bims-imicid 2023-04-16 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒04‒16
27 papers selected by
Dylan Ryan
University of Cambridge

CD8+ T cells promote HIV latency by remodeling CD4+ T cell metabolism to enhance their survival, quiescence, and stemness.
Cell-Intrinsic CD38 Expression Sustains Exhausted CD8+ T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection.
Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2.
Metabolism in type 2 immune responses.
T regulatory cells metabolism: The influence on functional properties and treatment potential.
Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer.
NOX4-TIM23 interaction regulates NOX4 mitochondrial import and metabolic reprogramming.
Lipid metabolism in Th17 cell function.
Metabolic challenges and interventions in CAR T cell therapy.
Maternal diet alters long-term innate immune cell memory in fetal and juvenile hematopoietic stem and progenitor cells in nonhuman primate offspring.
Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity.
Optimal LC-MS metabolomic profiling reveals emergent changes to monocyte metabolism in response to lipopolysaccharide.
Identification and Characterization of Alveolar and Recruited Lung Macrophages during Acute Lung Inflammation.
Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages.
Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors.
Metabolic Factors at the Crossroads of Periparturient Immunity and Inflammation.
A Mycobacterium tuberculosis Effector Targets Mitochondrion, Controls Energy Metabolism, and Limits Cytochrome c Exit.
Pulmonary Immune Response Regulation, Genotoxicity, and Metabolic Reprogramming by Menthol and Tobacco Flavored E-Cigarette Exposures in Mice.
mleS in Staphylococcus aureus Contributes to Microaerobic Metabolic Activity, Abscess Formation, and Survival in Macrophages.
Complementary gene regulation by NRF1 and NRF2 protects against hepatic cholesterol overload.
IRG1/Itaconate induces metabolic reprogramming to suppress ER-positive breast cancer cell growth.
Single-cell RNA sequencing reveals XBP1-SLC38A2 axis as a metabolic regulator in cytotoxic T lymphocytes in multiple myeloma.
The nano-windmill exerts superior anti-inflammatory effects via reducing choline uptake to inhibit macrophage activation.
Rab26 promotes macrophage phagocytosis through regulation of MFN2 trafficking to mitochondria.
Immunometabolism at the basis of health and disease; an editorial.
Regulating T-cell metabolic reprogramming and blocking PD-1 co-promote personalized postoperative autologous nanovaccines.
Modulation of Dietary Fatty Acids in an Open-Label Study Improves Psoriasis and Dampens the Inflammatory Activation Status.

Immunity. 2023 Mar 29. pii: S1074-7613(23)00130-9. [Epub ahead of print]

CD8+ T cells promote HIV latency by remodeling CD4+ T cell metabolism to enhance their survival, quiescence, and stemness.

Simona Mutascio, Talia Mota, Lavinia Franchitti, Ashish A Sharma, Abigail Willemse, Sydney N Bergstresser, Hong Wang, Maura Statzu, Gregory K Tharp, Jared Weiler, Rafick-Pierre Sékaly, Steven E Bosinger, Mirko Paiardini, Guido Silvestri, R Brad Jones, Deanna A Kulpa.

  HIV infection persists during antiretroviral therapy (ART) due to a reservoir of latently infected cells that harbor replication-competent virus and evade immunity. Previous ex vivo studies suggested that CD8+ T cells from people with HIV may suppress HIV expression via non-cytolytic mechanisms, but the mechanisms responsible for this effect remain unclear. Here, we used a primary cell-based in vitro latency model and demonstrated that co-culture of autologous activated CD8+ T cells with HIV-infected memory CD4+ T cells promoted specific changes in metabolic and/or signaling pathways resulting in increased CD4+ T cell survival, quiescence, and stemness. Collectively, these pathways negatively regulated HIV expression and ultimately promoted the establishment of latency. As shown previously, we observed that macrophages, but not B cells, promoted latency in CD4+ T cells. The identification of CD8-specific mechanisms of pro-latency activity may favor the development of approaches to eliminate the viral reservoir in people with HIV.

Keywords:  CD8 T cells; CD8 suppression; HIV; HIV cure; HIV latency; HIV reservoir; T cell biology

DOI:  https://doi.org/10.1016/j.immuni.2023.03.010
J Virol. 2023 Apr 11. e0022523

Cell-Intrinsic CD38 Expression Sustains Exhausted CD8+ T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection.

Julia M DeRogatis, Emily N Neubert, Karla M Viramontes, Monique L Henriquez, Dequina A Nicholas, Roberto Tinoco.

  Acute and chronic viral infections result in the differentiation of effector and exhausted T cells with functional and phenotypic differences that dictate whether the infection is cleared or progresses to chronicity. High CD38 expression has been observed on CD8+ T cells across various viral infections and tumors in patients, suggesting an important regulatory function for CD38 on responding T cells. Here, we show that CD38 expression was increased and sustained on exhausted CD8+ T cells following chronic lymphocytic choriomeningitis virus (LCMV) infection, with lower levels observed on T cells from acute LCMV infection. We uncovered a cell-intrinsic role for CD38 expression in regulating the survival of effector and exhausted CD8+ T cells. We observed increased proliferation and function of Cd38-/- CD8+ progenitor exhausted T cells compared to those of wild-type (WT) cells. Furthermore, decreased oxidative phosphorylation and glycolytic potential were observed in Cd38-/- CD8+ T cells during chronic but not acute LCMV infection. Our studies reveal that CD38 has a dual cell-intrinsic function in CD8+ T cells, where it decreases proliferation and function yet supports their survival and metabolism. These findings show that CD38 is not only a marker of T cell activation but also has regulatory functions on effector and exhausted CD8+ T cells. IMPORTANCE Our study shows how CD38 expression is regulated on CD8+ T cells responding during acute and chronic viral infection. We observed higher CD38 levels on CD8+ T cells during chronic viral infection compared to levels during acute viral infection. Deleting CD38 had an important cell-intrinsic function in ensuring the survival of virus-specific CD8+ T cells throughout the course of viral infection. We found defective metabolism in Cd38-/- CD8+ T cells arising during chronic infection and changes in their progenitor T cell phenotype. Our studies revealed a dual cell-intrinsic role for CD38 in limiting proliferation and granzyme B production in virus-specific exhausted T cells while also promoting their survival. These data highlight new avenues for research into the mechanisms through which CD38 regulates the survival and metabolism of CD8+ T cell responses to viral infections.

