bims-imicid 2022-04-24 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022‒04‒24
25 papers selected by
Dylan Ryan
University of Cambridge

The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function.
The Role of Metabolic Dysfunction in T-Cell Exhaustion During Chronic Viral Infection.
Type I interferon antagonism of the JMJD3-IRF4 pathway modulates macrophage activation and polarization.
Ex vivo activated CD4+ T cells from young calves exhibit Th2-biased effector function with distinct metabolic reprogramming compared to adult cows.
Immunometabolism-fit: How exercise and training can modify T cell and macrophage metabolism in health and disease.
Pulsed-Ultrasound Irradiation Induces the Production of Itaconate and Attenuates Inflammatory Responses in Macrophages.
Improving Mitochondrial Function in Viral Infection: Targeting Cellular Metabolism.
Regulating metabolism to shape immune function: Lessons from Drosophila.
Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target.
Mitochondria Transfer to CD4+ T Cells May Alleviate Rheumatoid Arthritis by Suppressing Pro-Inflammatory Cytokine Production.
Macrophage programming is regulated by a cooperative interaction between fatty acid binding protein 5 and peroxisome proliferator-activated receptor γ.
Targeting colonic macrophages improves glycemic control in high-fat diet-induced obesity.
2D Transition Metal Dichalcogenides Trigger Trained Immunity in Human Macrophages through Epigenetic and Metabolic Pathways.
CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate.
Impact of Drp1-Mediated Mitochondrial Dynamics on T Cell Immune Modulation.
Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer.
Microbiota-derived tryptophan metabolites in vascular inflammation and cardiovascular disease.
ILC precursors differentiate into metabolically distinct ILC1-like cells during Mycobacterium tuberculosis infection.
KLF7 Alleviates Atherosclerotic Lesions and Inhibits Glucose Metabolic Reprogramming in Macrophages by Regulating HDAC4/miR-148b-3p/NCOR1.
TRPM2 deficiency in mice protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages.
SHP2/SPI1axis promotes glycolysis and the inflammatory response of macrophages in Helicobacter pylori-induced pediatric gastritis.
c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses.
The gut microbial metabolite formate exacerbates colorectal cancer progression.
Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity.
Serum Amyloid A is not obligatory for high-fat, high-sucrose, cholesterol-fed diet-induced obesity and its metabolic and inflammatory complications.

Cell Metab. 2022 Apr 18. pii: S1550-4131(22)00127-9. [Epub ahead of print]

The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function.

Mathias Wenes, Alison Jaccard, Tania Wyss, Noelia Maldonado-Pérez, Shao Thing Teoh, Anouk Lepez, Fabrice Renaud, Fabien Franco, Patrice Waridel, Céline Yacoub Maroun, Benjamin Tschumi, Nina Dumauthioz, Lianjun Zhang, Alena Donda, Francisco Martín, Denis Migliorini, Sophia Y Lunt, Ping-Chih Ho, Pedro Romero.

  Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+ T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8+ T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8+ T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses.

Keywords:  T cell memory; chimeric antigen receptor T cell therapy; immunometabolism; mitochondrial pyruvate carrier; tumor-infiltrating lymphocyte metabolism

DOI:  https://doi.org/10.1016/j.cmet.2022.03.013
Front Immunol. 2022 ;13 843242

The Role of Metabolic Dysfunction in T-Cell Exhaustion During Chronic Viral Infection.

Kehong Zheng, Xiaojun Zheng, Wei Yang.

  T cells are important components of adaptive immunity that protect the host against invading pathogens during infection. Upon recognizing the activation signals, naïve and/or memory T cells will initiate clonal expansion, trigger differentiation into effector populations and traffic to the inflamed sites to eliminate pathogens. However, in chronic viral infections, such as those caused by human immunodeficiency virus (HIV), hepatitis B and C (HBV and HCV), T cells exhibit impaired function and become difficult to clear pathogens in a state known as T-cell exhaustion. The activation and function persistence of T cells demand for dynamic changes in cellular metabolism to meet their bioenergetic and biosynthetic demands, especially the augmentation of aerobic glycolysis, which not only provide efficient energy generation, but also fuel multiple biochemical intermediates that are essential for nucleotide, amino acid, fatty acid synthesis and mitochondria function. Changes in cellular metabolism also affect the function of effectors T cells through modifying epigenetic signatures. It is widely accepted that the dysfunction of T cell metabolism contributes greatly to T-cell exhaustion. Here, we reviewed recent findings on T cells metabolism under chronic viral infection, seeking to reveal the role of metabolic dysfunction played in T-cell exhaustion.

Keywords:  PD-1; T-cell exhaustion; chronic viral infection; glycolysis; metabolism

DOI:  https://doi.org/10.3389/fimmu.2022.843242
Cell Rep. 2022 Apr 19. pii: S2211-1247(22)00480-6. [Epub ahead of print]39(3): 110719

Type I interferon antagonism of the JMJD3-IRF4 pathway modulates macrophage activation and polarization.

Kevin Ming-Chin Lee, Adrian A Achuthan, David P De Souza, Tanya J Lupancu, Katrina J Binger, Man K S Lee, Yangsong Xu, Malcolm J McConville, Nicole A de Weerd, Dragana Dragoljevic, Paul J Hertzog, Andrew J Murphy, John A Hamilton, Andrew J Fleetwood.

