bims-imicid 2023-10-15 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒10‒15
34 papers selected by
Dylan Ryan, University of Cambridge

Metabolic support by macrophages sustains colonic epithelial homeostasis.
Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.
Macrophage-derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection.
Integrated transcriptomic and metabolomic analysis reveals the metabolic programming of GM-CSF- and M-CSF- differentiated mouse macrophages.
Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease.
BRD4 regulates glycolysis-dependent Nos2 expression in macrophages upon H. pylori infection.
Oxalate disrupts monocyte and macrophage cellular function via Interleukin-10 and mitochondrial reactive oxygen species (ROS) signaling.
Glycolysis-cholesterol metabolic axis in immuno-oncology microenvironment: emerging role in immune cells and immunosuppressive signaling.
The yin and yang of itaconate metabolism and its impact on the tumor microenvironment.
ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia.
Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction.
Metabolic and mitochondrial dysregulation in CD4+ T cells from HIV-positive women on combination anti-retroviral therapy.
Effects of lysine deacetylase inhibitor treatment on LPS responses of alveolar-like macrophages.
STAT3 modulates CD4+ T mitochondrial dynamics and function in aging.
4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1.
Berberine ameliorates collagen-induced arthritis in mice by restoring macrophage polarization via AMPK/mTORC1 pathway switching glycolytic reprogramming.
Common pathogenic bacteria-induced reprogramming of the host proteinogenic amino acids metabolism.
Activation-induced shift in nutrient preference and function-specific nutrient dependence in human neutrophils.
Distinctly altered lipid components in hepatocellular carcinoma relate to impaired T cell-dependent antitumor immunity.
Immunometabolic regulation during the presence of microorganisms and parasitoids in insects.
HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation.
Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose.
Succinate metabolism: a promising therapeutic target for inflammation, ischemia/reperfusion injury and cancer.
Suppression of HIV and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters.
Editorial: The connections of immune metabolic mechanisms with aging-related diseases.
Host cell sensing and restoration of mitochondrial function and metabolism within Helicobacter pylori VacA intoxicated cells.
Exosomes released from PD-L1+ tumor associated macrophages promote peritoneal metastasis of epithelial ovarian cancer by up-regulating T cell lipid metabolism.
Inhibiting Glutamine Metabolism Blocks Coronavirus Replication in Mammalian Cells.
Inhibition of mitochondrial translation ameliorates Imiquimod-induced psoriasis-like skin inflammation by targeting Vγ4+ γδ T cells.
Cellular iron governs the host response to malaria.
Myeloid PTP1B deficiency protects against atherosclerosis by improving cholesterol homeostasis through an AMPK-dependent mechanism.
Polyphenol-rich diet mediates interplay between macrophage-neutrophil and gut microbiota to alleviate intestinal inflammation.
The metabolite butyrate produced by gut microbiota inhibits cachexia-associated skeletal muscle atrophy by regulating intestinal barrier function and macrophage polarization.
15-keto-PGE2 alleviates nonalcoholic steatohepatitis through its covalent modification of NF-κB factors.

Cell Metab. 2023 Sep 29. pii: S1550-4131(23)00341-8. [Epub ahead of print]

Metabolic support by macrophages sustains colonic epithelial homeostasis.

Stephanie Deborah Fritsch, Nyamdelger Sukhbaatar, Karine Gonzales, Alishan Sahu, Loan Tran, Andrea Vogel, Mario Mazic, Jayne Louise Wilson, Stephan Forisch, Hannah Mayr, Raimund Oberle, Jakob Weiszmann, Martin Brenner, Roeland Vanhoutte, Melanie Hofmann, Sini Pirnes-Karhu, Christoph Magnes, Torben Kühnast, Wolfram Weckwerth, Christoph Bock, Kristaps Klavins, Markus Hengstschläger, Christine Moissl-Eichinger, Gernot Schabbauer, Gerda Egger, Eija Pirinen, Steven H L Verhelst, Thomas Weichhart.

  The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently characterized signals from the microenvironment. Here, we showed that colonic macrophages were located directly adjacent to epithelial crypt cells in mice, where they metabolically supported epithelial cell proliferation in an mTORC1-dependent manner. Specifically, deletion of tuberous sclerosis complex 2 (Tsc2) in macrophages activated mTORC1 signaling that protected against colitis-induced intestinal damage and induced the synthesis of the polyamines spermidine and spermine. Epithelial cells ingested these polyamines and rewired their cellular metabolism to optimize proliferation and defense. Notably, spermine directly stimulated proliferation of colon epithelial cells and colon organoids. Genetic interference with polyamine production in macrophages altered global polyamine levels in the colon and modified epithelial cell proliferation. Our results suggest that macrophages act as "commensals" that provide metabolic support to promote efficient self-renewal of the colon epithelium.

Keywords:  arginase-1; homeostasis; immunometabolism; intestine; mTOR; mTORC1; macrophages; polyamines; spermine

DOI:  https://doi.org/10.1016/j.cmet.2023.09.010
Mol Cell Biol. 2023 ;43(10): 531-546

Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.

Leah I Susser, My-Anh Nguyen, Michele Geoffrion, Christina Emerton, Mireille Ouimet, Mireille Khacho, Katey J Rayner.

  During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated "M1", or pro-resolving/alternatively "M2" macrophages. Although the classification of macrophages is general and assumes there are distinct phenotypes, in reality macrophages exist across a spectrum and must transform from a pro-inflammatory state to a proresolving state following an inflammatory insult. To adapt to changing metabolic needs of the cell, mitochondria undergo fusion and fission, which have important implications for cell fate and function. We hypothesized that mitochondrial fission and fusion directly contribute to macrophage function during the pro-inflammatory and proresolving phases. In the present study, we find that mitochondrial length directly contributes to macrophage phenotype, primarily during the transition from a pro-inflammatory to a proresolving state. Phenocopying the elongated mitochondrial network (by disabling the fission machinery using siRNA) leads to a baseline reduction in the inflammatory marker IL-1β, but a normal inflammatory response to LPS, similar to control macrophages. In contrast, in macrophages with a phenocopied fragmented phenotype (by disabling the fusion machinery using siRNA) there is a heightened inflammatory response to LPS and increased signaling through the ATF4/c-Jun transcriptional axis compared to control macrophages. Importantly, macrophages with a fragmented mitochondrial phenotype show increased expression of proresolving mediator arginase 1 and increased phagocytic capacity. Promoting mitochondrial fragmentation caused an increase in cellular lactate, and an increase in histone lactylation which caused an increase in arginase 1 expression. These studies demonstrate that a fragmented mitochondrial phenotype is critical for the proresolving response in macrophages and specifically drive epigenetic changes via lactylation of histones following an inflammatory insult.

Keywords:  fission; fusion; histone lactylation; inflammation resolution; macrophages; mitochondrial metabolism

DOI:  https://doi.org/10.1080/10985549.2023.2253131
EMBO J. 2023 Oct 09. e114086

Macrophage-derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection.

Gabriela Krejčová, Cecilia Morgantini, Helena Zemanová, Volker M Lauschke, Julie Kovářová, Jiří Kubásek, Pavla Nedbalová, Nick Kamps-Hughes, Martin Moos, Myriam Aouadi, Tomáš Doležal, Adam Bajgar.

  The immune response is an energy-demanding process that must be coordinated with systemic metabolic changes redirecting nutrients from stores to the immune system. Although this interplay is fundamental for the function of the immune system, the underlying mechanisms remain elusive. Our data show that the pro-inflammatory polarization of Drosophila macrophages is coupled to the production of the insulin antagonist ImpL2 through the activity of the transcription factor HIF1α. ImpL2 production, reflecting nutritional demands of activated macrophages, subsequently impairs insulin signaling in the fat body, thereby triggering FOXO-driven mobilization of lipoproteins. This metabolic adaptation is fundamental for the function of the immune system and an individual's resistance to infection. We demonstrated that analogically to Drosophila, mammalian immune-activated macrophages produce ImpL2 homolog IGFBP7 in a HIF1α-dependent manner and that enhanced IGFBP7 production by these cells induces mobilization of lipoproteins from hepatocytes. Hence, the production of ImpL2/IGFBP7 by macrophages represents an evolutionarily conserved mechanism by which macrophages alleviate insulin signaling in the central metabolic organ to secure nutrients necessary for their function upon bacterial infection.