Keywords:  CD38; CD8+ T cell; LCMV; T cell exhaustion; T cells; chronic viral infection; effector T cell; metabolism

DOI:  https://doi.org/10.1128/jvi.00225-23
Nat Cell Biol. 2023 Apr;25(4): 592-603

Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2.

Haissi Cui, Jolene K Diedrich, Douglas C Wu, Justin J Lim, Ryan M Nottingham, James J Moresco, John R Yates, Benjamin J Blencowe, Alan M Lambowitz, Paul Schimmel.

Cells respond to perturbations such as inflammation by sensing changes in metabolite levels. Especially prominent is arginine, which has known connections to the inflammatory response. Aminoacyl-tRNA synthetases, enzymes that catalyse the first step of protein synthesis, can also mediate cell signalling. Here we show that depletion of arginine during inflammation decreased levels of nuclear-localized arginyl-tRNA synthetase (ArgRS). Surprisingly, we found that nuclear ArgRS interacts and co-localizes with serine/arginine repetitive matrix protein 2 (SRRM2), a spliceosomal and nuclear speckle protein, and that decreased levels of nuclear ArgRS correlated with changes in condensate-like nuclear trafficking of SRRM2 and splice-site usage in certain genes. These splice-site usage changes cumulated in the synthesis of different protein isoforms that altered cellular metabolism and peptide presentation to immune cells. Our findings uncover a mechanism whereby an aminoacyl-tRNA synthetase cognate to a key amino acid that is metabolically controlled during inflammation modulates the splicing machinery.

DOI: https://doi.org/10.1038/s41556-023-01118-8
Immunity. 2023 Apr 11. pii: S1074-7613(23)00127-9. [Epub ahead of print]56(4): 723-741

Metabolism in type 2 immune responses.

Agnieszka M Kabat, Erika L Pearce, Edward J Pearce.

The immune response is tailored to the environment in which it takes place. Immune cells sense and adapt to changes in their surroundings, and it is now appreciated that in addition to cytokines made by stromal and epithelial cells, metabolic cues provide key adaptation signals. Changes in immune cell activation states are linked to changes in cellular metabolism that support function. Furthermore, metabolites themselves can signal between as well as within cells. Here, we discuss recent progress in our understanding of how metabolic regulation relates to type 2 immunity firstly by considering specifics of metabolism within type 2 immune cells and secondly by stressing how type 2 immune cells are integrated more broadly into the metabolism of the organism as a whole.

DOI: https://doi.org/10.1016/j.immuni.2023.03.007
Front Immunol. 2023 ;14 1122063

T regulatory cells metabolism: The influence on functional properties and treatment potential.

Martyna Tomaszewicz, Anna Ronowska, Maciej Zieliński, Agnieszka Jankowska-Kulawy, Piotr Trzonkowski.

  CD4+CD25highFoxP3+ regulatory T cells (Tregs) constitute a small but substantial fraction of lymphocytes in the immune system. Tregs control inflammation associated with infections but also when it is improperly directed against its tissues or cells. The ability of Tregs to suppress (inhibit) the immune system is possible due to direct interactions with other cells but also in a paracrine fashion via the secretion of suppressive compounds. Today, attempts are made to use Tregs to treat autoimmune diseases, allergies, and rejection after bone marrow or organ transplantation. There is strong evidence that the metabolic program of Tregs is connected with the phenotype and function of these cells. A modulation towards a particular metabolic stage of Tregs may improve or weaken cells' stability and function. This may be an essential tool to drive the immune system keeping it activated during infections or suppressed when autoimmunity occurs.

Keywords:  adenosine; autoimmunity; fatty acid oxidation; glycolysis; ischemia; mTOR; metabolism; mitochondria

DOI:  https://doi.org/10.3389/fimmu.2023.1122063
Cancer Immunol Res. 2023 Apr 14. OF1-OF16

Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer.

Dominique C Hinshaw, Gloria A Benavides, Brandon J Metge, Courtney A Swain, Sarah C Kammerud, Heba A Alsheikh, Amr Elhamamsy, Dongquan Chen, Victor Darley-Usmar, Jeffrey C Rathmell, Robert S Welner, Rajeev S Samant, Lalita A Shevde.

The tumor immune microenvironment dynamically evolves to support tumor growth and progression. Immunosuppressive regulatory T cells (Treg) promote tumor growth and metastatic seeding in patients with breast cancer. Deregulation of plasticity between Treg and Th17 cells creates an immune regulatory framework that enables tumor progression. Here, we discovered a functional role for Hedgehog (Hh) signaling in promoting Treg differentiation and immunosuppressive activity, and when Hh activity was inhibited, Tregs adopted a Th17-like phenotype complemented by an enhanced inflammatory profile. Mechanistically, Hh signaling promoted O-GlcNAc modifications of critical Treg and Th17 transcription factors, Foxp3 and STAT3, respectively, that orchestrated this transition. Blocking Hh reprogramed Tregs metabolically, dampened their immunosuppressive activity, and supported their transdifferentiation into inflammatory Th17 cells that enhanced the recruitment of cytotoxic CD8+ T cells into tumors. Our results demonstrate a previously unknown role for Hh signaling in the regulation of Treg differentiation and activity and the switch between Tregs and Th17 cells in the tumor microenvironment.

DOI: https://doi.org/10.1158/2326-6066.CIR-22-0426
J Biol Chem. 2023 Apr 10. pii: S0021-9258(23)00337-X. [Epub ahead of print] 104695

NOX4-TIM23 interaction regulates NOX4 mitochondrial import and metabolic reprogramming.