  Metabolic adaptations can directly influence the scope and scale of macrophage activation and polarization. Here we explore the impact of type I interferon (IFNβ) on macrophage metabolism and its broader impact on cytokine signaling pathways. We find that IFNβ simultaneously increased the expression of immune-responsive gene 1 and itaconate production while inhibiting isocitrate dehydrogenase activity and restricting α-ketoglutarate accumulation. IFNβ also increased the flux of glutamine-derived carbon into the tricarboxylic acid cycle to boost succinate levels. Combined, we identify that IFNβ controls the cellular α-ketoglutarate/succinate ratio. We show that by lowering the α-ketoglutarate/succinate ratio, IFNβ potently blocks the JMJD3-IRF4-dependent pathway in GM-CSF and IL-4 activated macrophages. The suppressive effects of IFNβ on JMJD3-IRF4-dependent responses, including M2 polarization and GM-CSF-induced inflammatory pain, were reversed by supplementation with α-ketoglutarate. These results reveal that IFNβ modulates macrophage activation and polarization through control of the cellular α-ketoglutarate/succinate ratio.

Keywords:  CP: Immunology; CP: Metabolism; granulocyte macrophage colony-stimulating factor; interleukin-4; isocitrate dehydrogenase; macrophage polarization; metabolism; succinate; type I interferon; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.celrep.2022.110719
Vet Immunol Immunopathol. 2022 Apr 12. pii: S0165-2427(22)00038-1. [Epub ahead of print]248 110418

Ex vivo activated CD4+ T cells from young calves exhibit Th2-biased effector function with distinct metabolic reprogramming compared to adult cows.

Jordan M Eder, Randy E Sacco.

  As maternal passive immunity wanes at 6-8 weeks, young calves must rely on their own naïve and developing immune system for protection against pathogens. Typically, an infection in the young induces a T cell-mediated response, which skews towards a Th2 phenotype and results in a reduced effector response. Our study examines the implications this transitional period of immunocompetency has on cellular metabolism in young calves, focusing on effector function of CD4+ T cells in comparison to those from adult cows. Results from sorted CD4+ T cells from young calves and adult cows activated by α-CD3:α-CD28, show that young calves exhibit a significantly greater propensity to produce the Th2 cytokine, IL-4, in comparison to IFN-γ. Concomitantly, cells from young calves and adult cows exhibit no statistical difference in cell surface marker expression induced by α-CD3:α-CD28 stimulation. Metabolically, activated CD4+ T cells from young calves show significantly greater utilization of mitochondrial respiration, measured by oxygen consumption rate (OCR), and greater glycolytic reserve, measured by extracellular acidification rate (ECAR). However, adult cows have a significantly higher change in glycolytic rate after α-CD3:α-CD28 stimulation compared to young calves. Further, CD4+ T cells from young calves have an increased mRNA expression signature associated with glycolytic metabolism (GAPDH, HK2, FBP1, HIF1A) and Th2-associated metabolic signaling (RPTOR) in comparison to adult cows. The distinct metabolic phenotype and associated gene expression in activated CD4+ T cells may be intrinsic drivers of the Th2-biased response by young calves. Additionally, CD4+ recent thymic emigrant cells (RTEs) may further contribute to altered effector function, as they are preferential precursors to Tregs, and based on the microenvironment, have the propensity to polarize toward Th2. Evaluation of T cell master transcription regulators, as well as measuring signal joint T cell receptor excision circles between young calves and adult cows, we observed a significantly increased proportion of RTEs from sorted CD4+ T cells. In this study, we show a unique metabolic profile exhibited by activated CD4+ T cells from young calves in which mitochondrial respiration and glycolytic capacity is significantly increased compared to adult cows.

Keywords:  Adult cows; Aerobic glycolysis; CD4(+) T cells; Effector function; Mitochondrial respiration; Young calves

DOI:  https://doi.org/10.1016/j.vetimm.2022.110418
Exerc Immunol Rev. 2022 ;28 29-46

Immunometabolism-fit: How exercise and training can modify T cell and macrophage metabolism in health and disease.

José Cesar Rosa-Neto, Fábio Santos Lira, Jonathan Peter Little, Graham Landells, Hashim Islam, Bénédicte Chazaud, David B Pyne, Ana Maria Teixeira, Helena Batatinha, Barbara Moura Antunes, Luciele Guerra Minuzzi, Jana Palmowski, Richard J Simpson, Karsten Krüger.

BACKGROUND: The term immunometabolism describes cellular and molecular metabolic processes that control the immune system and the associated immune responses. Acute exercise and regular physical activity have a substantial influence on the metabolism and the immune system, so that both processes are closely associated and influence each other bidirectionally.SCOPE OF REVIEW: We limit the review here to focus on metabolic phenotypes and metabolic plasticity of T cells and macrophages to describe the complex role of acute exercise stress and regular physical activity on these cell types. The metabolic and immunological consequences of the social problem of inactivity and how, conversely, an active lifestyle can break this vicious circle, are then described. Finally, these aspects are evaluated against the background of an aging society.
MAJOR CONCLUSIONS: T cells and macrophages show high sensitivity to changes in their metabolic environment, which indirectly or directly affects their central functions. Physical activity and sedentary behaviour have an important influence on metabolic status, thereby modifying immune cell phenotypes and influencing immunological plasticity. A detailed understanding of the interactions between acute and chronic physical activity, sedentary behaviour, and the metabolic status of immune cells, can help to target the dysregulated immune system of people who live in a much too inactive society.