Keywords:  Drosophila; ImpL2; insulin resistance; lipoproteins; macrophage polarization

DOI:  https://doi.org/10.15252/embj.2023114086
Front Immunol. 2023 ;14 1230772

Integrated transcriptomic and metabolomic analysis reveals the metabolic programming of GM-CSF- and M-CSF- differentiated mouse macrophages.

Qianyue Zhang, Qiaoling Song, Shan Liu, Yuting Xu, Danling Gao, Peizhe Lu, Yuantao Liu, Guanghui Zhao, Lihong Wu, Chenyang Zhao, Jinbo Yang.

  Macrophages play a critical role in the inflammatory response and tumor development. Macrophages are primarily divided into pro-inflammatory M1-like and anti-inflammatory M2-like macrophages based on their activation status and functions. In vitro macrophage models could be derived from mouse bone marrow cells stimulated with two types of differentiation factors: GM-CSF (GM-BMDMs) and M-CSF (M-BMDMs), to represent M1- and M2-like macrophages, respectively. Since macrophage differentiation requires coordinated metabolic reprogramming and transcriptional rewiring in order to fulfill their distinct roles, we combined both transcriptome and metabolome analysis, coupled with experimental validation, to gain insight into the metabolic status of GM- and M-BMDMs. The data revealed higher levels of the tricarboxylic acid cycle (TCA cycle), oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and urea and ornithine production from arginine in GM-BMDMs, and a preference for glycolysis, fatty acid storage, bile acid metabolism, and citrulline and nitric oxide (NO) production from arginine in M-BMDMs. Correlation analysis with the proteomic data showed high consistency in the mRNA and protein levels of metabolic genes. Similar results were also obtained when compared to RNA-seq data of human monocyte derived macrophages from the GEO database. Furthermore, canonical macrophage functions such as inflammatory response and phagocytosis were tightly associated with the representative metabolic pathways. In the current study, we identified the core metabolites, metabolic genes, and functional terms of the two distinct mouse macrophage populations. We also distinguished the metabolic influences of the differentiation factors GM-CSF and M-CSF, and wish to provide valuable information for in vitro macrophage studies.

Keywords:  GM-CSF; M-CSF; immunometabolism; macrophage differentiation; metabolome; transcriptome

DOI:  https://doi.org/10.3389/fimmu.2023.1230772
Front Immunol. 2023 ;14 1219422

Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease.

Hoyul Lee, Jae-Han Jeon, Eun Soo Kim.

  Mitochondria has emerged as a critical ruler of metabolic reprogramming in immune responses and inflammation. In the context of colitogenic T cells and IBD, there has been increasing research interest in the metabolic pathways of glycolysis, pyruvate oxidation, and glutaminolysis. These pathways have been shown to play a crucial role in the metabolic reprogramming of colitogenic T cells, leading to increased inflammatory cytokine production and tissue damage. In addition to metabolic reprogramming, mitochondrial dysfunction has also been implicated in the pathogenesis of IBD. Studies have shown that colitogenic T cells exhibit impaired mitochondrial respiration, elevated levels of mROS, alterations in calcium homeostasis, impaired mitochondrial biogenesis, and aberrant mitochondria-associated membrane formation. Here, we discuss our current knowledge of the metabolic reprogramming and mitochondrial dysfunctions in colitogenic T cells, as well as the potential therapeutic applications for treating IBD with evidence from animal experiments.

Keywords:  IBD - inflammatory bowel disease; T cell; immunometabolism; inflammation; mitochondria; treatment

DOI:  https://doi.org/10.3389/fimmu.2023.1219422
Cell Mol Gastroenterol Hepatol. 2023 Oct 09. pii: S2352-345X(23)00180-7. [Epub ahead of print]

BRD4 regulates glycolysis-dependent Nos2 expression in macrophages upon H. pylori infection.

Nikita Modi, Yanheng Chen, Xingchen Dong, Xiangming Hu, Gee W Lau, Keith T Wilson, Richard M Peek, Lin-Feng Chen.

  BACKGROUND & AIMS: Metabolic reprogramming is essential for the activation and functions of macrophages, including bacterial killing and cytokine production. Bromodomain-containing protein 4 (BRD4) has emerged as a critical regulator of innate immune response. However, the potential role of BRD4 in metabolic reprogramming of macrophage activation upon H. pylori infection remains unclear.METHODS: Bone marrow-derived macrophages (BMDMs) from WT and Brd4-myeloid deletion conditional knockout mice (Brd4-CKO) were infected with H. pylori. RNA sequencing was performed to evaluate the differential gene expression between WT and Brd4-deficient BMDMs upon infection. An in vivo model of WT and Brd4-CKO mice was used to confirm the role of BRD4 in innate immune response to H. pylori infection.
RESULTS: Depletion of Brd4 in BMDMs impaired H. pylori-induced glycolysis. Additionally, H. pylori-induced expression of glycolytic genes, including Glucose transporter type 1 (Glut1) and Hexokinase 2 (Hk2), was decreased in Brd4-deficient BMDMs. BRD4 was recruited to promoters of Glut1 and Hk2 via Hypoxia-inducible factor 1 alpha (HIF-1α), facilitating their expression. BRD4-mediated glycolysis stabilized H. pylori-induced nitric oxide synthase (Nos2) mRNA to produce nitric oxide (NO). The NO-mediated killing of H. pylori decreased in Brd4-deficient BMDMs, which was rescued by pyruvate. Furthermore, Brd4-CKO mice infected with H. pylori exhibited reduced gastric inflammation, increased H. pylori colonization and reduced iNOS expression in gastric macrophages.
CONCLUSIONS: Our study identified BRD4 as a key regulator of HIF-1α-dependent glycolysis and macrophage activation. Furthermore, we demonstrate a novel regulatory role of BRD4 in innate immunity through glycolysis to stabilize Nos2 mRNA for NO production to eliminate H. pylori infection.

Keywords:  BRD4; H. pylori; HIF-1α; glycolysis; iNOS

DOI:  https://doi.org/10.1016/j.jcmgh.2023.10.001
Redox Biol. 2023 Oct 04. pii: S2213-2317(23)00320-8. [Epub ahead of print]67 102919

Oxalate disrupts monocyte and macrophage cellular function via Interleukin-10 and mitochondrial reactive oxygen species (ROS) signaling.

Parveen Kumar, Emma Laurence, David K Crossman, Dean G Assimos, Michael P Murphy, Tanecia Mitchell.

  Oxalate is a small compound found in certain plant-derived foods and is a major component of calcium oxalate (CaOx) kidney stones. Individuals that consume oxalate enriched meals have an increased risk of forming urinary crystals, which are precursors to CaOx kidney stones. We previously reported that a single dietary oxalate load induces nanocrystalluria and reduces monocyte cellular bioenergetics in healthy adults. The purpose of this study was to extend these investigations to identify specific oxalate-mediated mechanisms in monocytes and macrophages. We performed RNA-Sequencing analysis on monocytes isolated from healthy subjects exposed to a high oxalate (8 mmol) dietary load. RNA-sequencing revealed 1,198 genes were altered and Ingenuity Pathway Analysis demonstrated modifications in several pathways including Interleukin-10 (IL-10) anti-inflammatory cytokine signaling, mitochondrial metabolism and function, oxalic acid downstream signaling, and autophagy. Based on these findings, we hypothesized that oxalate induces mitochondrial and lysosomal dysfunction in monocytes and macrophages via IL-10 and reactive oxygen species (ROS) signaling which can be reversed with exogenous IL-10 or Mitoquinone (MitoQ; a mitochondrial targeted antioxidant). We exposed monocytes and macrophages to oxalate in an in-vitro setting which caused oxidative stress, a decline in IL-10 cytokine levels, mitochondrial and lysosomal dysfunction, and impaired autophagy in both cell types. Administration of exogenous IL-10 and MitoQ attenuated these responses. These findings suggest that oxalate impairs metabolism and immune response via IL-10 signaling and mitochondrial ROS generation in both monocytes and macrophages which can be potentially limited or reversed. Future studies will examine the benefits of these therapies on CaOx crystal formation and growth in vivo.

Keywords:  Dietary oxalate; IL-10; Lysosome; Macrophages; Metabolism; Mitochondria; Monocytes; Transcriptomics

DOI:  https://doi.org/10.1016/j.redox.2023.102919
Cell Biosci. 2023 Oct 13. 13(1): 189

Glycolysis-cholesterol metabolic axis in immuno-oncology microenvironment: emerging role in immune cells and immunosuppressive signaling.

Jing Jin, Qijie Zhao, Zhigong Wei, Keliang Chen, Yonglin Su, Xiaolin Hu, Xingchen Peng.