Jyotsana Pandey, Jennifer L Larson-Casey, Mallikarjun H Patil, Rutwij Joshi, Chun-Sun Jiang, Yong Zhou, Chao He, A Brent Carter.

Pulmonary fibrosis is a progressive lung disease characterized by macrophage activation. Asbestos-induced expression of NADPH oxidase 4 (NOX4) in lung macrophages mediates fibrotic progression by the generation of mitochondrial ROS, modulating mitochondrial biogenesis, and promoting apoptosis resistance; however, the mechanism(s) by which NOX4 localizes to mitochondria during fibrosis is not known. Here we show that NOX4 localized to the mitochondrial matrix following asbestos exposure in lung macrophages by a direct interaction with TIM23. TIM23 and NOX4 interaction was found in lung macrophages from human subjects with asbestosis, while it was absent in mice harboring a conditional deletion of NOX4 in lung macrophages. This interaction was localized to the proximal transmembrane region of NOX4. Mechanistically, TIM23 augmented NOX4-induced mitochondrial ROS and metabolic reprogramming to oxidative phosphorylation (OXPHOS). Silencing TIM23 decreased mitochondrial ROS and OXPHOS. These observations highlight the important role of the mitochondrial translocase TIM23 interaction with NOX4. Moreover, this interaction is required for mitochondrial redox signaling and metabolic reprogramming in lung macrophages.

DOI: https://doi.org/10.1016/j.jbc.2023.104695
Pharmacol Ther. 2023 Apr 08. pii: S0163-7258(23)00075-X. [Epub ahead of print] 108411

Lipid metabolism in Th17 cell function.

Toshio Kanno, Takahiro Nakajima, Keisuke Miyako, Yusuke Endo.

  Among the subset of T helper cells, Th17 cells are known to play a crucial role in the pathogenesis of various autoimmune disorders, such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. The master transcription factor retinoid-related orphan receptor gamma t (RORγt), a nuclear hormone receptor, plays a vital role in inducing Th17-cell differentiation. Recent findings suggest that metabolic control is critical for Th17-cell differentiation, particularly through the engagement of de novo lipid biosynthesis. Inhibition of lipid biosynthesis, either through the use of pharmacological inhibitors or by the deficiency of related enzymes in CD4+ T cells, results in significant suppression of Th17-cell differentiation. Mechanistic studies indicate that metabolic fluxes through both the fatty acid and cholesterol biosynthetic pathways are essential for controlling RORγt activity through the generation of a lipid ligand of RORγt. This review highlights recent findings that underscore the significant role of lipid metabolism in the differentiation and function of Th17 cells, as well as elucidating the distinctive molecular pathways that drive the activation of RORγt by cellular lipid metabolism. We further elaborate on a pioneering therapeutic approach for ameliorating autoimmune disorders via the inhibition of RORγt.

Keywords:  Lipid metabolism; Nuclear receptor; RORγt; Th17 cells

DOI:  https://doi.org/10.1016/j.pharmthera.2023.108411
Sci Immunol. 2023 Apr 14. 8(82): eabq3016

Metabolic challenges and interventions in CAR T cell therapy.

Jhan-Jie Peng, Limei Wang, Zhiyu Li, Cheng-Lung Ku, Ping-Chih Ho.

Chimeric antigen receptor (CAR) T cells have achieved true clinical success in treating hematological malignancy patients, laying the foundation of CAR T cells as a new pillar of cancer therapy. Although these promising effects have generated strong interest in expanding the treatment of CAR T cells to solid tumors, reproducible demonstration of clinical efficacy in the setting of solid tumors has remained challenging to date. Here, we review how metabolic stress and signaling in the tumor microenvironment, including intrinsic determinants of response to CAR T cell therapy and extrinsic obstacles, restrict the efficacy of CAR T cell therapy in cancer treatment. In addition, we discuss the use of novel approaches to target and rewire metabolic programming for CAR T cell manufacturing. Last, we summarize strategies that aim to improve the metabolic adaptability of CAR T cells to enhance their potency in mounting antitumor responses and survival within the tumor microenvironment.

DOI: https://doi.org/10.1126/sciimmunol.abq3016
Cell Rep. 2023 Apr 13. pii: S2211-1247(23)00404-7. [Epub ahead of print]42(4): 112393

Maternal diet alters long-term innate immune cell memory in fetal and juvenile hematopoietic stem and progenitor cells in nonhuman primate offspring.

Michael J Nash, Evgenia Dobrinskikh, Taylor K Soderborg, Rachel C Janssen, Diana L Takahashi, Tyler A Dean, Oleg Varlamov, Jon D Hennebold, Maureen Gannon, Kjersti M Aagaard, Carrie E McCurdy, Paul Kievit, Bryan C Bergman, Kenneth L Jones, Eric M Pietras, Stephanie R Wesolowski, Jacob E Friedman.

  Maternal overnutrition increases inflammatory and metabolic disease risk in postnatal offspring. This constitutes a major public health concern due to increasing prevalence of these diseases, yet mechanisms remain unclear. Here, using nonhuman primate models, we show that maternal Western-style diet (mWSD) exposure is associated with persistent pro-inflammatory phenotypes at the transcriptional, metabolic, and functional levels in bone marrow-derived macrophages (BMDMs) from 3-year-old juvenile offspring and in hematopoietic stem and progenitor cells (HSPCs) from fetal and juvenile bone marrow and fetal liver. mWSD exposure is also associated with increased oleic acid in fetal and juvenile bone marrow and fetal liver. Assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling of HSPCs and BMDMs from mWSD-exposed juveniles supports a model in which HSPCs transmit pro-inflammatory memory to myeloid cells beginning in utero. These findings show that maternal diet alters long-term immune cell developmental programming in HSPCs with proposed consequences for chronic diseases featuring altered immune/inflammatory activation across the lifespan.