Keywords: Exercise; Immune System; Inflammation; Metabolism; Sedentary behavior
J Inflamm Res. 2022 ;15 2387-2395

Pulsed-Ultrasound Irradiation Induces the Production of Itaconate and Attenuates Inflammatory Responses in Macrophages.

Atomu Yamaguchi, Noriaki Maeshige, Xiaoqi Ma, Mikiko Uemura, Hikari Noguchi, Mami Matsuda, Yuya Nishimura, Tomohisa Hasunuma, Hiroyo Kondo, Hidemi Fujino.

  Background: Itaconate is a key metabolite in the innate immune system and exerts strong anti-inflammatory effects in macrophages. For the production of itaconate in macrophages, immune-responsive gene 1 (IRG1) is an imperative enzyme, and activating the IRG1-itaconate pathway is reported to alleviate inflammatory diseases by upregulating nuclear factor-erythroid 2-related factor 2 (NRF2). However, there are very few reports on strategies to increase itaconate production. Ultrasound therapy is a widely used intervention for anti-inflammatory and soft-tissue regeneration purposes. Here we show the effect of ultrasound irradiation on the production of itaconate in macrophages.Methods: Murine bone marrow-derived macrophages (BMDMs) were exposed to pulsed ultrasound (3.0 W/cm2) for 5 minutes. Three hours after irradiation, the intracellular levels of metabolites and mRNA expression levels of Irg1 and Nrf2 were measured using CE/MS and qPCR, respectively. To evaluate macrophage inflammation status, 3 h after irradiation, the cells were stimulated with 100 ng/mL lipopolysaccharide (LPS) for 1.5 h and the mRNA expression levels of pro-inflammatory factors (Il-1β, Il-6, and Tnf-α) were measured. Student's t-test, one-way ANOVA and Tukey's multiple comparison test were used for statistical processing, and the significance level was set to less than 5%.
Results: Ultrasound irradiation significantly increased the intracellular itaconate level and the expression levels of Irg1 and Nrf2 in BMDMs. Upregulation of Il-1β, Il-6, and Tnf-α by LPS was significantly suppressed in BMDMs treated with ultrasound. Ultrasound irradiation did not affect cell viability and apoptosis.
Conclusion: Ultrasound irradiation induces the production of itaconate by upregulating Irg1 expression and attenuates inflammatory responses in macrophages via Nrf2. These results suggest that ultrasound is a potentially useful method to increase itaconate production in macrophages.

Keywords:  IRG1; NRF2; inflammation; itaconate; macrophage; pulsed-ultrasound

DOI:  https://doi.org/10.2147/JIR.S361609
Am J Respir Cell Mol Biol. 2022 Apr 20.

Improving Mitochondrial Function in Viral Infection: Targeting Cellular Metabolism.

Brydie R Huckestein, John F Alcorn.

DOI: https://doi.org/10.1165/rcmb.2022-0096ED
Semin Cell Dev Biol. 2022 Apr 16. pii: S1084-9521(22)00127-6. [Epub ahead of print]

Regulating metabolism to shape immune function: Lessons from Drosophila.

Michelle L Bland.

  Infection with pathogenic microbes is a severe threat that hosts manage by activating the innate immune response. In Drosophila melanogaster, the Toll and Imd signaling pathways are activated by pathogen-associated molecular patterns to initiate cellular and humoral immune processes that neutralize and kill invaders. The Toll and Imd signaling pathways operate in organs such as fat body and gut that control host nutrient metabolism, and infections or genetic activation of Toll and Imd signaling also induce wide-ranging changes in host lipid, carbohydrate and protein metabolism. Metabolic regulation by immune signaling can confer resistance to or tolerance of infection, but it can also lead to pathology and susceptibility to infection. These immunometabolic phenotypes are described in this review, as are changes in endocrine signaling and gene regulation that mediate survival during infection. Future work in the field is anticipated to determine key variables such as sex, dietary nutrients, life stage, and pathogen characteristics that modify immunometabolic phenotypes and, importantly, to uncover the mechanisms used by the immune system to regulate metabolism.

Keywords:  Drosophila; Infection; Innate immunity; Metabolism

DOI:  https://doi.org/10.1016/j.semcdb.2022.04.002
Elife. 2022 Apr 19. pii: e76071. [Epub ahead of print]11

Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target.

Ujjwal Neogi, Nazif Elaldi, Sofia Appelberg, Anoop Ambikan, Emma Kennedy, Stuart Dowall, Binnur K Bagci, Soham Gupta, Jimmy E Rodriguez, Sara Svensson-Akusjärvi, Vanessa Monteil, Akos Vegvari, Rui Benfeitas, Akhil Banerjea, Friedemann Weber, Roger Hewson, Ali Mirazimi.

  The pathogenesis and host-viral interactions of the Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches, including biological network analysis in elucidating the complex host-viral response, interrogates the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) followed by untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level host's metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and concordant with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at the system level and during progressive replication.

Keywords:  CCHFV; immunology; infectious disease; inflammation; metabolic control; microbiology; transcriptomics; viruses

DOI:  https://doi.org/10.7554/eLife.76071
Immunometabolism. 2022 ;pii: e220009. [Epub ahead of print]4(2):

Mitochondria Transfer to CD4+ T Cells May Alleviate Rheumatoid Arthritis by Suppressing Pro-Inflammatory Cytokine Production.

Rocky Giwa, Jonathan R Brestoff.