  Cell proliferation and function require nutrients, energy, and biosynthesis activity to duplicate repertoires for each daughter. It is therefore not surprising that tumor microenvironment (TME) metabolic reprogramming primarily orchestrates the interaction between tumor and immune cells. Tumor metabolic reprogramming affords bioenergetic, signaling intermediates, and biosynthesis requirements for both malignant and immune cells. Different immune cell subsets are recruited into the TME, and these manifestations have distinct effects on tumor progression and therapeutic outcomes, especially the mutual contribution of glycolysis and cholesterol metabolism. In particularly, glycolysis-cholesterol metabolic axis interconnection plays a critical role in the TME modulation, and their changes in tumor metabolism appear to be a double-edged sword in regulating various immune cell responses and immunotherapy efficacy. Hence, we discussed the signature manifestation of the glycolysis-cholesterol metabolic axis and its pivotal role in tumor immune regulation. We also highlight how hypothetical combinations of immunotherapy and glycolysis/cholesterol-related metabolic interventions unleash the potential of anti-tumor immunotherapies, as well as developing more effective personalized treatment strategies.

Keywords:  Glycolysis-Cholesterol Metabolic Axis; Immune Cells; Immunosuppressive; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s13578-023-01138-9
Curr Opin Biotechnol. 2023 Oct 06. pii: S0958-1669(23)00106-4. [Epub ahead of print]84 102996

The yin and yang of itaconate metabolism and its impact on the tumor microenvironment.

Fangfang Chen, Birte Dowerg, Thekla Cordes.

The tumor microenvironment (TME) consists of a network of metabolically interconnected tumor and immune cell types. Macrophages influence the metabolic composition within the TME, which directly impacts the metabolic state and drug response of tumors. The accumulation of oncometabolites, such as succinate, fumarate, and 2-hydroxyglutarate, represents metabolic vulnerabilities in cancer that can be targeted therapeutically. Immunometabolites are emerging as metabolic regulators of the TME impacting immune cell functions and cancer cell growth. Here, we discuss recent discoveries on the potential impact of itaconate on the TME. We highlight how itaconate influences metabolic pathways relevant to immune responses and cancer cell proliferation. We also consider the therapeutic implications of manipulating itaconate metabolism as an immunotherapeutic strategy to constrain tumor growth.

DOI: https://doi.org/10.1016/j.copbio.2023.102996
Cell Rep. 2023 Oct 11. pii: S2211-1247(23)01218-4. [Epub ahead of print]42(10): 113206

ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia.

Tuan Anh Phu, Ngan K Vu, Martin Ng, Alex S Gao, Joshua S Stoolman, Navdeep S Chandel, Robert L Raffai.

  Apolipoprotein E (ApoE) is recognized for its pleiotropic properties that suppress inflammation. We report that ApoE serves as a metabolic rheostat that regulates microRNA control of glycolytic and mitochondrial activity in myeloid cells and hematopoietic stem and progenitor cells (HSPCs). ApoE expression in myeloid cells increases microRNA-146a, which reduces nuclear factor κB (NF-κB)-driven GLUT1 expression and glycolytic activity. In contrast, ApoE expression reduces microRNA-142a, which increases carnitine palmitoyltransferase 1a (CPT1A) expression, fatty acid oxidation, and oxidative phosphorylation. Improved mitochondrial metabolism by ApoE expression causes an enrichment of tricarboxylic acid (TCA) cycle metabolites and nicotinamide adenine dinucleotide (NAD+) in macrophages. The study of mice with conditional ApoE expression supports the capacity of ApoE to foster microRNA-controlled immunometabolism. Modulation of microRNA-146a and -142a in the hematopoietic system of hyperlipidemic mice using RNA mimics and antagonists, respectively, improves mitochondrial metabolism, which suppresses inflammation and hematopoiesis. Our findings unveil microRNA regulatory circuits, controlled by ApoE, that exert metabolic control over hematopoiesis and inflammation in hyperlipidemia.

Keywords:  ApoE; CP: Metabolism; CPT1A; Glut1; fatty acid oxidation; hematopoiesis; inflammation; macrophage; microRNA-142a; microRNA-146a; mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.113206
Nat Commun. 2023 Oct 13. 14(1): 6454

Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction.

Angélica María Sabogal-Guáqueta, Alejandro Marmolejo-Garza, Marina Trombetta-Lima, Asmaa Oun, Jasmijn Hunneman, Tingting Chen, Jari Koistinaho, Sarka Lehtonen, Arjan Kortholt, Justina C Wolters, Barbara M Bakker, Bart J L Eggen, Erik Boddeke, Amalia Dolga.

Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation (OXPHOS) to glycolysis or alterations in other metabolic pathways. However, most of the experimental findings have been acquired in murine immune cells, and little is known about the metabolic reprogramming of human microglia. In this study, we investigate the transcriptomic, proteomic, and metabolic profiles of mouse and iPSC-derived human microglia challenged with the TLR4 agonist LPS. We demonstrate that both species display a metabolic shift and an overall increased glycolytic gene signature in response to LPS treatment. The metabolic reprogramming is characterized by the upregulation of hexokinases in mouse microglia and phosphofructokinases in human microglia. This study provides a direct comparison of metabolism between mouse and human microglia, highlighting the species-specific pathways involved in immunometabolism and the importance of considering these differences in translational research.

DOI: https://doi.org/10.1038/s41467-023-42096-7
PLoS One. 2023 ;18(10): e0286436

Metabolic and mitochondrial dysregulation in CD4+ T cells from HIV-positive women on combination anti-retroviral therapy.

Matrona Akiso, Magdalene Ameka, Kewreshini Naidoo, Robert Langat, Janet Kombo, Delories Sikuku, Thumbi Ndung'u, Marcus Altfeld, Omu Anzala, Marianne Mureithi.

BACKGROUND: For optimal functionality, immune cells require a robust and adaptable metabolic program that is fueled by dynamic mitochondrial activity. In this study, we investigate the metabolic alterations occurring in immune cells during HIV infection and antiretroviral therapy by analyzing the uptake of metabolic substrates and mitochondrial phenotypes. By delineating changes in immune cell metabolic programming during HIV, we may identify novel potential therapeutic targets to improve anti-viral immune responses.METHODS: After consent and voluntary participation was confirmed, whole blood was drawn from HIV uninfected women and women with chronic HIV infection on long-term combination antiretroviral therapy (HIV/cART). Peripheral blood mononuclear cells-derived immune cells were directly incubated with different fluorescently tagged metabolites and markers of mitochondrial activity: FITC-2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose), FITC-BODIPY (4,4-Difluoro-5,7-Dimethyl-4-Bora-3a,4a-Diaza-s-Indacene-3-Hexadecanoic Acid), FITC-MitoTracker Green and APC-MitoTracker Deep Red. The uptake of glucose and fats and the mitochondrial mass and potential were measured using flow cytometry. All values are reported quantitatively as geometric means of fluorescence intensity.
RESULTS: During chronic HIV infection, cellular uptake of glucose increases in HIV+ dendritic cells in particular. CD4+ T cells had the lowest uptake of glucose and fats compared to all other cells regardless of HIV status, while CD8+ T cells took up more fatty acids. Interestingly, despite the lower utilization of glucose and fats in CD4+ T cells, mitochondrial mass increased in HIV+ CD4+ T cells compared to HIV negative CD4+ T-cells. HIV+ CD4+ T cells also had the highest mitochondrial potential.
CONCLUSIONS: Significant disparities in the utilization of substrates by leukocytes during chronic HIV/cART exist. Innate immune cells increased utilization of sugars and fats while adaptive immune cells displayed lower glucose and fat utilization despite having a higher mitochondrial activity. Our findings suggest that cART treated HIV-infected CD4+ T cells be dysfunctional or may prefer alternative fuel sources not included in these studies. This underscores the importance of understanding the metabolic effects of HIV treatment on immune function.

DOI: https://doi.org/10.1371/journal.pone.0286436
J Leukoc Biol. 2023 Oct 09. pii: qiad121. [Epub ahead of print]

Effects of lysine deacetylase inhibitor treatment on LPS responses of alveolar-like macrophages.

Sara Russo, Marcel Kwiatkowski, Justina C Wolters, Albert Gerding, Jos Hermans, Natalia Govorukhina, Rainer Bischoff, Barbro N Melgert.

