bims-imicid 2022-03-13 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022‒03‒13
27 papers selected by
Dylan Ryan
University of Cambridge

Metabolic dynamics instructs CD8+ T cell differentiation and functions.
Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses.
A Deep Insight Into Regulatory T Cell Metabolism in Renal Disease: Facts and Perspectives.
CD146 Associates with Gp130 to Control a Macrophage Pro-inflammatory Program That Regulates the Metabolic Response to Obesity.
New Immunometabolic Strategy Based on Cell Type-Specific Metabolic Reprogramming in the Tumor Immune Microenvironment.
Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo.
Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity.
Monosodium urate crystals regulate a unique JNK-dependent macrophage metabolic and inflammatory response.
Sulforaphane Reduces Pro-Inflammatory Response To Palmitic Acid In Monocytes And Adipose Tissue Macrophages.
Glutaminase 2 Promotes Interleukin-2 Production in CD4+ T cells by Supporting Antioxidant Defense.
Transcriptome analysis revealed a two-step transformation of vascular smooth muscle cells to macrophage-like cells.
The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis.
Epstein-Barr virus latency programs dynamically sensitize B cells to ferroptosis.
Metabolites and metabolic pathways associated with rheumatoid arthritis and systemic lupus erythematosus.
NOD1 splenic activation confers ferroptosis protection and reduces macrophage recruitment under pro-atherogenic conditions.
Circulating Tregs accumulate in omental tumors and acquire adipose-resident features.
Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses.
G6PD is a critical enabler of hypoxia-induced accumulation of macrophages and platelets in mice lungs and contributor to lung inflammation.
Succinate/IL-1β Signaling Axis Promotes the Inflammatory Progression of Endothelial and Exacerbates Atherosclerosis.
Adipocyte-derived PGE2 is required for intermittent fasting-induced Treg proliferation and improvement of insulin sensitivity.
A genome-scale gain-of-function CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T therapy.
MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization.
Functional implications of neutrophil metabolism during ischemic tissue repair.
Modulatory Effects of Fractalkine on Inflammatory Response and Iron Metabolism of Lipopolysaccharide and Lipoteichoic Acid-Activated THP-1 Macrophages.
Suppressing fatty acid synthase by type I interferon and chemical inhibitors as a broad spectrum anti-viral strategy against SARS-CoV-2.
Mycobacterium tuberculosis Acetyltransferase Suppresses Oxidative Stress by Inducing Peroxisome Formation in Macrophages.
Targeted metabolomics analysis of serum and Mycobacterium tuberculosis antigen-stimulated blood cultures of pediatric patients with active and latent tuberculosis.

Eur J Immunol. 2022 Mar 06.

Metabolic dynamics instructs CD8+ T cell differentiation and functions.

Alessio Bevilacqua, Zhiyu Li, Ping-Chih Ho.

  Cytotoxic CD8+ T cells are a key element of the adaptative immune system to protect the organism against infections and malignant cells. During their activation and response T cells undergo different metabolic pathways to support their energetic needs according to their localization and function. However, it has also been recently appreciated that this metabolic reprogramming also directly supports T cells lineage differentiation. Accordingly, metabolic deficiencies and prolonged stress exposure can impact T cell differentiation and skew them into exhausted state. Here, we review how metabolism defines CD8+ T cells differentiation and function. Moreover, we cover the principal metabolic dysregulation that promotes the exhausted phenotype under tumor or chronic virus condition. Finally, we summarize recent strategies to reprogram impaired metabolic pathways to promote CD8+ T cells effector function and survival. This article is protected by copyright. All rights reserved.

Keywords:  T cell differentiation; T cell exhaustion; T cells; infection; metabolism

DOI:  https://doi.org/10.1002/eji.202149486
Front Immunol. 2022 ;13 837669

Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses.

David Bargiela, Pedro P Cunha, Pedro Veliça, Iosifina P Foskolou, Laura Barbieri, Helene Rundqvist, Randall S Johnson.