Keywords:  CP: Immunology; DoHaD; Western-style diet; epigenetics; fatty acid; glycolysis; hematopoiesis; inflammation; macrophage; obesity

DOI:  https://doi.org/10.1016/j.celrep.2023.112393
Cell Mol Immunol. 2023 Apr 12.

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity.

Elien Grajchen, Melanie Loix, Paulien Baeten, Beatriz F Côrte-Real, Ibrahim Hamad, Sam Vanherle, Mansour Haidar, Jonas Dehairs, Jelle Y Broos, James M Ntambi, Robert Zimmermann, Rolf Breinbauer, Piet Stinissen, Niels Hellings, Sanne G S Verberk, Gijs Kooij, Martin Giera, Johannes V Swinnen, Bieke Broux, Markus Kleinewietfeld, Jerome J A Hendriks, Jeroen F J Bogie.

  The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.

Keywords:  Autoimmunity; Fatty acid metabolism; Multiple sclerosis; Regulatory T cells; Stearoyl-CoA desaturase-1

DOI:  https://doi.org/10.1038/s41423-023-01011-2
Front Immunol. 2023 ;14 1116760

Optimal LC-MS metabolomic profiling reveals emergent changes to monocyte metabolism in response to lipopolysaccharide.

Emma Leacy, Isabella Batten, Laetitia Sanelli, Matthew McElheron, Gareth Brady, Mark A Little, Hania Khouri.

  Introduction: Immunometabolism examines the links between immune cell function and metabolism. Dysregulation of immune cell metabolism is now an established feature of innate immune cell activation. Advances in liquid chromatography mass spectrometry (LC-MS) technologies have allowed discovery of unique insights into cellular metabolomics. Here we have studied and compared different sample preparation techniques and data normalisation methods described in the literature when applied to metabolomic profiling of human monocytes.Methods: Primary monocytes stimulated with lipopolysaccharide (LPS) for four hours was used as a study model. Monocytes (n=24) were freshly isolated from whole blood and stimulated for four hours with lipopolysaccharide (LPS). A methanol-based extraction protocol was developed and metabolomic profiling carried out using a Hydrophilic Interaction Liquid Chromatography (HILIC) LC-MS method. Data analysis pipelines used both targeted and untargeted approaches, and over 40 different data normalisation techniques to account for technical and biological variation were examined. Cytokine levels in supernatants were measured by ELISA.
Results: This method provided broad coverage of the monocyte metabolome. The most efficient and consistent normalisation method was measurement of residual protein in the metabolite fraction, which was further validated and optimised using a commercial kit. Alterations to the monocyte metabolome in response to LPS can be detected as early as four hours post stimulation. Broad and profound changes in monocyte metabolism were seen, in line with increased cytokine production. Elevated levels of amino acids and Krebs cycle metabolites were noted and decreases in aspartate and β-alanine are also reported for the first time. In the untargeted analysis, 154 metabolite entities were significantly altered compared to unstimulated cells. Pathway analysis revealed the most prominent changes occurred to (phospho-) inositol metabolism, glycolysis, and the pentose phosphate pathway.
Discussion: These data report the emergent changes to monocyte metabolism in response to LPS, in line with reports from later time points. A number of these metabolites are reported to alter inflammatory gene expression, which may facilitate the increases in cytokine production. Further validation is needed to confirm the link between metabolic activation and upregulation of inflammatory responses.

Keywords:  LC-MS; LPS; data normalization; metabolomics; monocyte

DOI:  https://doi.org/10.3389/fimmu.2023.1116760
J Immunol. 2023 Apr 12. pii: ji2200694. [Epub ahead of print]

Identification and Characterization of Alveolar and Recruited Lung Macrophages during Acute Lung Inflammation.

Wei Han, Harikrishna Tanjore, Yang Liu, Raphael P Hunt, Sergey S Gutor, Ana P M Serezani, Timothy S Blackwell.

To precisely identify mouse resident alveolar macrophages (AMs) and bone marrow (BM)-derived macrophages, we developed a technique to separately label AMs and BM-derived macrophages with a fluorescent lipophilic dye followed by FACS. We showed that this technique overcomes issues in cell identification related to dynamic shifts in cell surface markers that occurs during lung inflammation. We then used this approach to track macrophage subsets at different time points after intratracheal (i.t.) instillation of Escherichia coli LPS. By isolating BM-derived macrophages and AMs, we demonstrated that BM-derived macrophages were enriched in expression of genes in signal transduction and immune system activation pathways whereas resident AMs were enriched in cellular processes, such as lysosome/phagosome pathways, efferocytosis, and metabolic pathways related to fatty acids and peroxisomes. Taken together, these data indicate that more accurate identification of macrophage origin can result in improved understanding of differential phenotypes and functions between AMs and BM-derived macrophages in the lungs.

DOI: https://doi.org/10.4049/jimmunol.2200694
Redox Biol. 2023 Apr 05. pii: S2213-2317(23)00097-6. [Epub ahead of print]62 102696

Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages.

Shuai Zhao, Lei Zhou, Qin Wang, Jia-Hao Cao, Yan Chen, Wei Wang, Bo-Da Zhu, Zhi-Hong Wei, Rong Li, Cong-Ye Li, Geng-Yao Zhou, Zhi-Jun Tan, He-Ping Zhou, Cheng-Xiang Li, Hao-Kao Gao, Xu-Jun Qin, Kun Lian.