  Macrophages are key immune cells that can adapt their metabolic phenotype in response to different stimuli. Lysine deacetylases (KDAC) are important enzymes regulating inflammatory gene expression and KDAC inhibitors have been shown to exert anti-inflammatory effects in models of chronic obstructive pulmonary disease (COPD). We hypothesized that these anti-inflammatory effects may be associated with metabolic changes in macrophages. To validate this hypothesis, we used an unbiased and a targeted proteomic approach to investigate metabolic enzymes as well as LC- and GC-MS to quantify metabolites in combination with the measurement of functional parameters in primary murine alveolar-like macrophages after lipopolysaccharide (LPS)-induced activation in the presence or absence of KDAC inhibition. We found that KDAC inhibition resulted in reduced production of inflammatory mediators such as TNF-α and IL-1β. However, only minor changes in macrophage metabolism were observed, as only one of the KDAC inhibitors slightly increased mitochondrial respiration while no changes in metabolite levels were seen. However, KDAC inhibition specifically enhanced expression of proteins involved in ubiquitination, which may be a driver of the anti-inflammatory effects of KDAC inhibitors. Our data illustrate that a multi-omics approach provides novel insights into how macrophages interact with cues from their environment. More detailed studies investigating ubiquitination as a potential driver of KDAC inhibition will help developing novel anti-inflammatory drugs for difficult to treat diseases such as COPD.

Keywords:  Lung; immunometabolism; metabolome analysis; multi-omics; proteasome; proteome analysis

DOI:  https://doi.org/10.1093/jleuko/qiad121
Aging Cell. 2023 Oct 13. e13996

STAT3 modulates CD4+ T mitochondrial dynamics and function in aging.

Emelia Zukowski, Marco Sannella, Jack Donato Rockhold, Gabriella H Kalantar, Jingting Yu, Sara SantaCruz-Calvo, Madison K Kuhn, Nasun Hah, Ling Ouyang, Tzu-Wen Wang, Lyanne Murphy, Heather Marszalkowski, Kaleigh Gibney, Micah J Drummond, Elizabeth A Proctor, Hatice Hasturk, Barbara S Nikolajczyk, Leena P Bharath.

  Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria-targeted STAT3 inhibitor, Mtcur-1 lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and function in T cells from older adults and partially recapitulated aging-related cytokine profiles. Our data show the mechanistic link among mitoSTAT3, mitochondrial dynamics, function, and T-cell cytokine production.

Keywords:  CD4+ T cells; Th17 cytokines; aging; cytokines; inflammaging; mitochondria; mitochondrial STAT3; naïve CD4+ T cells

DOI:  https://doi.org/10.1111/acel.13996
J Virol. 2023 Oct 12. e0132523

4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1.

Pau Ribó-Molina, Hauke J Weiss, Balasubramanian Susma, Stefan van Nieuwkoop, Leentje Persoons, Yunan Zheng, Melanie Ruzek, Dirk Daelemans, Ron A M Fouchier, Luke A J O'Neill, Bernadette G van den Hoogen.

  In recent years, especially since the outbreak of the severe acute respiratory syndrome coronavirus 2 pandemic, the cell-permeable itaconate derivative 4-octyl itaconate (4-OI) has gained traction as a potential antiviral agent. Here, we demonstrate that 4-OI inhibits replication of multiple influenza A viruses (IAV) by restricting nuclear export of viral ribonucleoproteins, a key step in the IAV replication cycle. This nuclear retention is achieved by deactivation and subsequent degradation of chromosomal maintenance 1 protein (CRM1), also known as exportin 1 (XPO1), a host cell protein exploited by IAV during replication. 4-OI-mediated deactivation of CRM1 resulted in the accumulation of the IAV nucleoprotein, the Rev protein of feline immunodeficiency virus, as well as the natural CRM1 cargos p53 and p65, in the nucleus of treated cells. Further mechanism of action studies revealed that, similar to known CRM1 inhibitors, 4-OI modifies a key cysteine in the cargo binding pocket of CRM1 at position 528 through an alkylation reaction called 2,3-dicarboxypropylation. Subsequent studies in a cell line in which the cysteine at position 528 in CRM1 protein was substituted by a serine confirmed that modification of this residue was indeed the cause for the observed inhibitory effect induced by 4-OI on CRM1 function. Overall, this study demonstrated a mechanism through which 4-OI directly interferes with the replication cycle of CRM1-dependent viruses, which contributes to the understanding of the antiviral and anti-inflammatory properties of this multifaceted immuno-metabolite.IMPORTANCEItaconate derivates, as well as the naturally produced metabolite, have been proposed as antivirals against influenza virus. Here, the mechanism behind the antiviral effects of exogenous 4-octyl itaconate (4-OI), a derivative of itaconate, against the influenza A virus replication is demonstrated. The data indicate that 4-OI targets the cysteine at position 528 of the CRM1 protein, resulting in inhibition of the nuclear export of viral ribonucleoprotein complexes in a similar manner as previously described for other selective inhibitors of nuclear export. These results postulate a mechanism not observed before for this immuno-metabolite derivative. This knowledge is helpful for the development of derivatives of 4-OI as potential antiviral and anti-inflammatory therapeutics.

Keywords:  4-OI; CRM1; antiviral; influenza virus; itaconate

DOI:  https://doi.org/10.1128/jvi.01325-23
Int Immunopharmacol. 2023 Oct 10. pii: S1567-5769(23)01349-8. [Epub ahead of print]124(Pt B): 111024

Berberine ameliorates collagen-induced arthritis in mice by restoring macrophage polarization via AMPK/mTORC1 pathway switching glycolytic reprogramming.

Jing-Wen Cheng, Yun Yu, Shi-Ye Zong, Wei-Wei Cai, Ying Wang, Yi-Ning Song, Hao Xian, Fang Wei.

  Dysfunction of macrophage polarization majorly contributes to the progression of rheumatoid arthritis (RA). Polarization and functions of activated macrophages are closely associated with the reprogramming of intracellular metabolisms. Previously, we demonstrated that the anti-arthritis effect of berberine (BBR) in rats with adjuvant-induced arthritis (AA) may be related to AMP-activated protein kinase (AMPK) activation (a key regulator in the biological energy metabolism), and balanced macrophage polarization. However, the specific molecular mechanism of BBR in macrophage metabolism is yet to be elucidated. In this study, we clarified that BBR ameliorated articular inflammation and restored M1/M2 ratio in collagen-induced arthritis (CIA) mice in an AMPK-dependent manner. Mechanistically, BBR reversed the effects of mTORC1 agonist leucine (Leu) on regulating macrophage polarization through activation of AMPK to switch glycolytic reprogramming. Furthermore, BBR inhibition of mTORC1 rely on activation of AMPK to phosphorylate raptor and TSC2 instead of destroying its structure. Our study revealed that the activation of AMPK is required for the BBR-mediated anti-arthritis effect by downregulating mTORC1/HIF-1α and inhibiting the glycolysis in M1 macrophages.

Keywords:  AMPK; Berberine; Collagen-induced arthritis; Glycolysis; Macrophage polarization; mTORC1

DOI:  https://doi.org/10.1016/j.intimp.2023.111024
Amino Acids. 2023 Oct 09.

Common pathogenic bacteria-induced reprogramming of the host proteinogenic amino acids metabolism.

Xiao-Yue Li, Zi-Xin Zeng, Zhi-Xing Cheng, Yi-Lin Wang, Liang-Jun Yuan, Zhi-Yong Zhai, Wei Gong.

  Apart from cancer, metabolic reprogramming is also prevalent in other diseases, such as bacterial infections. Bacterial infections can affect a variety of cells, tissues, organs, and bodies, leading to a series of clinical diseases. Common Pathogenic bacteria include Helicobacter pylori, Salmonella enterica, Mycobacterium tuberculosis, Staphylococcus aureus, and so on. Amino acids are important and essential nutrients in bacterial physiology and support not only their proliferation but also their evasion of host immune defenses. Many pathogenic bacteria or opportunistic pathogens infect the host and lead to significant changes in metabolites, especially the proteinogenic amino acids, to inhibit the host's immune mechanism to achieve its immune evasion and pathogenicity. Here, we review the regulation of host metabolism, while host cells are infected by some common pathogenic bacteria, and discuss how amino acids of metabolic reprogramming affect bacterial infections, revealing the potential adjunctive application of amino acids alongside antibiotics.

Keywords:  Amino acids; Bacterial infections; Metabolic reprogramming; Nutrition

DOI:  https://doi.org/10.1007/s00726-023-03334-w
bioRxiv. 2023 Sep 26. pii: 2023.09.25.559385. [Epub ahead of print]

Activation-induced shift in nutrient preference and function-specific nutrient dependence in human neutrophils.