  CD4+ T cells contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). These cells infiltrate the joints of RA patients and produce cytokines, including Tumor necrosis factor (TNF)-α, that drive joint inflammation and bone destruction. Although biologic therapeutics targeting T cells and TNF-α have benefited patients suffering from RA, some patients are refractory to these therapies, develop antibodies that neutralize these biologics, or develop undesirable side effects. Recent studies indicate that CD4+ T cell cytokine production is regulated in part by specific metabolic modules, suggesting that immunometabolic pathways could represent a novel therapeutic strategy for T cell-mediated diseases such as RA. Wu et al. (2021) demonstrate that mitochondrial function is impaired in CD4+ T cells from RA patients, leading to reduced levels of various citric acid cycle metabolites (e.g., aspartate) that regulate TNF-α production. Treatment of RA-associated T cells with purified mitochondria was sufficient to restore these metabolic defects, limit production of numerous pro-inflammatory cytokines such as TNF-α and IL-17A, and reduce the development of RA-like disease in a humanized mouse model. These data suggest that T cells can be metabolically "re-engineered" ex vivo with exogenous mitochondria and that this mitochondria transfer approach confers anti-inflammatory properties that may reduce disease severity in RA and possibly other rheumatologic diseases. Increasing our understanding of how intercellular mitochondria transfer occurs may identify novel biological pathways that can be targeted therapeutically or harnessed to support cell engineering.

Keywords:  CD4 T cells; mitochondria; rheumatoid arthritis

DOI:  https://doi.org/10.20900/immunometab20220009
FASEB J. 2022 May;36(5): e22300

Macrophage programming is regulated by a cooperative interaction between fatty acid binding protein 5 and peroxisome proliferator-activated receptor γ.

Manale El Kharbili, Katja Aviszus, Sarah K Sasse, Xiaoyun Zhao, Karina A Serban, Susan M Majka, Anthony N Gerber, Fabienne Gally.

  Resolution of inflammation is an active process that is tightly regulated to achieve repair and tissue homeostasis. In the absence of resolution, persistent inflammation underlies the pathogenesis of chronic lung disease such as chronic obstructive pulmonary disease (COPD) with recurrent exacerbations. Over the course of inflammation, macrophage programming transitions from pro-inflammatory to pro-resolving, which is in part regulated by the nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ). Our previous work demonstrated an association between Fatty Acid Binding Protein 5 (FABP5) expression and PPARγ activity in peripheral blood mononuclear cells of healthy and COPD patients. However, a role for FABP5 in macrophage programming has not been examined. Here, using a combination of in vitro and in vivo approaches, we demonstrate that FABP5 is necessary for PPARγ activation. In turn, PPARγ acts directly to increase FABP5 expression in primary human alveolar macrophages. We further illustrate that lack of FABP5 expression promotes a pro-inflammatory macrophage programming with increased secretion of pro-inflammatory cytokines and increased chromatin accessibility for pro-inflammatory transcription factors (e.g., NF-κB and MAPK). And finally, real-time cell metabolic analysis using the Seahorse technology shows an inhibition of oxidative phosphorylation in FABP5-deficient macrophages. Taken together, our data indicate that FABP5 and PPARγ reciprocally regulate each other's expression and function, consistent with a novel positive feedback loop between the two factors that mediates macrophage pro-resolving programming. Our studies highlight the importance of defining targets and regulatory mechanisms that control the resolution of inflammation and may serve to inform novel interventional strategies directed towards COPD.

Keywords:  FABP5; PPARγ; macrophage polarization; resolution of inflammation

DOI:  https://doi.org/10.1096/fj.202200128R
Commun Biol. 2022 Apr 19. 5(1): 370

Targeting colonic macrophages improves glycemic control in high-fat diet-induced obesity.

Theresa V Rohm, Lena Keller, Angela J T Bosch, Shefaa AlAsfoor, Zora Baumann, Amandine Thomas, Sophia J Wiedemann, Laura Steiger, Elise Dalmas, Josua Wehner, Leila Rachid, Catherine Mooser, Bahtiyar Yilmaz, Nerea Fernandez Trigo, Annaise J Jauch, Stephan Wueest, Daniel Konrad, Sandrine Henri, Jan H Niess, Petr Hruz, Stephanie C Ganal-Vonarburg, Julien Roux, Daniel T Meier, Claudia Cavelti-Weder.

The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD). Concurrent with glucose intolerance, pro-inflammatory/monocyte-derived colonic macrophages increased in mice fed a HFD. A link between macrophage numbers and glycemia was established by pharmacological dose-dependent ablation of macrophages. In particular, colon-specific macrophage depletion by intrarectal clodronate liposomes improved glucose tolerance, insulin sensitivity, and insulin secretion capacity. Colonic macrophage activation upon HFD was characterized by an interferon response and a change in mitochondrial metabolism, which converged in mTOR as a common regulator. Colon-specific mTOR inhibition reduced pro-inflammatory macrophages and ameliorated insulin secretion capacity, similar to colon-specific macrophage depletion, but did not affect insulin sensitivity. Thus, pharmacological targeting of colonic macrophages could become a potential therapy in obesity to improve glycemic control.

DOI: https://doi.org/10.1038/s42003-022-03305-z
Small. 2022 Apr 18. e2107816

2D Transition Metal Dichalcogenides Trigger Trained Immunity in Human Macrophages through Epigenetic and Metabolic Pathways.

Guotao Peng, Sandeep Keshavan, Lucia Delogu, Yuyoung Shin, Cinzia Casiraghi, Bengt Fadeel.