  As the essential amino acids, branched-chain amino acid (BCAA) from diets is indispensable for health. BCAA supplementation is often recommended for patients with consumptive diseases or healthy people who exercise regularly. Latest studies and ours reported that elevated BCAA level was positively correlated with metabolic syndrome, diabetes, thrombosis and heart failure. However, the adverse effect of BCAA in atherosclerosis (AS) and its underlying mechanism remain unknown. Here, we found elevated plasma BCAA level was an independent risk factor for CHD patients by a human cohort study. By employing the HCD-fed ApoE-/- mice of AS model, ingestion of BCAA significantly increased plaque volume, instability and inflammation in AS. Elevated BCAA due to high dietary BCAA intake or BCAA catabolic defects promoted AS progression. Furthermore, BCAA catabolic defects were found in the monocytes of patients with CHD and abdominal macrophages in AS mice. Improvement of BCAA catabolism in macrophages alleviated AS burden in mice. The protein screening assay revealed HMGB1 as a potential molecular target of BCAA in activating proinflammatory macrophages. Excessive BCAA induced the formation and secretion of disulfide HMGB1 as well as subsequent inflammatory cascade of macrophages in a mitochondrial-nuclear H2O2 dependent manner. Scavenging nuclear H2O2 by overexpression of nucleus-targeting catalase (nCAT) effectively inhibited BCAA-induced inflammation in macrophages. All of the results above illustrate that elevated BCAA promotes AS progression by inducing redox-regulated HMGB1 translocation and further proinflammatory macrophage activation. Our findings provide novel insights into the role of animo acids as the daily dietary nutrients in AS development, and also suggest that restricting excessive dietary BCAA consuming and promoting BCAA catabolism may serve as promising strategies to alleviate and prevent AS and its subsequent CHD.

Keywords:  Atherosclerosis (AS); Branched-chain amino acid (BCAA); HMGB1; Hydrogen peroxide (H(2)O(2)); Inflammation; Macrophage; Mitochondria

DOI:  https://doi.org/10.1016/j.redox.2023.102696
Cancers (Basel). 2023 Mar 29. pii: 2043. [Epub ahead of print]15(7):

Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors.

Min Chen, Huanrong Lan, Shiya Yao, Ketao Jin, Yun Chen.

  The metabolism of tumors and immune cells in the tumor microenvironment (TME) can affect the fate of cancer and immune responses. Metabolic reprogramming can occur following the activation of metabolic-related signaling pathways, such as phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR). Moreover, various tumor-derived immunosuppressive metabolites following metabolic reprogramming also affect antitumor immune responses. Evidence shows that intervention in the metabolic pathways of tumors or immune cells can be an attractive and novel treatment option for cancer. For instance, administrating inhibitors of various signaling pathways, such as phosphoinositide 3-kinases (PI3Ks), can improve T cell-mediated antitumor immune responses. However, dual pathway inhibitors can significantly suppress tumor growth more than they inhibit each pathway separately. This review discusses the latest metabolic interventions by dual pathway inhibitors as well as the advantages and disadvantages of this therapeutic approach.

Keywords:  cancer therapy; dual inhibitor; metabolic intervention; metabolic reprogramming

DOI:  https://doi.org/10.3390/cancers15072043
Vet Clin North Am Food Anim Pract. 2023 Apr 07. pii: S0749-0720(23)00023-3. [Epub ahead of print]

Metabolic Factors at the Crossroads of Periparturient Immunity and Inflammation.

Angel Abuelo, Sabine Mann, Genaro Andres Contreras.

  Periparturient cows have the highest risk for disease and culling in the adult dairy herd. This risk is compounded by the multiple physiological changes of metabolism and immune function occurring around calving that alter the cow's inflammatory response. In this article, the authors summarize the current knowledge on immunometabolism in the periparturient cow, discussing major changes in immune and metabolic function around parturition that will facilitate the assessment of periparturient cow management programs.

Keywords:  Bovine immunometabolism; Periparturient inflammation; Periparturient period; Postpartum inflammatory dysregulation; Postpartum nutrient deficit

DOI:  https://doi.org/10.1016/j.cvfa.2023.02.012
Microbiol Spectr. 2023 Apr 10. e0106623

A Mycobacterium tuberculosis Effector Targets Mitochondrion, Controls Energy Metabolism, and Limits Cytochrome c Exit.

Marianne Martin, Angelique deVisch, Yves-Marie Boudehen, Philippe Barthe, Claude Gutierrez, Obolbek Turapov, Talip Aydogan, Laurène Heriaud, Jerome Gracy, Olivier Neyrolles, Galina V Mukamolova, François Letourneur, Martin Cohen-Gonsaud.

  Host metabolism reprogramming is a key feature of Mycobacterium tuberculosis (Mtb) infection that enables the survival of this pathogen within phagocytic cells and modulates the immune response facilitating the spread of the tuberculosis disease. Here, we demonstrate that a previously uncharacterized secreted protein from Mtb, Rv1813c, manipulates the host metabolism by targeting mitochondria. When expressed in eukaryotic cells, the protein is delivered to the mitochondrial intermembrane space and promotes the enhancement of host ATP production by boosting the oxidative phosphorylation metabolic pathway. Furthermore, the release of cytochrome c from mitochondria, an early apoptotic event in response to short-term oxidative stress, is delayed in Rv1813c-expressing cells. This study reveals a novel class of mitochondria targeting effectors from Mtb that might participate in host cell metabolic reprogramming and apoptosis control during Mtb infections. IMPORTANCE In this article, using a combination of techniques (bioinformatics, structural biology, and cell biology), we identified and characterized a new class of effectors present only in intracellular mycobacteria. These proteins specifically target host cell mitochondria when ectopically expressed in cells. We showed that one member of this family (Rv1813c) affects mitochondria metabolism in a way that might twist the immune response. This effector also inhibits the cytochrome c exit from mitochondria, suggesting that it might alter normal host cell apoptotic capacities, one of the first defenses of immune cells against Mtb infection.

Keywords:  Mycobacterium tuberculosis; apoptosis; metabolism; mitochondria

DOI:  https://doi.org/10.1128/spectrum.01066-23
Toxicol Sci. 2023 Apr 13. pii: kfad033. [Epub ahead of print]

Pulmonary Immune Response Regulation, Genotoxicity, and Metabolic Reprogramming by Menthol and Tobacco Flavored E-Cigarette Exposures in Mice.