Emily C Britt, Xin Qing, James A Votava, Jorgo Lika, Andrew Wagner, Simone Shen, Nicholas L Arp, Hamidullah Khan, Stefan M Schieke, Christopher D Fletcher, Anna Huttenlocher, Jing Fan.

Neutrophils are the first responders in innate immunity. Neutrophils can perform a variety of effector functions which are associated with specific metabolic demand. The utilization of various metabolic sources, including extracellular glucose, intracellular glycogen, and other alternative substrates, have been found critical for neutrophil fitness and functions in recent studies. However, the quantitative contribution of these nutrients under specific conditions and the relative dependence of various cell functions on specific nutrients remain unclear. Here using ex vivo and in vivo isotopic tracing, we revealed that under resting condition, human peripheral blood neutrophils, in contrast to in vitro cultured human neutrophil-like cell lines, rely on glycogen as a major direct source of glycolysis and pentose phosphate pathway. Extracellular glucose contributes slightly less than half, and other sources have minor contributions. Upon activation with a diversity of stimuli (including zymosan A, TNFα, PMA, LPS, or Pseudomonas aeruginosa ), neutrophils undergo a significant nutrient preference shift, with glucose becoming the dominant metabolic source. The shift to glucose utilization is often rapid and driven by multi-fold increases in glucose uptake, which is mechanistically mediated by the phosphorylation and translocation of GLUT1. At the same time, cycling between gross glycogenesis and glycogenolysis is also substantially increased, while the net flux favors sustained or increased glycogen storage. Different effector functions of activated neutrophils have specific nutrient dependence. The oxidative burst is most dependent on extracellular glucose, while the release of neutrophil extracellular traps can be flexibly supported by either glucose or glycogen utilization. Shifting neutrophil away from glycogen utilization increases migration and fungal control. Together, these results quantitatively characterize fundamental features of neutrophil metabolism and elucidate how metabolic remodeling supports and shapes neutrophil functions upon activation.

DOI: https://doi.org/10.1101/2023.09.25.559385
Hepatol Int. 2023 Oct 12.

Distinctly altered lipid components in hepatocellular carcinoma relate to impaired T cell-dependent antitumor immunity.

Xue Cheng, Wei Wang, Ziyao Zhang, Haoquan Zhang, Peng Zhu, Ran He, Mi Wu, Ting Zhou, Ying Jiang, Lang Jiang, Yiqing Chen, Zhihui Liang, Xiongwen Wu, Xiufang Weng.

  BACKGROUND AND AIMS: T cells are master effectors of anti-tumor immunity in cancer. Recent studies suggest that altered lipid metabolism imposed by the tumor microenvironment constrains anti-tumor immunity. However, the tumor-associated lipid species changes that dampen T cell ability to control tumor progression are not fully understood. Here, we plan to clarify the influences of distinctly altered lipid components in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) on T-cell function, aiming to seek lipid metabolic targets for improving T cell anti-tumor effects.METHODS: Tumor tissues and non-tumor liver from HCC patients were collected for RNA-sequencing, lipid profiling and T cell characterizing, followed by correlation analysis. Additionally, the effects of significantly changed lipid components on anti-tumor potential of T cells were tested by in vitro cell experiments and/or in vivo tumor inoculated model.
RESULTS: Altered lipid metabolism coincides with impaired T cell response in HBV-related HCC. Characteristic lipid composition, significantly marked by accumulation of long-chain acylcarnitines (LCACs) and reduction of lysophosphatidylcholines (LPCs), are found in the tumor tissue. Notably, LCACs accumulated are associated with T cells exhaustion and deficient functionality, while LPCs correlate to anti-tumor effects of T cells. In particular, supplement of LPCs, including LPC (20:0) and LPC (22:0), directly promote the activation and IFN-γ secretion of T cells in vitro, and suppress tumor growth in vivo.
CONCLUSIONS: Our study highlights the distinctly changed lipid components closely related to T cell dysregulation in HCC, and suggests a promising strategy by decreasing LCACs and increasing LPCs for anti-tumor immunotherapy.

Keywords:  Anti-tumor immunity; Deficient functionality; Hepatocellular carcinoma; IFN-γ secretion; Lipid metabolism; Long-chain acylcarnitines; Lysophosphatidylcholines; T cells exhaustion; Tumor metabolic microenvironment; Tumor-infiltrated T cells

DOI:  https://doi.org/10.1007/s12072-023-10595-w
Front Immunol. 2023 ;14 905467

Immunometabolic regulation during the presence of microorganisms and parasitoids in insects.

Shirong Li, Jing Wang, Xing Tian, Shahzad Toufeeq, Wuren Huang.

  Multicellular organisms live in environments containing diverse nutrients and a wide variety of microbial communities. On the one hand, the immune response of organisms can protect from the intrusion of exogenous microorganisms. On the other hand, the dynamic coordination of anabolism and catabolism of organisms is a necessary factor for growth and reproduction. Since the production of an immune response is an energy-intensive process, the activation of immune cells is accompanied by metabolic transformations that enable the rapid production of ATP and new biomolecules. In insects, the coordination of immunity and metabolism is the basis for insects to cope with environmental challenges and ensure normal growth, development and reproduction. During the activation of insect immune tissues by pathogenic microorganisms, not only the utilization of organic resources can be enhanced, but also the activated immune cells can usurp the nutrients of non-immune tissues by generating signals. At the same time, insects also have symbiotic bacteria in their body, which can affect insect physiology through immune-metabolic regulation. This paper reviews the research progress of insect immune-metabolism regulation from the perspective of insect tissues, such as fat body, gut and hemocytes. The effects of microorganisms (pathogenic bacteria/non-pathogenic bacteria) and parasitoids on immune-metabolism were elaborated here, which provide guidance to uncover immunometabolism mechanisms in insects and mammals. This work also provides insights to utilize immune-metabolism for the formulation of pest control strategies.

Keywords:  Drosophila; IMD/Toll; immunometabolism; insects; insulin signaling; pathogenic; symbiotic bacteria

DOI:  https://doi.org/10.3389/fimmu.2023.905467
Hepatol Commun. 2023 11 01. pii: e0294. [Epub ahead of print]7(11):

HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation.

Jiaxin Bei, Ye Chen, Qianbing Zhang, Xiaobin Wang, Liteng Lin, Jingjun Huang, Wensou Huang, Mingyue Cai, Weiguo Cai, Yongjian Guo, Kangshun Zhu.

BACKGROUND: It is now understood that HBV can induce innate and adaptive immune response disorders by affecting immunosuppressive macrophages, resulting in chronic HBV infection. However, the underlying mechanism is not fully understood. Dysregulated protein acetylation can reportedly influence the differentiation and functions of innate immune cells by coordinating metabolic signaling. This study aims to assess whether HBV suppresses macrophage-mediated innate immune responses by affecting protein acetylation and to elucidate the underlying mechanisms of HBV immune escape.METHODS: We investigated the effect of HBV on the acetylation levels of human THP-1 macrophages and identified potential targets of acetylation that play a role in glucose metabolism. Metabolic and immune phenotypes of macrophages were analyzed using metabolomic and flow cytometry techniques. Western blot, immunoprecipitation, and immunofluorescence were performed to measure the interactions between deacetylase and acetylated targets. Chronic HBV persistent infected mice were established to evaluate the role of activating the tricarboxylic acid (TCA) cycle in macrophages for HBV clearance.
RESULTS: Citrate synthase/pyruvate dehydrogenase complex hyperacetylation in macrophages after HBV stimulation inhibited their enzymatic activities and was associated with impaired TCA cycle and M2-like polarization. HBV downregulated Sirtuin 3 (SIRT3) expression in macrophages by means of the toll-like receptor 2 (TLR2)-NF-κB- peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α) axis, resulting in citrate synthase/pyruvate dehydrogenase complex hyperacetylation. In vivo administration of the TCA cycle agonist dichloroacetate inhibited macrophage M2-like polarization and effectively reduced the number of serum HBV DNA copies.
CONCLUSIONS: HBV-induced citrate synthase/pyruvate dehydrogenase complex hyperacetylation negatively modulates the innate immune response by impairing the TCA cycle of macrophages. This mechanism represents a potential therapeutic target for controlling HBV infection.

DOI: https://doi.org/10.1097/HC9.0000000000000294
bioRxiv. 2023 Sep 25. pii: 2023.09.23.559091. [Epub ahead of print]

Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose.

