increased cellular lipid accumulation in macrophages and paralleled by a reduction in mRNA of the cholesterol efflux transporters Abca1, Abcg1 and Apoe. T0901317 reduced lipid loading and increased Abca1 and Abcg1 expression in macrophages exposed to arthritic serum and increased ABCA1 levels in atherosclerotic lesions of arthritic mice. Moreover, arthritic clinical score was also attenuated with T0901317.
Conclusion: Taken together, we show that the LXR agonist T0901317 rescues impaired atherosclerotic lesion regression in murine arthritis because of enhanced cholesterol efflux transporter expression and reduced foam cell development in atherosclerotic lesions.

Keywords:  atherosclerosis; cholesterol metabolism; inflammation; monocytes; rheumatoid arthritis

DOI:  https://doi.org/10.1002/cti2.1446
Exp Ther Med. 2023 May;25(5): 234

Gain‑of‑function of IDO in DCs inhibits T cell immunity by metabolically regulating surface molecules and cytokines.

Fengge Wang, Lei Liu, Juncheng Wang, Meng Liu, Wenjie Zhang, Lin Zhao, Chengfeng Zhai, Yuekang Xu.

  Both tolerogenicity and immunogenicity of dendritic cells (DCs) are regulated by their intracellular metabolism. As a rate-limiting enzyme of tryptophan (Trp) metabolism, indoleamine 2,3-dioxygenase (IDO) is involved in regulating the functions of numerous cell types, including DCs, a subset of which has a high capacity for producing IDO to control over-activated inflammation. To identify the mechanisms of IDO in DCs, stable DC lines with both gain- and reduction-of-function of IDO were established using a recombinant DNA technique. Although the IDO variation did not affect DC survival and migration, it altered Trp metabolism and other features of DCs analyzed by high-performance liquid chromatography and flow cytometry. On the surface of the DCs, IDO inhibited co-stimulatory CD86 but promoted co-inhibitory programmed cell death ligand 1 expression, and suppressed the antigen uptake, which ultimately led to the compromised ability of DCs to activate T cells. Furthermore, IDO also suppressed IL-12 secretion but enhanced that of IL-10 in DCs, which eventually induced T cells into tolerogenic phenotypes by inhibiting the differentiation of Th1 but promoting that of regulatory T cells. Collectively, the findings of the present study demonstrated that IDO is a key molecule for tolerogenic DC induction by metabolically regulating surface molecule and cytokine expression. This conclusion may lead to the targeted development of therapeutic drugs for autoimmune diseases.

Keywords:  3-dioxygenase; T cell immunity; dendritic cells; gene recombination; indoleamine 2; tryptophan metabolism

DOI:  https://doi.org/10.3892/etm.2023.11933
Eur J Nutr. 2023 Apr 27.

Maternal diet supplementation with high-docosahexaenoic-acid canola oil, along with arachidonic acid, promotes immune system development in allergy-prone BALB/c mouse offspring at 3 weeks of age.

Dhruvesh Patel, Jaqueline Munhoz, Susan Goruk, Sue Tsai, Caroline Richard, Catherine J Field.

   PURPOSE: To study the effects of feeding docosahexaenoic acid (DHA, derived from novel canola oil), with same amount of arachidonic acid (ARA), supplemented diet to lactating dams on the immune system development of suckled offspring using a T helper type-2 (Th2)-dominant BALB/c mouse.
METHODS: Dams received nutritionally complete control (no ARA or DHA) or DHA + ARA diet (1% DHA and 1% ARA of total fatty acids) from 5 days pre-parturition to the end of 3-week suckling period. After euthanization, relevant tissues were collected to study fatty acids, splenocyte phenotype and function (ex vivo cytokines with/without lipopolysaccharide (LPS, bacterial challenge) or phorbol myristate acetate + ionomycin (PMAi) stimulation).
RESULTS: Feeding dams a DHA diet significantly increased the mammary gland milk phospholipid concentration of DHA and ARA. This resulted in 60% higher DHA levels in splenocyte phospholipids of the pups although ARA levels showed no difference. In dams fed DHA diet, significantly higher proportion of CD27+ cytotoxic T cell (CTL) and CXCR3+ CCR6- Th (enriched in Th1) were observed than control, but there were no differences in the splenocyte function upon PMAi (non-specific lymphocyte stimulant) stimulation. Pups from DHA-fed dams showed significantly higher IL-1β, IFN-γ and TNF-α (inflammatory cytokines) by LPS-stimulated splenocytes. This may be due to higher proportion of CD86+ macrophages and B cells (all p's < 0.05) in these pups, which may influence T cell polarization.
CONCLUSION: Plant-based source of DHA in maternal diet resulted in higher ex vivo production of inflammatory cytokines by splenocytes due to change in their phenotype, and this can skew T cell towards Th1 response in a Th2-dominant BALB/c mouse.

Keywords:  Arachidonic acid; Docosahexaenoic acid; Immune system; Nutritional immunology; Omega-3; Omega-6; Spleen; Suckling diet; T helper type-2

DOI:  https://doi.org/10.1007/s00394-023-03160-6
Aging Cell. 2023 Apr 26. e13856

Metabololipidomic and proteomic profiling reveals aberrant macrophage activation and interrelated immunomodulatory mediator release during aging.

Patrick Schädel, Anna Czapka, Nadja Gebert, Ilse Denise Jacobsen, Alessandro Ori, Oliver Werz.