  Targeting T cell metabolism is an established method of immunomodulation. Following activation, T cells engage distinct metabolic programs leading to the uptake and processing of nutrients that determine cell proliferation and differentiation. Redirection of T cell fate by modulation of these metabolic programs has been shown to boost or suppress immune responses in vitro and in vivo. Using publicly available T cell transcriptomic and proteomic datasets we identified vitamin B6-dependent transaminases as key metabolic enzymes driving T cell activation and differentiation. Inhibition of vitamin B6 metabolism using the pyridoxal 5'-phosphate (PLP) inhibitor, aminoxyacetic acid (AOA), suppresses CD8+ T cell proliferation and effector differentiation in a dose-dependent manner. We show that pyridoxal phosphate phosphatase (PDXP), a negative regulator of intracellular vitamin B6 levels, is under the control of the hypoxia-inducible transcription factor (HIF1), a central driver of T cell metabolism. Furthermore, by adoptive transfer of CD8 T cells into a C57BL/6 mouse melanoma model, we demonstrate the requirement for vitamin B6-dependent enzyme activity in mediating effective anti-tumor responses. Our findings show that vitamin B6 metabolism is required for CD8+ T cell proliferation and effector differentiation in vitro and in vivo. Targeting vitamin B6 metabolism may therefore serve as an immunodulatory strategy to improve anti-tumor immunotherapy.

Keywords:  CD8+ lymphocytes; hypoxia; immunotherapy; metabolism; vitamin B6

DOI:  https://doi.org/10.3389/fimmu.2022.837669
Front Immunol. 2022 ;13 826732

A Deep Insight Into Regulatory T Cell Metabolism in Renal Disease: Facts and Perspectives.

Zhongyu Han, Kuai Ma, Hongxia Tao, Hongli Liu, Jiong Zhang, Xiyalatu Sai, Yunlong Li, Mingxuan Chi, Qing Nian, Linjiang Song, Chi Liu.

  Kidney disease encompasses a complex set of diseases that can aggravate or start systemic pathophysiological processes through their complex metabolic mechanisms and effects on body homoeostasis. The prevalence of kidney disease has increased dramatically over the last two decades. CD4+CD25+ regulatory T (Treg) cells that express the transcription factor forkhead box protein 3 (Foxp3) are critical for maintaining immune homeostasis and preventing autoimmune disease and tissue damage caused by excessive or unnecessary immune activation, including autoimmune kidney diseases. Recent studies have highlighted the critical role of metabolic reprogramming in controlling the plasticity, stability, and function of Treg cells. They are also likely to play a vital role in limiting kidney transplant rejection and potentially promoting transplant tolerance. Metabolic pathways, such as mitochondrial function, glycolysis, lipid synthesis, glutaminolysis, and mammalian target of rapamycin (mTOR) activation, are involved in the development of renal diseases by modulating the function and proliferation of Treg cells. Targeting metabolic pathways to alter Treg cells can offer a promising method for renal disease therapy. In this review, we provide a new perspective on the role of Treg cell metabolism in renal diseases by presenting the renal microenvironment、relevant metabolites of Treg cell metabolism, and the role of Treg cell metabolism in various kidney diseases.

Keywords:  immune homeostasis; metabolic pathways; regulatory T cells; renal disease; tissue damage

DOI:  https://doi.org/10.3389/fimmu.2022.826732
Adv Sci (Weinh). 2022 Mar 08. e2103719

CD146 Associates with Gp130 to Control a Macrophage Pro-inflammatory Program That Regulates the Metabolic Response to Obesity.

Hongxia Duan, Lin Jing, Jianquan Xiang, Chenhui Ju, Zhenzhen Wu, Jingyu Liu, Xinran Ma, Xuehui Chen, Zheng Liu, Jing Feng, Xiyun Yan.