Golda Gross, Suha Alkadieri, Amilia Meir, Orit Itzhaki, Yarden Aharony-Tevet, Shahar Ben Yosef, Angi Zenab, Liat Shbiro, Amos Toren, Tal Yardeni, Elad Jacoby.

CD19 CAR-T cells have led to durable remissions in patients with refractory B-cell malignancies; nevertheless, most patients eventually relapse in the long term. Many interventions aimed at improving current products have been reported, with a subset of them focusing on a direct or indirect link to the metabolic state of the CAR-T cells. We assessed clinical products from an ongoing clinical trial utilizing CD19-28z CAR-T cells from patients with acute lymphoblastic leukemia. CAR-T clinical products leading to a complete response had significantly higher mitochondrial function (by oxygen consumption rate) irrespective of mitochondrial content. Next, we replaced the carbon source of the media from glucose to galactose to impact cellular metabolism. Galactose-containing media increased mitochondrial activity in CAR-T cells, and improved in vitro efficacy, without any consistent phenotypic change in memory profile. Finally, CAR-T cells produced in galactose-based glucose-free media resulted in increased mitochondrial activity. Using an in vivo model of Nalm6 injected mice, galactose-primed CAR-T cells significantly improved leukemia-free survival compared to standard glucose-cultured CAR-T cells. Our results prove the significance of mitochondrial metabolism on CAR-T cell efficacy and suggest a translational pathway to improve clinical products.

DOI: https://doi.org/10.1101/2023.09.23.559091
Front Cell Dev Biol. 2023 ;11 1266973

Succinate metabolism: a promising therapeutic target for inflammation, ischemia/reperfusion injury and cancer.

Wenhui Zhang, Ren Lang.

  Succinate serves as an essential circulating metabolite within the tricarboxylic acid (TCA) cycle and functions as a substrate for succinate dehydrogenase (SDH), thereby contributing to energy production in fundamental mitochondrial metabolic pathways. Aberrant changes in succinate concentrations have been associated with pathological states, including chronic inflammation, ischemia/reperfusion (IR) injury, and cancer, resulting from the exaggerated response of specific immune cells, thereby rendering it a central area of investigation. Recent studies have elucidated the pivotal involvement of succinate and SDH in immunity beyond metabolic processes, particularly in the context of cancer. Current scientific endeavors are concentrated on comprehending the functional repercussions of metabolic modifications, specifically pertaining to succinate and SDH, in immune cells operating within a hypoxic milieu. The efficacy of targeting succinate and SDH alterations to manipulate immune cell functions in hypoxia-related diseases have been demonstrated. Consequently, a comprehensive understanding of succinate's role in metabolism and the regulation of SDH is crucial for effectively targeting succinate and SDH as therapeutic interventions to influence the progression of specific diseases. This review provides a succinct overview of the latest advancements in comprehending the emerging functions of succinate and SDH in metabolic processes. Furthermore, it explores the involvement of succinate, an intermediary of the TCA cycle, in chronic inflammation, IR injury, and cancer, with particular emphasis on the mechanisms underlying succinate accumulation. This review critically assesses the potential of modulating succinate accumulation and metabolism within the hypoxic milieu as a means to combat various diseases. It explores potential targets for therapeutic interventions by focusing on succinate metabolism and the regulation of SDH in hypoxia-related disorders.

Keywords:  cancer; immune cells; inflammation; ischemia/reperfusion (IR) injury; succinate; succinate dehydrogenase (SDH)

DOI:  https://doi.org/10.3389/fcell.2023.1266973
bioRxiv. 2023 Sep 26. pii: 2023.09.25.559154. [Epub ahead of print]

Suppression of HIV and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters.

B Celia Cui, Marina Aksenova, Aliaksandra Sikirzhytskaya, Diana Odhiambo, Elizaveta Korunova, Vitali Sikirzhytski, Hao Ji, Diego Altomare, Eugenia Broude, Norma Frizzell, Rosemarie Booze, Michael D Wyatt, Michael Shtutman.

HIV-associated neurological disorder (HAND) is a serious complication of HIV infection, marked by neurotoxicity induced by viral proteins like Tat. Substance abuse exacerbates neurocognitive impairment in people living with HIV. There is an urgent need for effective therapeutic strategies to combat HAND comorbid with Cocaine Use Disorder (CUD). Our analysis of the HIV and cocaine-induced transcriptomes in primary cortical cultures revealed a significant overexpression of the macrophage-specific gene, aconitate decarboxylase 1 (Acod1), caused by the combined insults of HIV and cocaine. ACOD1 protein converts the tricarboxylic acid intermediate cis-aconitate into itaconate during the activation of inflammation. The itaconate produced facilitates cytokine production and subsequently activates anti-inflammatory transcription factors, shielding macrophages from infection-induced cell death. While the role of itaconate' in limiting inflammation has been studied in peripheral macrophages, its immunometabolic function remains unexplored in HIV and cocaine-exposed microglia. We assessed in this model system the potential of 4-octyl-itaconate (4OI), a cell-penetrable esterified form of itaconate known for its potent anti-inflammatory properties and potential therapeutic applications. We administered 4OI to primary cortical cultures exposed to Tat and cocaine. 4OI treatment increased the number of microglial cells in both untreated and Tat±Cocaine-treated cultures and also reversed the morphological altercations induced by Tat and cocaine. In the presence of 4OI, microglial cells also appeared more ramified, resembling the quiescent microglia. Consistent with these results, 4OI treatment inhibited the secretion of the proinflammatory cytokines IL-1α, IL-1β, IL-6, and MIP1-α induced by Tat and cocaine. Transcriptome profiling further determined that Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (Nqo1), Glutathione S-transferase Pi (Gstp1), and glutamate cysteine ligase catalytic (Gclc), were most significantly activated in Tat-4OI treated cultures, relative to Tat alone. Further, genes associated with cytoskeleton dynamics in inflammatory microglia were downregulated by 4OI treatment. Together, the results strongly suggest 4-octyl-itaconate holds promise as a potential candidate for therapeutic development aimed at addressing HAND coupled with CUD comorbidities.Abstract Figure:

DOI: https://doi.org/10.1101/2023.09.25.559154
Front Cell Dev Biol. 2023 ;11 1295264

Editorial: The connections of immune metabolic mechanisms with aging-related diseases.

Ozlem Tufanli, Mevlut Citir, Changjun Yin, Emiel P C Van der Vorst, Ismail Cimen.



Keywords:  aging-related diseases; immune cells; immunometabolism; metabolic mechanisms; metabolites

DOI:  https://doi.org/10.3389/fcell.2023.1295264
mBio. 2023 Oct 10. e0211723

Host cell sensing and restoration of mitochondrial function and metabolism within Helicobacter pylori VacA intoxicated cells.

Ami Y Seeger, Faisal Zaidi, Sammy Alhayek, Rachel M Jones, Huzaifa Zohair, Robin L Holland, Ik-Jung Kim, Steven R Blanke.

  Helicobacter pylori vacuolating cytotoxin A (VacA) is an intracellular-acting protein exotoxin that induces mitochondrial dysfunction and energy depletion within host cells. Although exposure to VacA results in mitochondrial dysfunction, one recent study revealed that, following limited exposure to VacA, mitochondrial function and cellular ATP levels were restored in a time-dependent manner. Studies performed to address the mechanism by which host cells detect and respond to intracellular VacA identified the adenosine monophosphate (AMP)-activated protein kinase (AMPK) as a sensor of toxin-dependent alterations in cellular energy status. Activation of AMPK in response to VacA was demonstrated to orchestrate alterations in mitochondrial dynamics which resulted in restoration of mitochondrial function. Specifically, upregulation of dynamin-related protein 1 (Drp-1)-dependent mitochondrial fission resulted in reversible fragmentation of filamentous mitochondria and time-dependent reduction in mitochondrial-associated VacA, suggesting that fragmentation is important for removal of VacA from mitochondria. Cells with reduced levels of Drp-1 were more susceptible to VacA-dependent cell death, suggesting that mitochondrial dynamics is important for maintaining cell viability through the reduction in mitochondrial-associated toxin. Collectively, these studies support a model that cellular recovery and survival in response to VacA-dependent mitochondrial dysfunction is linked to host cell modulation of mitochondrial dynamics. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies. IMPORTANCE Persistent human gastric infection with Helicobacter pylori is the single most important risk factor for development of gastric malignancy, which is one of the leading causes of cancer-related deaths worldwide. An important virulence factor for Hp colonization and severity of gastric disease is the protein exotoxin VacA, which is secreted by the bacterium and modulates functional properties of gastric cells. VacA acts by damaging mitochondria, which impairs host cell metabolism through impairment of energy production. Here, we demonstrate that intoxicated cells have the capacity to detect VacA-mediated damage, and orchestrate the repair of mitochondrial function, thereby restoring cellular health and vitality. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies.