Thivanka Muthumalage, Irfan Rahman.

  Menthol and tobacco flavors are available for almost all tobacco products, including electronic cigarettes (e-cigs). These flavors are a mixture of chemicals with overlapping constituents. There are no comparative toxicity studies of these flavors produced by different manufacturers. We hypothesized that acute exposure to menthol and tobacco-flavored e-cig aerosols induces inflammatory, genotoxicity, and metabolic responses in mouse lungs. We compared two brands, A and B, e-cig flavors (PG/VG, menthol, and tobacco) with and without nicotine for their inflammatory response, genotoxic markers, altered genes and proteins in the context of metabolism by exposing mouse strains, C57BL/6J (Th1-mediated) and BALB/cJ (Th2-mediated). Brand A nicotine-free menthol exposure caused increased neutrophils and differential T-lymphocyte influx in bronchoalveolar lavage fluid (BALF) and induced significant immunosuppression, while brand A tobacco with nicotine elicited an allergic inflammatory response with increased Eotaxin, IL-6, and RANTES levels. Brand B elicited a similar inflammatory response in menthol flavor exposure. Upon e-cig exposure, genotoxicity markers, significantly increased in lung tissue. These inflammatory and genotoxicity responses were associated with altered NLRP3 inflammasome and TRPA1 induction by menthol flavor. Nicotine decreased surfactant protein D and increased PAI-1 by menthol and tobacco flavors, respectively. Integration of inflammatory and metabolic pathway gene expression analysis showed immunometabolic regulation in T-cells via PI3K/Akt/p70S6k-mTOR axis associated with suppressed immunity/allergic immune response. Overall, this study showed comparative toxicity of flavored e-cig aerosols, unraveling potential signaling pathways of nicotine and flavor-mediated pulmonary toxicological responses, and emphasized the need for standardized toxicity testing for appropriate premarket authorization of e-cigarette products.

Keywords:  E-cigarettes; ENDS; flavors; hypersensitivity; immunometabolism; menthol; nicotine; tobacco

DOI:  https://doi.org/10.1093/toxsci/kfad033
Microbiol Spectr. 2023 Apr 13. e0090923

mleS in Staphylococcus aureus Contributes to Microaerobic Metabolic Activity, Abscess Formation, and Survival in Macrophages.

Fengning Chen, Yuyao Yin, Hongbin Chen, Shuguang Li, Guankun Yin, Hui Wang.

  Staphylococcus aureus is subdivided into lineages termed sequence types (STs), infections of which necessitate the expression of virulence factors and metabolic adaptation to the host niche. Given that mechanisms underlying the dynamic replacement of sequence types in S. aureus populations have yet to be sufficiently determined, we investigated the role of metabolic determinants in epidemic clones. mleS, encoding the NAD+-dependent malolactic enzyme, was found to be carried by the epidemic clones ST59 and ST398, although not by ST239 and ST5. The genomic location of mleS in the metabolism-associated region flanked by the thiol-specific redox system and glycolysis operon implies that it plays significant roles in metabolism and pathogenesis. Mouse skin abscess caused by the BS19-mleS mutant strain (isogenic mleS mutant in an ST59 isolate) was significantly attenuated and associated with reductions in interleukin-6 (IL-6) and lactic acid production. mleS deletion also impaired S. aureus biofilm formation and survival in RAW264.7 cells. The BS19-mleS-mutant was also characterized by reduced ATP and lactic acid production under microaerobic conditions; however, NAD+/NADH levels remained unaffected. mleS is thus identified as an epidemiological marker that plays an important role in the microaerobic metabolism and pathogenesis of epidemic S. aureus clones. IMPORTANCE Given the importance of metabolic adaptation during infection, new insights are required regarding the pathogenesis of S. aureus, particularly for epidemic clones. We accordingly investigated the role of metabolic determinants that are unique to the epidemic clones ST59 and ST398. Our results provide evidence that the NAD+-dependent malolactic enzyme-coding gene mleS is an epidemiological marker that plays an important role in the microaerobic metabolism and pathogenesis of epidemic S. aureus clones.

Keywords:  NAD+-dependent malolactic enzyme coding gene (mleS); Staphylococcus aureus; macrophage survival; metabolism; mouse skin abscess

DOI:  https://doi.org/10.1128/spectrum.00909-23
Cell Rep. 2023 Apr 14. pii: S2211-1247(23)00410-2. [Epub ahead of print]42(4): 112399

Complementary gene regulation by NRF1 and NRF2 protects against hepatic cholesterol overload.

May G Akl, Lei Li, Raquel Baccetto, Sadhna Phanse, Qingzhou Zhang, Michael J Trites, Sherin McDonald, Hiroyuki Aoki, Mohan Babu, Scott B Widenmaier.

  Hepatic cholesterol overload promotes steatohepatitis. Insufficient understanding of liver stress defense impedes therapy development. Here, we elucidate the role of stress defense transcription factors, nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2), in counteracting cholesterol-linked liver stress. Using a diet that increases liver cholesterol storage, expression profiles and phenotypes of liver from mice with hepatocyte deficiency of NRF1, NRF2, or both are compared with controls, and chromatin immunoprecipitation sequencing is undertaken to identify target genes. Results show NRF1 and NRF2 co-regulate genes that eliminate cholesterol and mitigate inflammation and oxidative damage. Combined deficiency, but not deficiency of either alone, results in severe steatohepatitis, hepatic cholesterol overload and crystallization, altered bile acid metabolism, and decreased biliary cholesterol. Moreover, therapeutic effects of NRF2-activating drug bardoxolone require NRF1 and are supplemented by NRF1 overexpression. Thus, we discover complementary gene programming by NRF1 and NRF2 that counteract cholesterol-associated fatty liver disease progression.