  The mechanism of obesity-related metabolic dysfunction involves the development of systemic inflammation, largely mediated by macrophages. Switching of M1-like adipose tissue macrophages (ATMs) to M2-like ATMs, a population of macrophages associated with weight loss and insulin sensitivity, is considered a viable therapeutic strategy for obesity-related metabolic syndrome. However, mechanisms for reestablishing the polarization of ATMs remain elusive. This study demonstrates that CD146+ ATMs accumulate in adipose tissue during diet-induced obesity and are associated with increased body weight, systemic inflammation, and obesity-induced insulin resistance. Inactivating the macrophage CD146 gene or antibody targeting of CD146 alleviates obesity-related chronic inflammation and metabolic dysfunction. Macrophage CD146 interacts with Glycoprotein 130 (Gp130), the common subunit of the receptor signaling complex for the interleukin-6 family of cytokines. CD146/Gp130 interaction promotes pro-inflammatory polarization of ATMs by activating JNK signaling and inhibiting the activation of STAT3, a transcription factor for M2-like polarization. Disruption of their interaction by anti-CD146 antibody or interleukin-6 steers ATMs toward anti-inflammatory polarization, thus attenuating obesity-induced chronic inflammation and metabolic dysfunction in mice. The results suggest that macrophage CD146 is an important determinant of pro-inflammatory polarization and plays a pivotal role in obesity-induced metabolic dysfunction. CD146 could constitute a novel therapeutic target for obesity complications.

Keywords:  CD146; Gp130; macrophage polarization; obesity

DOI:  https://doi.org/10.1002/advs.202103719
Cells. 2022 Feb 22. pii: 768. [Epub ahead of print]11(5):

New Immunometabolic Strategy Based on Cell Type-Specific Metabolic Reprogramming in the Tumor Immune Microenvironment.

Ji-Yong Sung, Jae-Ho Cheong.

  Immunometabolism is an emerging discipline in cancer immunotherapy. Tumor tissues are heterogeneous and influenced by metabolic reprogramming of the tumor immune microenvironment (TIME). In the TIME, multiple cell types interact, and the tumor and immune cells compete for limited nutrients, resulting in altered anticancer immunity. Therefore, metabolic reprogramming of individual cell types may influence the outcomes of immunotherapy. Understanding the metabolic competition for access to limited nutrients between tumor cells and immune cells could reveal the breadth and complexity of the TIME and aid in developing novel therapeutic approaches for cancer. In this review, we highlight that, when cells compete for nutrients, the prevailing cell type gains certain advantages over other cell types; for instance, if tumor cells prevail against immune cells for nutrients, the former gains immune resistance. Thus, a strategy is needed to selectively suppress such resistant tumor cells. Although challenging, the concept of cell type-specific metabolic pathway inhibition is a potent new strategy in anticancer immunotherapy.

Keywords:  immune checkpoint inhibitor; immunometabolism; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3390/cells11050768
Front Immunol. 2022 ;13 748375

Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo.

Tae Seok Oh, Damian C Hutchins, Rabina Mainali, Kevin H Goslen, Matthew A Quinn.

  A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of in vitro myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopie the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with in vitro myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. We also show 4-octyl itaconate suppresses injury-induced MYOG expression in vivo. More importantly, our findings suggest the therapeutic potential of itaconate, and its derivatives could be limited due to deleterious effects on myogenesis.

Keywords:  C2C12; itaconate; myogenesis; succinate; succinate dehydrogenase

DOI:  https://doi.org/10.3389/fimmu.2022.748375
Sci Transl Med. 2022 Mar 09. 14(635): eabj6879

Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity.

Christian Schwartz, Viviane Schmidt, Andrea Deinzer, Heike C Hawerkamp, Emily Hams, Jasmin Bayerlein, Ole Röger, Moritz Bailer, Christian Krautz, Amr El Gendy, Moustafa Elshafei, Helen M Heneghan, Andrew E Hogan, Donal O'Shea, Padraic G Fallon.

Obesity has become a major health problem in the industrialized world. Immune regulation plays an important role in adipose tissue homeostasis; however, the initial events that shift the balance from a noninflammatory homeostatic environment toward inflammation leading to obesity are poorly understood. Here, we report a role for the costimulatory molecule programmed death-ligand 1 (PD-L1) in the limitation of diet-induced obesity. Functional ablation of PD-L1 on dendritic cells (DCs) using conditional knockout mice increased weight gain and metabolic syndrome during diet-induced obesity, whereas PD-L1 expression on type 2 innate lymphoid cells (ILC2s), T cells, and macrophages was dispensable for obesity control. Using in vitro cocultures, DCs interacted with T cells and ILC2s via the PD-L1:PD-1 axis to inhibit T helper type 1 proliferation and promote type 2 polarization, respectively. A role for PD-L1 in adipose tissue regulation was also shown in humans, with a positive correlation between PD-L1 expression in visceral fat of people with obesity and elevated body weight. Thus, we define a mechanism of adipose tissue homeostasis controlled by the expression of PD-L1 by DCs, which may be a clinically relevant finding with regard to immune-related adverse events during immune checkpoint inhibitor therapy.