Keywords:  AMPK; Helicobacter pylori; VacA; dynamin-related protein 1; mitochondrial depolarization; mitochondrial dynamics; mitochondrial dysfunction; proton motive force; transmembrane potential; vacuolating cytotoxin

DOI:  https://doi.org/10.1128/mbio.02117-23
Biochem Biophys Rep. 2023 Dec;36 101542

Exosomes released from PD-L1+ tumor associated macrophages promote peritoneal metastasis of epithelial ovarian cancer by up-regulating T cell lipid metabolism.

Jun Ma, Qianqian Cen, Qingzhu Wang, Li Liu, Jieru Zhou.

  Epithelial ovarian cancer (EOC) tends to metastasize to the peritoneum, and the prognosis of patients is poor. In the peritoneum of patients with EOC, TAMs (tumor associated macrophages) regulate the imbalance of T cell ratio and promote the progression and metastasis of EOC. However, the mechanism of peritoneal metastasis in EOC patients remains unclear. Here, we confirmed that the percentages of PD-L1+ TAMs in EOC tissues increased significantly, and TAMs-derived PD-L1+ exosomes affected the transcription factor PPARα to up-regulate the expression of CPT1A in CD8+ T cells, promote fatty acid oxidation, and increase reactive oxygen species to cause cell damage. The apoptosis of CD8+ T cells was increased, and the expressions of their exhaustion markers LAG3, TIM-3, and PD-1 were also up-regulated. TAMs affect T cell function through lipid metabolism, leading to peritoneal immune imbalance and promoting peritoneal metastasis of EOC. This study reveals the mechanism by which TAMs in the peritoneal microenvironment regulate T cell lipid metabolism through exosome delivery of PD-L1, and the effect of lipid metabolism on T cell function, reveals the molecular mechanism of tumor immune microenvironment affecting EOC metastasis, and further explores related pathways whether molecular blockade can be used as a means to intervene in disease progression is expected to establish a new strategy for the diagnosis and treatment of EOC.

Keywords:  CD8+ T cells; Epithelial ovarian cancer; PD-L1; Peritoneal metastasis; Tumor associated macrophages

DOI:  https://doi.org/10.1016/j.bbrep.2023.101542
bioRxiv. 2023 Sep 28. pii: 2023.09.27.559756. [Epub ahead of print]

Inhibiting Glutamine Metabolism Blocks Coronavirus Replication in Mammalian Cells.

Kai Su Greene, Annette Choi, Matthew Chen, Nianhui Yang, Ruizhi Li, Yijian Qiu, Michael J Lukey, Katherine S Rojas, Jonathan Shen, Kristin F Wilson, William P Katt, Gary R Whittaker, Richard A Cerione.

Developing therapeutic strategies against COVID-19 has gained widespread interest given the likelihood that new viral variants will continue to emerge. Here we describe one potential therapeutic strategy which involves targeting members of the glutaminase family of mitochondrial metabolic enzymes (GLS and GLS2), which catalyze the first step in glutamine metabolism, the hydrolysis of glutamine to glutamate. We show three examples where GLS expression increases during coronavirus infection of host cells, and another in which GLS2 is upregulated. The viruses hijack the metabolic machinery responsible for glutamine metabolism to generate the building blocks for biosynthetic processes and satisfy the bioenergetic requirements demanded by the 'glutamine addiction' of virus-infected host cells. We demonstrate how genetic silencing of glutaminase enzymes reduces coronavirus infection and that newer members of two classes of small molecule allosteric inhibitors targeting these enzymes, designated as SU1, a pan-GLS/GLS2 inhibitor, and UP4, which is specific for GLS, block viral replication in mammalian epithelial cells. Overall, these findings highlight the importance of glutamine metabolism for coronavirus replication in human cells and show that glutaminase inhibitors can block coronavirus infection and thereby may represent a novel class of anti-viral drug candidates.Teaser: Inhibitors targeting glutaminase enzymes block coronavirus replication and may represent a new class of anti-viral drugs.

DOI: https://doi.org/10.1101/2023.09.27.559756
J Invest Dermatol. 2023 Oct 11. pii: S0022-202X(23)02924-X. [Epub ahead of print]

Inhibition of mitochondrial translation ameliorates Imiquimod-induced psoriasis-like skin inflammation by targeting Vγ4+ γδ T cells.

Ayesha Dhillon-LaBrooy, Kathrin L Braband, Eshraq Tantawy, Francesca Rampoldi, Yu-San Kao, Fatima Boukhallouk, Lis Noelia Velasquez, Panagiota Mamareli, Luana Silva, Luis Eduardo Alves Damasceno, Beate Weidenthaler-Barth, Luciana Berod, Luís Almeida, Tim Sparwasser.

  Psoriasis is an inflammatory skin disorder that is characterised by keratinocyte hyperproliferation in response to immune cell infiltration and cytokine secretion in the dermis. γδ T cells expressing the Vγ4 TCR chain are amongst the highest contributors of IL-17A, which is a major cytokine that drives a psoriasis flare, making Vγ4+ γδ T cells a suitable target to restrict psoriasis progression. Here we demonstrate that mitochondrial translation inhibition within Vγ4+ γδ T cells effectively reduced erythema, scaling, and skin thickening in a murine model of psoriatic disease. The antibiotic Linezolid, which blocks mitochondrial translation, inhibited the production of mitochondrial-encoded protein cytochrome c oxidase in Vγ4+ γδ T cells and systemically reduced the frequencies of IL-17A+ Vγ4+ γδ T cells, effectively resolving IL-17A-dependent inflammation. Inhibiting mitochondrial translation could be a novel metabolic approach to interrupt IL-17A signalling in Vγ4+ T cells and reduce psoriasis-like skin pathophysiology.

Keywords:  Antibiotics; Imiquimod; Linezolid; Mitochondria; Psoriasis

DOI:  https://doi.org/10.1016/j.jid.2023.09.275
PLoS Pathog. 2023 Oct 09. 19(10): e1011679

Cellular iron governs the host response to malaria.

Sarah K Wideman, Joe N Frost, Felix C Richter, Caitlin Naylor, José M Lopes, Nicole Viveiros, Megan R Teh, Alexandra E Preston, Natasha White, Shamsideen Yusuf, Simon J Draper, Andrew E Armitage, Tiago L Duarte, Hal Drakesmith.

Malaria and iron deficiency are major global health problems with extensive epidemiological overlap. Iron deficiency-induced anaemia can protect the host from malaria by limiting parasite growth. On the other hand, iron deficiency can significantly disrupt immune cell function. However, the impact of host cell iron scarcity beyond anaemia remains elusive in malaria. To address this, we employed a transgenic mouse model carrying a mutation in the transferrin receptor (TfrcY20H/Y20H), which limits the ability of cells to internalise iron from plasma. At homeostasis TfrcY20H/Y20H mice appear healthy and are not anaemic. However, TfrcY20H/Y20H mice infected with Plasmodium chabaudi chabaudi AS showed significantly higher peak parasitaemia and body weight loss. We found that TfrcY20H/Y20H mice displayed a similar trajectory of malaria-induced anaemia as wild-type mice, and elevated circulating iron did not increase peak parasitaemia. Instead, P. chabaudi infected TfrcY20H/Y20H mice had an impaired innate and adaptive immune response, marked by decreased cell proliferation and cytokine production. Moreover, we demonstrated that these immune cell impairments were cell-intrinsic, as ex vivo iron supplementation fully recovered CD4+ T cell and B cell function. Despite the inhibited immune response and increased parasitaemia, TfrcY20H/Y20H mice displayed mitigated liver damage, characterised by decreased parasite sequestration in the liver and an attenuated hepatic immune response. Together, these results show that host cell iron scarcity inhibits the immune response but prevents excessive hepatic tissue damage during malaria infection. These divergent effects shed light on the role of iron in the complex balance between protection and pathology in malaria.

DOI: https://doi.org/10.1371/journal.ppat.1011679
J Transl Med. 2023 Oct 12. 21(1): 715

Myeloid PTP1B deficiency protects against atherosclerosis by improving cholesterol homeostasis through an AMPK-dependent mechanism.

Helk Oliver, Dekeryte Ruta, Dawn Thompson, Sarah Kamli-Salino, Sam Philip, Heather M Wilson, Nimesh Mody, Mirela Delibegovic.