Keywords:  CP: Metabolism; cholesterol; fatty liver disease; immunometabolism; steatohepatitis; stress defense; transcription factor

DOI:  https://doi.org/10.1016/j.celrep.2023.112399
Am J Cancer Res. 2023 ;13(3): 1067-1081

IRG1/Itaconate induces metabolic reprogramming to suppress ER-positive breast cancer cell growth.

Hsueh-Chun Wang, Wei-Chao Chang, Der-Yen Lee, Xing-Guo Li, Mien-Chie Hung.

Most breast cancers are estrogen receptor (ER)-positive, targeted by endocrine therapies, but chemoresistance remains a significant challenge in treating the disease. Altered intracellular metabolite has closely connected with the pathogenic process of breast cancer and drug resistance. Itaconate is an anti-inflammatory metabolite generated from converting cis-aconitate in the tricarboxylic acid (TCA) cycle by the immune response gene 1 (IRG1). However, the potential role of IRG1/Itaconate in the crosstalk of metabolic pathways and tumor development is currently unknown. We tested the hypothesis that IRG1/Itaconate controls metabolic homeostasis to modulate breast cancer cell growth. We showed that breast cancers harboring an IRG1 deletion displayed a worse prognosis than those without IRG1 deletion; approximately 70% of breast cancer with IRG1 deletion were ER-positive. There was no significant difference in the IRG1 copy number, mRNA, and protein levels between ER-positive and ER-negative breast cancer cell lines and breast tumors. Itaconate selectively inhibited ER-positive breast cancer cell growth via the blockade of DNA synthesis and the induction of apoptosis. Mechanistically, IRG1 overexpression led to decreased intermediate levels of glycolysis, the TCA cycle, and lipid metabolism to compromise the entire biomass and energy of the cell. Itaconate inhibited the enzymatic activity of succinate dehydrogenase (SDH) in the mitochondrial electron-transport chain, concomitant with reactive oxygen species (ROS) production and the decreased adenylate kinase (AK) activities, which, in turn, induced AMP-activated protein kinase (AMPK) activation to restore metabolic homeostasis. These results suggest a new regulatory pathway whereby IRG1/Itaconate controls metabolic homeostasis in ER-positive breast cancer cells, which may contribute to developing more efficacious therapeutic strategies for breast cancer.

Keywords: Breast cancer; estrogen receptor; immune response gene 1; itaconate; metabolic reprogramming; tricarboxylic acid cycle
Cancer Lett. 2023 Apr 11. pii: S0304-3835(23)00122-2. [Epub ahead of print] 216171

Single-cell RNA sequencing reveals XBP1-SLC38A2 axis as a metabolic regulator in cytotoxic T lymphocytes in multiple myeloma.

Yike Wan, Mengping Chen, Xin Li, Xiaofeng Han, Lu Zhong, Fei Xiao, Jia Liu, Jing Xiang, Jinxing Jiang, Xiaotong Chen, Junling Liu, Hua Li, Bin Li, Honghui Huang, Jian Hou.

  The mechanisms underlying the functional impairment and metabolic reprogramming of T lymphocytes in multiple myeloma (MM) have not been fully elucidated. In this study, single-cell RNA sequencing was used to compare gene expression profiles in T cells in bone marrow and peripheral blood of 10 newly diagnosed MM patients versus 3 healthy donors. Unbiased bioinformatics analysis revealed 9 cytotoxic T cell clusters. All 9 clusters in MM had higher expression of senescence markers (e.g., KLRG1 and CTSW) than the healthy control; some had higher expression of exhaustion-related markers (e.g., LAG3 and TNFRSF14). Pathway enrichment analyses showed downregulated amino acid metabolism and upregulated unfolded protein response (UPR) pathways, along with absent expression of glutamine transporter SLC38A2 and increased expression of UPR hallmark XBP1 in cytotoxic T cells in MM. In vitro studies revealed that XBP1 inhibited SLC38A2 by directly binding to its promoter, and silencing SLC38A2 resulted in decreased glutamine uptake and immune dysfunction of T cells. This study provided a landscape description of the immunosuppressive and metabolic features in T lymphocytes in MM, and suggested an important role of XBP1-SLC38A2 axis in T cell function.

Keywords:  Cell exhaustion; Cell senescence; Glutamine metabolism; Immune microenvironment; Unfolded protein response

DOI:  https://doi.org/10.1016/j.canlet.2023.216171
Cell Prolif. 2023 Apr 13. e13470

The nano-windmill exerts superior anti-inflammatory effects via reducing choline uptake to inhibit macrophage activation.

Nanxin Liu, Yuke Zhong, Xiaoxiao Pang, Mingzheng Li, Richard D Cannon, Li Mei, Xiaoxiao Cai, Ping Ji.

Macrophages' activation plays a central role during the development and progression of inflammation, while the regulation of metabolic reprogramming of macrophages has been recently identified as a novel strategy for anti-inflammatory therapies. Our previous studies have found that tetrahedral framework nucleic acid (tFNA) plays a mild anti-inflammatory effect by inhibiting macrophage activation, but the specific mechanism remains unclear. Here, by metabolomics and RNA sequencing, choline uptake is identified to be significantly repressed by decreased slc44a1 expression in tFNA-treated activated macrophages. Inspired by this result, combined with the excellent delivery capacities of tFNA, siR-slc44a1 is loaded into the tFNA to develop a new tFNA-based small interfering RNA (siRNA) delivery system named 'nano-windmill,' which exhibits a synergetic role by targeting slc44a1, finally blowing up the anti-inflammatory effects of tFNA to inhibit macrophages activation via reducing choline uptake. By confirming its anti-inflammatory effects in chronic (periodontitis) and acute (sepsis) inflammatory disease, the tFNA-based nanomedicine developed for inflammatory diseases may provide broad prospects for tFNA upgrading and various biological applications such as anti-inflammatory.

DOI: https://doi.org/10.1111/cpr.13470
FEBS J. 2023 Apr 15.

Rab26 promotes macrophage phagocytosis through regulation of MFN2 trafficking to mitochondria.