  Trained immunity is a recently described phenomenon whereby cells of the innate immune system undergo long-term epigenetic and/or metabolic reprogramming following a short-term interaction with microbes or microbial products. Here, it is shown that 2D transition metal dichalcogenides (TMDs) trigger trained immunity in primary human monocyte-derived macrophages. First, aqueous dispersions of 2D crystal formulations of MoS2 and WS2 are tested, and no cytotoxicity is found despite avid uptake of these materials by macrophages. However, when macrophages are pre-exposed to TMDs, followed by a resting period, this causes a marked modulation of immune-specific gene expression upon subsequent challenge with a microbial agent (i.e., bacterial lipopolysaccharides). Specifically, MoS2 triggers trained immunity through an epigenetic pathway insofar as the histone methyltransferase inhibitor methylthioadenosine reverses these effects. Furthermore, MoS2 triggers an elevation of cyclic adenosine monophosphate (cAMP) levels in macrophages and increased glycolysis is also evidenced in cells subjected to MoS2 training, pointing toward a metabolic rewiring of the cells. Importantly, it is observed that MoS2 triggers the upregulation of Mo-dependent enzymes in macrophages, thus confirming that Mo is bioavailable in these cells. In conclusion, MoS2 is identified as a novel inducer of trained immunity. Thus, TMDs could potentially be harnessed as immunomodulatory agents.

Keywords:  2D materials; epigenetic regulation; macrophages; trained immunity

DOI:  https://doi.org/10.1002/smll.202107816
J Exp Med. 2022 Jun 06. pii: e20211314. [Epub ahead of print]219(6):

CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate.

Yiliang Chen, Jue Zhang, Weiguo Cui, Roy L Silverstein.

CD36 is a type 2 cell surface scavenger receptor widely expressed in many immune and non-immune cells. It functions as both a signaling receptor responding to DAMPs and PAMPs, as well as a long chain free fatty acid transporter. Recent studies have indicated that CD36 can integrate cell signaling and metabolic pathways through its dual functions and thereby influence immune cell differentiation and activation, and ultimately help determine cell fate. Its expression along with its dual functions in both innate and adaptive immune cells contribute to pathogenesis of common diseases, including atherosclerosis and tumor progression, which makes CD36 and its downstream effectors potential therapeutic targets. This review comprehensively examines the dual functions of CD36 in a variety of immune cells, especially macrophages and T cells. We also briefly discuss CD36 function in non-immune cells, such as adipocytes and platelets, which impact the immune system via intercellular communication. Finally, outstanding questions in this field are provided for potential directions of future studies.

DOI: https://doi.org/10.1084/jem.20211314
Front Immunol. 2022 ;13 873834

Impact of Drp1-Mediated Mitochondrial Dynamics on T Cell Immune Modulation.

Jun Song, Xiaofang Yi, Ruolin Gao, Li Sun, Zhixuan Wu, Shuling Zhang, Letian Huang, Chengbo Han, Jietao Ma.

  In recent years, various breakthroughs have been made in tumor immunotherapy that have contributed to prolonging the survival of tumor patients. However, only a subset of patients respond to immunotherapy, which limits its use. One reason for this is that the tumor microenvironment (TME) hinders the migration and infiltration of T cells and affects their continuous functioning, resulting in an exhausted phenotype. Therefore, clarifying the mechanism by which T cells become exhausted is of significance for improving the efficacy of immunotherapy. Several recent studies have shown that mitochondrial dynamics play an important role in the immune surveillance function of T cells. Dynamin-related protein 1 (Drp1) is a key protein that mediates mitochondrial fission and maintains the mitochondrial dynamic network. Drp1 regulates various activities of T cells in vivo by mediating the activation of a series of pathways. In addition, abnormal mitochondrial dynamics were observed in exhausted T cells in the TME. As a potential target for immunotherapy, in this review, we describe in detail how Drp1 regulates various physiological functions of T cells and induces changes in mitochondrial dynamics in the TME, providing a theoretical basis for further research.

Keywords:  T cell exhaustion; dynamin-related protein 1; immunotherapy; mitochondrial dynamics; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.873834
Cell Death Dis. 2022 Apr 20. 13(4): 378

Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer.

Lin Zhao, Yuanyuan Liu, Simiao Zhang, Lingyu Wei, Hongbing Cheng, Jinsheng Wang, Jia Wang.

Metabolic disorders and abnormal immune function changes occur in tumor tissues and cells to varying degrees. There is increasing evidence that reprogrammed energy metabolism contributes to the development of tumor suppressive immune microenvironment and influences the course of gastric cancer (GC). Current studies have found that tumor microenvironment (TME) also has important clinicopathological significance in predicting prognosis and therapeutic efficacy. Novel approaches targeting TME therapy, such as immune checkpoint blockade (ICB), metabolic inhibitors and key enzymes of immune metabolism, have been involved in the treatment of GC. However, the interaction between GC cells metabolism and immune metabolism and how to make better use of these immunotherapy methods in the complex TME in GC are still being explored. Here, we discuss how metabolic reprogramming of GC cells and immune cells involved in GC immune responses modulate anti-tumor immune responses, as well as the effects of gastrointestinal flora in TME and GC. It is also proposed how to enhance anti-tumor immune response by understanding the targeted metabolism of these metabolic reprogramming to provide direction for the treatment and prognosis of GC.