  Macrophages adapt distinct pro-inflammatory (M1-like) and pro-resolving (M2-like) phenotypes with specific tasks in the immune response and tissue homeostasis. Altered macrophage responses with age are causative for unresolved inflammation, so-called inflammaging, and lead to higher infection susceptibility with unfavorable progression. Here, we reveal molecular determinants of age-related changes in phenotypic functions of murine peritoneal macrophages (PM) by employing comprehensive mass spectrometry-based proteomics (4746 protein groups) and metabololipidomics (>40 lipid mediators). Divergent expression of various macrophage-specific marker proteins and signaling pathways indicates aberrant PM phenotypes in old mice which detrimentally impact their capabilities to release immunomodulatory chemokines and cytokines. We show that aging strikingly compromises the polarization process of macrophages to adapt either pro-inflammatory or pro-resolving phenotypes, thereby yielding aberrant and afunctional macrophage subtypes that cannot be readily assigned to either a typical M1 or M2 phenotype. In particular, the phenotypic adaptation of the bacteria-challenged metabololipidome in macrophages related to inflammation is severely limited by age, which persists across ex vivo polarization towards M1 and M2a macrophages. Our results establish distinct age-associated PM phenotypes outside of the simplified M1 and M2 dichotomy and challenge the dogma of increased pro-inflammatory macrophage pre-activation due to aging by revealing maladaptive functions throughout all phases of inflammation, including resolution.

Keywords:  aging; eicosanoids; inflammation; lipidomics; macrophage activation; mediators of inflammation; peritoneal macrophages; proteomics

DOI:  https://doi.org/10.1111/acel.13856
Int J Mol Sci. 2023 Apr 15. pii: 7323. [Epub ahead of print]24(8):

Weighted Gene Co-Expression Network Analysis Identifies a Functional Guild and Metabolite Cluster Mediating the Relationship between Mucosal Inflammation and Adherence to the Mediterranean Diet in Ulcerative Colitis.

Jaclyn C Strauss, Natasha Haskey, Hena R Ramay, Tarini Shankar Ghosh, Lorian M Taylor, Munazza Yousuf, Christina Ohland, Kathy D McCoy, Richard J M Ingram, Subrata Ghosh, Remo Panaccione, Maitreyi Raman.

  Diet influences the pathogenesis and clinical course of inflammatory bowel disease (IBD). The Mediterranean diet (MD) is linked to reductions in inflammatory biomarkers and alterations in microbial taxa and metabolites associated with health. We aimed to identify features of the gut microbiome that mediate the relationship between the MD and fecal calprotectin (FCP) in ulcerative colitis (UC). Weighted gene co-expression network analysis (WGCNA) was used to identify modules of co-abundant microbial taxa and metabolites correlated with the MD and FCP. The features considered were gut microbial taxa, serum metabolites, dietary components, short-chain fatty acid and bile acid profiles in participants that experienced an increase (n = 13) or decrease in FCP (n = 16) over eight weeks. WGCNA revealed ten modules containing sixteen key features that acted as key mediators between the MD and FCP. Three taxa (Faecalibacterium prausnitzii, Dorea longicatena, Roseburia inulinivorans) and a cluster of four metabolites (benzyl alcohol, 3-hydroxyphenylacetate, 3-4-hydroxyphenylacetate and phenylacetate) demonstrated a strong mediating effect (ACME: -1.23, p = 0.004). This study identified a novel association between diet, inflammation and the gut microbiome, providing new insights into the underlying mechanisms of how a MD may influence IBD. See clinicaltrials.gov (NCT04474561).

Keywords:  diet; inflammatory bowel disease; metabolomics; microbiome; ulcerative colitis; weighted gene co-expression analysis (WGCNA)

DOI:  https://doi.org/10.3390/ijms24087323
J Crohns Colitis. 2023 Apr 24. pii: jjad073. [Epub ahead of print]

A Mediterranean Diet Pattern improves intestinal inflammation concomitant with reshaping of the bacteriome in ulcerative colitis: A randomized controlled trial.

Natasha Haskey, Mehrbod Estaki, Jiayu Ye, Rachel K Shim, Sunny Singh, Levinus A Dieleman, Kevan Jacobson, Deanna L Gibson.

   BACKGROUND & AIMS: Dietary patterns are important in managing ulcerative colitis (UC), given their influence on gut microbiome-host symbiosis and inflammation. We investigated whether the Mediterranean Diet Pattern (MDP) vs the Canadian Habitual Diet Pattern (CHD) would impact disease activity, inflammation and the gut microbiome in patients with quiescent UC.
METHODS: We performed a prospective, randomized control trial in adults (65% female; median age 47 y) with quiescent UC in an outpatient setting from 2017 to 2021. Participants were randomized to a MDP (n=15) or CHD (n=13) for 12 weeks. Disease activity (Simple Clinical Colitis Activity Index) and fecal calprotectin (FC) were measured at baseline and week 12. Stool samples were analyzed by 16S rRNA gene amplicon sequencing.
RESULTS: The diet was well-tolerated by the MDP group. At week 12, 75% (9/12) of participants in the CHD had a FC >100 μg/g, versus 20% (3/15) of participants in the MDP group. The MDP group had higher levels of total fecal short-chain fatty acids (SCFAs) (p=0.01), acetic acid (p=0.03) and butyric acid (p=0.03) compared to the CHD. Furthermore, the MDP-induced alterations in microbial species associated with a protective role in colitis (Alistipes finegoldii and Flavonifractor plautii), as well as the production of SCFAs (Ruminococcus bromii).
CONCLUSIONS: A MDP induces gut microbiome alterations associated with the maintenance of clinical remission and reduced FCin patients with quiescent UC. The data supports that a MDP is a sustainable diet pattern that could be recommended as a maintenance diet and adjunctive therapy for UC patients in clinical remission. ClinicalTrials.gov no: NCT0305371.

Keywords:  Mediterranean diet; inflammation; microbiome; ulcerative colitis

DOI:  https://doi.org/10.1093/ecco-jcc/jjad073