Di Wu, Yao Wang, Junxian Hu, Yuhang Xu, Daohui Gong, Pengfei Wu, Junkang Dong, Binfeng He, Hang Qian, Guansong Wang.

  Acute respiratory distress syndrome (ARDS) is an inflammatory disorder of the lungs caused by bacterial or viral infection. Timely phagocytosis and clearance of pathogens by macrophages are important in controlling inflammation and alleviating ARDS. However, the precise mechanism of macrophage phagocytosis remains to be explored. Here, we show that the expression of Rab26 is increased in E. coli or Pseudomonas aeruginosa (Pa)-stimulated bone marrow-derived macrophages (BMDM). Knocking out Rab26 reduced phagocytosis and bacterial clearance by macrophages. Rab26 interacts with mitochondrial fusion protein mitofusin-2 (MFN2) and affects mitochondrial ROS (mtROS) generation by regulating MFN2 transport. The levels of MFN2 in mitochondria were reduced in Rab26-deficient BMDMs, and the levels of mtROS and ATP were significantly decreased. Knocking down MFN2 using siRNA resulted in decreased phagocytosis and killing ability of macrophages. Rab26 knockout reduced phagocytosis and bacterial clearance by macrophages in vivo, significantly increased inflammatory factors, aggravated lung tissue damage, and increased mortality in mice. Our results demonstrate that Rab26 regulates phagocytosis and clearance of bacteria by mediating the transport of MFN2 to mitochondria in macrophages, thus alleviating ARDS in mice and potentially in humans.

Keywords:  Bacteria; MFN2; Macrophage; Phagocytosis; ROS; Rab26

DOI:  https://doi.org/10.1111/febs.16793
Biochim Biophys Acta Mol Basis Dis. 2023 Apr 06. pii: S0925-4439(23)00081-9. [Epub ahead of print] 166715

Immunometabolism at the basis of health and disease; an editorial.

Jan Van den Bossche, Tiffany Horng, Dylan G Ryan.

DOI: https://doi.org/10.1016/j.bbadis.2023.166715
Biomaterials. 2023 Mar 31. pii: S0142-9612(23)00112-6. [Epub ahead of print]297 122104

Regulating T-cell metabolic reprogramming and blocking PD-1 co-promote personalized postoperative autologous nanovaccines.

Lili Chang, Shunli Fu, Tong Gao, Xiao Sang, Han Yang, Xiaoqing Liu, Huizhen Yang, Yongjun Liu, Na Zhang.

  Cytotoxic T lymphocytes (CTLs) are central effector cells in antitumor immunotherapy. However, the complexity of immunosuppressive factors in the immune system contributes to the low response rates of current CTL-based immunotherapies. Here, we propose a novel holistic strategy including a priming response, promoting activity, and relieving suppression of CTLs, aiming to strengthen the effect of personalized postoperative autologous nanovaccines. The nanovaccine (C/G-HL-Man) fused the autologous tumor cell membrane with dual adjuvants (CpG and cGAMP), and could effectively accumulate in lymph nodes and promote antigen cross presentation by dendritic cells to prime a sufficient specific-CTL response. The PPAR-α agonist fenofibrate was used to regulate T-cell metabolic reprogramming to promote antigen-specific CTLs activity in the harsh metabolic tumor microenvironment. Finally, the PD-1 antibody was used to relieve the suppression of specific-CTLs in the immunosuppressive tumor microenvironment. In vivo, the C/G-HL-Man exhibited strong antitumor effect in the B16F10 murine tumor prevention model and the B16F10 postoperative recurrence model. In particular, combination therapy with nanovaccines, fenofibrate, and PD-1 antibody effectively inhibited the progression of recurrent melanoma and prolonged the survival time. Our work highlights the critical role of the T-cell metabolic reprogramming and PD-1 blocking in autologous nanovaccines, offering a novel strategy for strengthening the function of CTLs.

Keywords:  CpG and cGAMP; Cytotoxic T lymphocytes; PD-1 blocking; Postoperative autologous nanovaccines; T-cell metabolic reprogramming

DOI:  https://doi.org/10.1016/j.biomaterials.2023.122104
Nutrients. 2023 Mar 30. pii: 1698. [Epub ahead of print]15(7):

Modulation of Dietary Fatty Acids in an Open-Label Study Improves Psoriasis and Dampens the Inflammatory Activation Status.

Anja Saalbach, Anna-Theresa Seitz, Johannes Kohlmann, Lena Kalweit, Lisa Vogt, Lars Selig, Kathrin M Engel, Jan C Simon.

  Obesity and high abdominal fat mass are risk factors for developing the chronic inflammatory skin disease psoriasis. They are associated with increased incidence, prevalence and severity of the disease. A positive effect of weight loss on psoriasis activity has been shown in several studies. Obesity-related factors such as the dysregulation of glucose and lipid metabolism, the activation of adipose tissue and resultant persistent low-grade inflammation have been discussed as links of obesity and inflammatory diseases. Recently, we demonstrated a critical role of free fatty acids (FFAs) in obesity-mediated exacerbation of psoriatic skin inflammation in both mice and humans. In the present study, we translated these findings into a therapeutic intervention. An open-label study focusing on the dietary reduction of FFAs was conducted in patients with mild-to-moderate plaque psoriasis, and disease severity and serum markers of inflammation were analyzed. Here, we show that such a dietary intervention improves psoriatic disease activity independently of weight loss. Diet-related metabolic changes, such as a reduction in saturated free fatty acids (SFAs), may thus be more important than weight loss itself. Moreover, dietary intervention inhibited the overall pro-inflammatory activation status in patients, as shown by analysis of serum inflammatory parameters using the Olink platform. From our pilot study, we conclude that dietary intervention focusing on SFA reduction has the capacity to reduce disease activity and general inflammatory status in psoriasis patients.

Keywords:  fatty acids; inflammation; nutrition; obesity; psoriasis

DOI:  https://doi.org/10.3390/nu15071698