DOI: https://doi.org/10.1038/s41419-022-04821-w
Amino Acids. 2022 Apr 22.

Microbiota-derived tryptophan metabolites in vascular inflammation and cardiovascular disease.

Nadja Paeslack, Maximilian Mimmler, Stefanie Becker, Zhenling Gao, My Phung Khuu, Amrit Mann, Frano Malinarich, Tommy Regen, Christoph Reinhardt.

  The essential amino acid tryptophan (Trp) is metabolized by gut commensals, yielding in compounds that affect innate immune cell functions directly, but also acting on the aryl hydrocarbon receptor (AHR), thus regulating the maintenance of group 3 innate lymphoid cells (ILCs), promoting T helper 17 (TH17) cell differentiation, and interleukin-22 production. In addition, microbiota-derived Trp metabolites have direct effects on the vascular endothelium, thus influencing the development of vascular inflammatory phenotypes. Indoxyl sulfate was demonstrated to promote vascular inflammation, whereas indole-3-propionic acid and indole-3-aldehyde had protective roles. Furthermore, there is increasing evidence for a contributory role of microbiota-derived indole-derivatives in blood pressure regulation and hypertension. Interestingly, there are indications for a role of the kynurenine pathway in atherosclerotic lesion development. Here, we provide an overview on the emerging role of gut commensals in the modulation of Trp metabolism and its influence in cardiovascular disease development.

Keywords:  Atherosclerosis; Endothelium; Gut microbiota; Hypertension; Tryptophan metabolism; Vascular inflammation

DOI:  https://doi.org/10.1007/s00726-022-03161-5
Cell Rep. 2022 Apr 19. pii: S2211-1247(22)00476-4. [Epub ahead of print]39(3): 110715

ILC precursors differentiate into metabolically distinct ILC1-like cells during Mycobacterium tuberculosis infection.

Dan Corral, Alison Charton, Maria Z Krauss, Eve Blanquart, Florence Levillain, Emma Lefrançais, Tamara Sneperger, Zoï Vahlas, Jean-Philippe Girard, Gérard Eberl, Yannick Poquet, Jean-Charles Guéry, Rafael J Argüello, Yasmine Belkaid, Katrin D Mayer-Barber, Matthew R Hepworth, Olivier Neyrolles, Denis Hudrisier.

  Tissue-resident innate lymphoid cells (ILCs) regulate tissue homeostasis, protect against pathogens at mucosal surfaces, and are key players at the interface of innate and adaptive immunity. How ILCs adapt their phenotype and function to environmental cues within tissues remains to be fully understood. Here, we show that Mycobacterium tuberculosis (Mtb) infection alters the phenotype and function of lung IL-18Rα+ ILC toward a protective interferon-γ-producing ILC1-like population. This differentiation is controlled by type 1 cytokines and is associated with a glycolytic program. Moreover, a BCG-driven type I milieu enhances the early generation of ILC1-like cells during secondary challenge with Mtb. Collectively, our data reveal how tissue-resident ILCs adapt to type 1 inflammation toward a pathogen-tailored immune response.

Keywords:  CP: Immunology; CP: Microbiology; immunometabolism; innate lymphoid cell; mucosal immunity; tuberculosis

DOI:  https://doi.org/10.1016/j.celrep.2022.110715
Gerontology. 2022 Apr 19. 1-20

KLF7 Alleviates Atherosclerotic Lesions and Inhibits Glucose Metabolic Reprogramming in Macrophages by Regulating HDAC4/miR-148b-3p/NCOR1.

Fangyuan Chen, Juanli Li, Tao Zheng, Tao Chen, Zuyi Yuan.

  OBJECTIVES: Atherosclerosis (AS) remains a major contributor to death worldwide. This study sought to explore the role of Krüppel-like factor 7 (KLF7) in AS lesions via regulating glucose metabolic reprogramming (GMR) in macrophages.METHODS: AS mouse and cell models were established via high-fat-diet feeding and oxidized low-density lipoprotein (ox-LDL) induction. KLF7, histone deacetylase 4 (HDAC4), miR-148b-3p, and nuclear receptor corepressor 1 (NCOR1) expressions in aortic tissue and cells were detected via reverse transcription quantitative polymerase chain reaction or Western blotting. Parameters of AS lesions and mouse metabolism were detected via hematoxylin-eosin, oil red O, and Masson staining, assay kits, glucose tolerance test, and enzymatic analysis. Peritoneal macrophages of mice were isolated and cellular metabolism was detected via Seahorse metabolic flux analysis, assay kits, ELISA, and Western blotting. Bindings among KLF7, HDAC4, microRNA (miR)-148b-3p, and NCOR1 were testified via the dual-luciferase assay and chromatin immunoprecipitation assay.
RESULTS: KLF7 was poorly expressed in AS mice and ox-LDL-induced RAW264.7 cells. KLF7 overexpression attenuated AS lesions and rescued metabolic abnormities in AS mice, and reduced glucose intake and GMR in ox-LDL-induced RAW264.7 cells. Mechanically, KLF7 bound to the HDAC4 promoter to activate HDAC4. HDAC4 reduced H3 and H4 acetylation levels in the miR-148b promoter to inhibit miR-148b-3p and promote NCOR1 transcription. HDAC4 downregulation abolished the protective role of KLF7 overexpression in AS mice and ox-LDL-induced RAW264.7 cells via the miR-148b-3p/NCOR1 axis.
CONCLUSION: KLF7 bound to the HDAC4 promoter to activate HDAC4, inhibit miR-148b-3p via reducing acetylation level, and promote NCOR1 transcription, thereby limiting GMR in macrophages and alleviating AS lesions.