  OBJECTIVE: Atherosclerosis is a chronic inflammatory process induced by the influx and entrapment of excess lipoproteins into the intima media of arteries. Previously, our lab demonstrated that systemic PTP1B inhibition protects against atherosclerosis in preclinical LDLR-/- models. Similarly, it was shown that myeloid-specific PTP1B ablation decreases plaque formation and ameliorates dyslipidaemia in the ApoE-/- model of atherosclerosis. We hypothesized that the relevant improvements in dyslipidaemia following modification of PTP1B activation may either result from changes in hepatic cholesterol biosynthesis and/or increased uptake and degradation by liver-resident macrophages. We examined this in animal models and patients with coronary artery disease.METHODS: In this study, we determined the cholesterol-lowering effect of myeloid-PTP1B deletion in mice fed a high-fat high-cholesterol diet and examined effects on total cholesterol levels and lipoprotein profiles. We also determined the effects of PTP1B inhibition to oxLDL-C challenge on foam cell formation and cholesterol efflux in human monocytes/macrophages.
RESULTS: We present evidence that myeloid-PTP1B deficiency significantly increases the affinity of Kupffer cells for ApoB containing lipoproteins, in an IL10-dependent manner. We also demonstrate that PTP1B inhibitor, MSI-1436, treatment decreased foam cell formation in Thp1-derived macrophages and increased macrophage cholesterol efflux to HDL in an AMPK-dependent manner. We present evidence of three novel and distinct mechanisms regulated by PTP1B: an increase in cholesterol efflux from foam cells, decreased uptake of lipoproteins into intra-lesion macrophages in vitro and a decrease of circulating LDL-C and VLDL-C in vivo.
CONCLUSIONS: Overall, these results suggest that myeloid-PTP1B inhibition has atheroprotective effects through improved cholesterol handling in atherosclerotic lesions, as well as increased reverse cholesterol transport. Trial registration Research registry, researchregistry 3235. Registered 07 November 2017, https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5a01d0fce7e1904e93e0aac5/ .

Keywords:  Atherosclerosis; Cholesterol metabolism; Myeloid cells; PTP1B

DOI:  https://doi.org/10.1186/s12967-023-04598-2
Cell Death Dis. 2023 10 09. 14(10): 656

Polyphenol-rich diet mediates interplay between macrophage-neutrophil and gut microbiota to alleviate intestinal inflammation.

Dandan Han, Yujun Wu, Dongdong Lu, Jiaman Pang, Jie Hu, Xiangyu Zhang, Zhenyu Wang, Guolong Zhang, Junjun Wang.

Dietary phenolic acids alleviate intestinal inflammation through altering gut microbiota composition and regulating macrophage activation. However, it is unclear how individual phenolic acids affect the interactions between intestinal microbiota and macrophages in the context of inflammatory bowel disease (IBD). Here, we aim to elucidate the mechanism by which phenolic acids alleviate gut inflammation. Mice with or without depletion of macrophages were administered with four individual phenolic acids including chlorogenic, ferulic, caffeic, and ellagic acids, following dextran sulfate sodium (DSS) treatment. Gut microbiota depletion and fecal microbiota transplantation were further performed in mice to investigate the role of the gut microbiota in phenolic acid-mediated protective effect. Colitis severity was evaluated using histological, serological, and immunological measurements. Absence of intestinal microbiota and macrophage deteriorate the epithelial injury in DSS colitis. Chlorogenic acid mitigated colitis by reducing M1 macrophage polarization through suppression of pyruvate kinase M 2 (Pkm2)-dependent glycolysis and inhibition of NOD-like receptor protein 3 (Nlrp3) activation. However, ferulic acid-mediated reduction of colitis was neutrophil-dependent through diminishing the formation of neutrophil extracellular traps. On the other hand, the beneficial effects of caffeic acid and ellagic acid were dependent upon the gut microbiota. In fact, urolithin A (UroA), a metabolite transformed from ellagic acid by the gut microbiota, was found to alleviate colitis and enhance gut barrier function in an IL22-dependent manner. Overall, our findings demonstrated that the mechanisms by which phenolic acid protected against colitis were resulted from the interaction between gut microbiota and macrophage-neutrophil.

DOI: https://doi.org/10.1038/s41419-023-06190-4
Int Immunopharmacol. 2023 Oct 04. pii: S1567-5769(23)01326-7. [Epub ahead of print]124(Pt B): 111001

The metabolite butyrate produced by gut microbiota inhibits cachexia-associated skeletal muscle atrophy by regulating intestinal barrier function and macrophage polarization.

Hao Liu, Qiulei Xi, Shanjun Tan, Yidan Qu, Qingyang Meng, Yanni Zhang, Yuxi Cheng, Guohao Wu.

  OBJECTIVE: Cachexia, marked by muscle atrophy, poses substantial challenges for prevention and treatment. This study delves into the unclear role of butyrate, a gut microbiota metabolite, in cachexia by examining gut microbiota and short-chain fatty acid (SCFA) profiles in human and mouse fecal samples.METHODS: We analyzed cachexia-associated gut microbiota and SCFA profiles using 16S rRNA sequencing and metabolomic techniques. Mouse cachexia models were developed with C26 cells, and LPS was used to induce muscle cell atrophy in C2C12 cells. We evaluated butyrate's in vivo effects on intestinal health, muscle preservation, inflammation, and macrophage activity. In vitro studies focused on butyrate's influence on macrophage polarization and the subsequent effects on muscle cells.
RESULTS: Both cachexia patients and mice exhibited gut microbiota imbalances, irregular butyrate concentrations, and a decline in butyrate-producing bacteria. In vivo tests showed that butyrate counteract cachexia-induced muscle atrophy by adjusting the Akt/mTOR/Foxo3a and Fbox32/Trim63 pathways. These butyrate also bolstered intestinal barrier integrity, minimized endotoxin migration, and mitigated oxidative stress. Furthermore, butyrate curtailed inflammation and macrophage penetration in muscles. In vitro experimental results demonstrate that butyrate inhibit macrophage polarization towards the M1 phenotype and promote polarization towards the M2 phenotype. Both M1 and M2 macrophages influence the aforementioned pathways and oxidative stress, participating in the regulation of muscle cell atrophy.
CONCLUSION: Our study delineates the intricate interplay between gut microbiota dysbiosis, butyrate fluctuations, and cachexia progression. Butyrate not only reinforces the intestinal barrier but also orchestrates macrophage polarization, mitigating muscle atrophy and averting cachexia-induced muscle deterioration. Concurrently, the M1 and M2 macrophages play pivotal roles in modulating skeletal muscle cell atrophy. This highlights the potential of utilizing the gut-derived metabolite butyrate as a promising therapeutic approach for addressing cachexia-related issues.

Keywords:  Butyrate; Cachexia; Gut microbiota; Macrophages; Muscle atrophy

DOI:  https://doi.org/10.1016/j.intimp.2023.111001
iScience. 2023 Oct 20. 26(10): 107997

15-keto-PGE2 alleviates nonalcoholic steatohepatitis through its covalent modification of NF-κB factors.

Siow-Wey Hee, Yi-Cheng Chang, Lynn Su, Ing-Jung Chen, Yung-Ming Jeng, Meng-Lun Hsieh, Yu-Chia Chang, Fu-An Li, Daniel Liao, Shiau-Mei Chen, Lee-Ming Chuang.

  15-keto-PGE2 is one of the eicosanoids with anti-inflammatory properties. In this study, we demonstrated that 15-keto-PGE2 post-translationally modified the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) subunits p105/p50 and p65 at Cys59 and Cys120 sites, respectively, hence inhibiting the activation of NF-κB signaling in macrophages. In mice fed a high-fat and high-sucrose diet (HFHSD), 15-keto-PGE2 treatment reduced pro-inflammatory cytokines and fasting glucose levels. In mice with non-alcoholic steatohepatitis (NASH) induced by a prolonged HFHSD, 15-keto-PGE2 treatment significantly decreased liver inflammation, lowered serum levels of alanine transaminase (ALT) and aspartate transferase (AST), and inhibited macrophage infiltration. It also reduced lipid droplet size and downregulated key regulators of lipogenesis. These findings highlight the potential of 15-keto-PGE2, through NF-κB modification, in preventing the development and progression of steatohepatitis, emphasizing the significance of endogenous lipid mediators in the inflammatory response.

Keywords:  Cognitive neuroscience; Machine learning

DOI:  https://doi.org/10.1016/j.isci.2023.107997