Keywords:  Atherosclerosis; HDAC4; Histone deacetylase; Krüppel-like factor 7; Macrophage metabolic reprogramming

DOI:  https://doi.org/10.1159/000524029
Nat Cardiovasc Res. 2022 Apr;1(4): 344-360

TRPM2 deficiency in mice protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages.

Pengyu Zong, Jianlin Feng, Zhichao Yue, Albert S Yu, Jean Vacher, Evan R Jellison, Barbara Miller, Yasuo Mori, Lixia Yue.

  Atherosclerosis is the major cause of ischemic heart disease and stroke, the leading causes of mortality worldwide. The central pathological features of atherosclerosis include macrophage infiltration and foam cell formation. However, the detailed mechanisms regulating these two processes remain unclear. Here we show that oxidative stress-activated Ca2+-permeable transient receptor potential melastatin 2 (TRPM2) plays a critical role in atherogenesis. Both global and macrophage-specific Trpm2 deletion protect Apoe -/- mice against atherosclerosis. Trpm2 deficiency reduces oxidized low-density lipoprotein (oxLDL) uptake by macrophages, thereby minimizing macrophage infiltration, foam cell formation and inflammatory responses. Activation of the oxLDL receptor CD36 induces TRPM2 activity, and vice versa. In cultured macrophages, TRPM2 is activated by CD36 ligands oxLDL and thrombospondin-1 (TSP1), and deleting Trpm2 or inhibiting TRPM2 activity suppresses the activation of CD36 signaling cascade induced by oxLDL and TSP1. Our findings establish the TRPM2-CD36 axis as a molecular mechanism underlying atherogenesis, and suggest TRPM2 as a potential therapeutic target for atherosclerosis.

Keywords:  Atherosclerosis; CD36; Ca2+ signaling; TRPM2; TSP1; macrophages; oxLDL

DOI:  https://doi.org/10.1038/s44161-022-00027-7
Helicobacter. 2022 Apr 19. e12895

SHP2/SPI1axis promotes glycolysis and the inflammatory response of macrophages in Helicobacter pylori-induced pediatric gastritis.

Chuanying Li, Changyun Lu, Liangju Gong, Jia Liu, Chen Kan, Hong Zheng, Siying Wang.

  BACKGROUND: Macrophages, as innate immune cells, were reported to participate in the pathogenesis of Helicobacter pylori (H. pylori)-induced gastritis. However, the role and mechanism of macrophage dysfunction in H. pylori-associated pediatric gastritis remain unclear.MATERIALS AND METHODS: An RNA-sequencing assay was used to examine the differential gene expression in normal gastric antrum, non-H. pylori-infected tissue, and H. pylori-infected pediatric gastritis tissue. qPCR assays were applied to verify the expression of target genes. HE staining was performed to identify the occurrence of inflammation in the normal gastric antrum, non-H. pylori-infected tissue, and H. pylori-infected pediatric gastritis tissue. Western blotting was used to measure the expression of SHP2 in pediatric gastritis tissue. The metabolic profile of macrophages was determined via Seahorse metabolic analysis. Flow cytometry analysis was used to examine the level of reactive oxygen species (ROS).
RESULTS: We found that H. pylori -infected gastritis tissue exhibited many differentially expressed genes (DEGs) compared to gastritis tissue without H. pylori infection. Moreover, H. pylori -infected gastritis tissue showed many DEGs annotated with an overactive immune response. We identified that tyrosine-protein phosphatase nonreceptor type 11 (PTPN11), which encodes SHP2, was significantly increased in macrophages of H. pylori -infected gastritis tissue. Furthermore, we revealed that SHP2 could activate the glycolytic function of macrophages to promote H. pylori -induced inflammation. The transcription factor SPI1 , as the downstream molecule of SHP2, could be responsible for the regulation of metabolism-associated gene expression and inflammation.
CONCLUSION: Our study illustrated the molecular landscape of H. pylori-infected gastritis tissue in children and suggested that the SHP2/SPI1axis could be a novel therapeutic target in H. pylori-induced pediatric gastritis.

Keywords:   Helicobacter pylori ; immune response; macrophage

DOI:  https://doi.org/10.1111/hel.12895
Signal Transduct Target Ther. 2022 Apr 18. 7(1): 105

c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses.

Xu-Yan Wang, Yuan Wei, Bo Hu, Yuan Liao, Xiaodong Wang, Wen-Hua Wan, Chun-Xiang Huang, Mahepali Mahabati, Zheng-Yu Liu, Jing-Rui Qu, Xiao-Dan Chen, Dong-Ping Chen, Dong-Ming Kuang, Xue-Hao Wang, Yun Chen.

B cells secreting IL-10 functionally are recognized as functional regulatory B (Breg) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting Breg cells in humans is still lacking. Here, we demonstrate that, although IL-10 itself is anti-inflammatory, IL-10+ functional Breg cells in patients with systemic lupus erythematosus (SLE) display aggressive inflammatory features; these features shift their functions away from inducing CD8+ T cell tolerance and cause them to induce a pathogenic CD4+ T cell response. Functional Breg cells polarized by environmental factors (e.g., CPG-DNA) or directly isolated from patients with SLE mainly exhibit a CD24intCD27-CD38-CD69+/hi phenotype that is different from that of their precursors. Mechanistically, MAPK/ERK/P38-elicited sequential oncogenic c-Myc upregulation and enhanced glycolysis are necessary for the generation and functional maintenance of functional Breg cells. Consistently, strategies that abrogate the activity of ERK, P38, c-Myc, and/or cell glycolysis can efficiently eliminate the pathogenic effects triggered by functional Breg cells.

DOI: https://doi.org/10.1038/s41392-022-00948-6
Nat Metab. 2022 Apr 18.

The gut microbial metabolite formate exacerbates colorectal cancer progression.

Dominik Ternes, Mina Tsenkova, Vitaly Igorevich Pozdeev, Marianne Meyers, Eric Koncina, Sura Atatri, Martine Schmitz, Jessica Karta, Maryse Schmoetten, Almut Heinken, Fabien Rodriguez, Catherine Delbrouck, Anthoula Gaigneaux, Aurelien Ginolhac, Tam Thuy Dan Nguyen, Lea Grandmougin, Audrey Frachet-Bour, Camille Martin-Gallausiaux, Maria Pacheco, Lorie Neuberger-Castillo, Paulo Miranda, Nikolaus Zuegel, Jean-Yves Ferrand, Manon Gantenbein, Thomas Sauter, Daniel Joseph Slade, Ines Thiele, Johannes Meiser, Serge Haan, Paul Wilmes, Elisabeth Letellier.

The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance. Cocultures of F. nucleatum with patient-derived CRC cells display protumorigenic effects, along with a metabolic shift towards increased formate secretion and cancer glutamine metabolism. We further show that microbiome-derived formate drives CRC tumour invasion by triggering AhR signalling, while increasing cancer stemness. Finally, F. nucleatum or formate treatment in mice leads to increased tumour incidence or size, and Th17 cell expansion, which can favour proinflammatory profiles. Moving beyond observational studies, we identify formate as a gut-derived oncometabolite that is relevant for CRC progression.

DOI: https://doi.org/10.1038/s42255-022-00558-0
Biochem Biophys Res Commun. 2022 Apr 10. pii: S0006-291X(22)00558-7. [Epub ahead of print]609 183-188

Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity.

Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Kounosuke Oisaki, Daisuke Takaya, Daiji Sakata, Yoshihiro Izumi, Takaya Togo, Yuko Hattori, Kazufumi Kunimura, Tetsuya Sakurai, Teruki Honma, Takeshi Bamba, Masafumi Nakamura, Motomu Kanai, Makoto Suematsu, Yoshinori Fukui.

  Effective cancer immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute special microenvironments that exclude T cells and resist immunotherapy. Cholesterol sulfate (CS) is a product of sulfotransferase SULT2B1b and acts as an endogenous inhibitor of DOCK2, a Rac activator essential for migration and activation of lymphocytes. We have recently shown that cancer-derived CS prevents tumor infiltration by effector T cells. Therefore, SULT2B1b may be a therapeutic target to dampen CS-mediated immune evasion. Here, we identified 3β-hydroxy-5-cholenoic acid (3β-OH-5-Chln) as a cell-active inhibitor of SULT2B1b. 3β-OH-5-Chln inhibited the cholesterol sulfotransferase activity of SULT2B1b in vitro and suppressed CS production from cancer cells expressing SULT2B1b. In vivo administration of 3β-OH-5-Chln locally reduced CS level in murine CS-producing tumors and increased infiltration of CD8+ T cells. When combined with immune checkpoint blockade or antigen-specific T cell transfer, 3β-OH-5-Chln suppressed the growth of CS-producing tumors. These results demonstrate that pharmacological inhibition of SULT2B1b can promote antitumor immunity through suppressing CS-mediated T cell exclusion.

Keywords:  Cancer immunotherapy; Cholesterol sulfate; DOCK2; Immune evasion; SULT2B1b; T cell exclusion

DOI:  https://doi.org/10.1016/j.bbrc.2022.04.035
PLoS One. 2022 ;17(4): e0266688

Serum Amyloid A is not obligatory for high-fat, high-sucrose, cholesterol-fed diet-induced obesity and its metabolic and inflammatory complications.

Ailing Ji, Andrea C Trumbauer, Victoria P Noffsinger, Hayce Jeon, Avery C Patrick, Frederick C De Beer, Nancy R Webb, Lisa R Tannock, Preetha Shridas.

Several studies in the past have reported positive correlations between circulating Serum amyloid A (SAA) levels and obesity. However, based on limited number of studies involving appropriate mouse models, the role of SAA in the development of obesity and obesity-related metabolic consequences has not been established. Accordingly, herein, we have examined the role of SAA in the development of obesity and its associated metabolic complications in vivo using mice deficient for all three inducible forms of SAA: SAA1.1, SAA2.1 and SAA3 (TKO). Male and female mice were rendered obese by feeding a high fat, high sucrose diet with added cholesterol (HFHSC) and control mice were fed rodent chow diet. Here, we show that the deletion of SAA does not affect diet-induced obesity, hepatic lipid metabolism or adipose tissue inflammation. However, there was a modest effect on glucose metabolism. The results of this study confirm previous findings that SAA levels are elevated in adipose tissues as well as in the circulation in diet-induced obese mice. However, the three acute phase SAAs do not play a causative role in the development of obesity or obesity-associated adipose tissue inflammation and dyslipidemia.

DOI: https://doi.org/10.1371/journal.pone.0266688