DOI: https://doi.org/10.1126/scitranslmed.abj6879
Cell Rep. 2022 Mar 08. pii: S2211-1247(22)00222-4. [Epub ahead of print]38(10): 110489

Monosodium urate crystals regulate a unique JNK-dependent macrophage metabolic and inflammatory response.

Isidoro Cobo, Anyan Cheng, Jessica Murillo-Saich, Roxana Coras, Alyssa Torres, Yohei Abe, Addison J Lana, Johannes Schlachetzki, Ru Liu-Bryan, Robert Terkeltaub, Elsa Sanchez-Lopez, Christopher K Glass, Monica Guma.

  Monosodium urate crystals (MSUc) induce inflammation in vivo without prior priming, raising the possibility of an initial cell-autonomous phase. Here, using genome-wide transcriptomic analysis and biochemical assays, we demonstrate that MSUc alone induce a metabolic-inflammatory transcriptional program in non-primed human and murine macrophages that is markedly distinct to that induced by LPS. Genes uniquely upregulated in response to MSUc belong to lipid and amino acid metabolism, glycolysis, and SLC transporters. This upregulation leads to a metabolic rewiring in sera from individuals and mice with acute gouty arthritis. Mechanistically, the initiating inflammatory-metabolic changes in acute gout flares are regulated through a persistent expression and increased binding of JUN to the promoter of target genes through JNK signaling-but not P38-in a process that is different than after LPS stimulation and independent of inflammasome activation. Finally, pharmacological JNK inhibition limits MSUc-induced inflammation in animal models of acute gouty inflammation.

Keywords:  AP-1 activation; JNK; MSU crystals; SLC2A1; glycolysis; gout; macrophage; transcriptional regulation

DOI:  https://doi.org/10.1016/j.celrep.2022.110489
J Nutr Biochem. 2022 Mar 07. pii: S0955-2863(22)00049-3. [Epub ahead of print] 108978

Sulforaphane Reduces Pro-Inflammatory Response To Palmitic Acid In Monocytes And Adipose Tissue Macrophages.

Evan J Williams, Laurent Guilleminault, Bronwyn S Berthon, Shaun Eslick, Timothy Wright, Constantine Karihaloo, Mark Gately, Katherine J Baines, Lisa G Wood.

  BACKGROUND: Chronic low-grade systemic inflammation (SI), including activation of the NLRP3 inflammasome, is a feature of obesity, associated with increased circulating saturated fatty acids, such as palmitic acid (PA), and bacterial endotoxin lipopolysaccharide (LPS). PA and LPS may contribute to SI observed in obesity, while the dietary antioxidant sulforaphane has been shown to reduce activation of the NLRP3 inflammasome. This study investigated immune cell responses from obese subjects to PA, and the effects of sulforaphane on NLRP3 activation/inflammation.METHODS: Peripheral blood monocytes isolated from obese (n=8) and non-obese (n=8) subjects and adipose tissue macrophages (ATMs) isolated from visceral fat obtained from obese subjects (n=10) during bariatric surgery were pre-treated with/without sulforaphane (40µM) for 3hours then stimulated with PA (500µM) +/- LPS (1ng/mL monocytes; 100ng/mL ATMs) for 15hours. Culture supernatants were assessed for TNF-α and IL-1β by ELISA, NLRP3 inflammasome gene expression was assessed by qPCR.
RESULTS: IL-1β and NLRP3 expression were higher in both unstimulated and PA treated monocytes from obese compared to non-obese subjects. In ATMs neither PA alone or combined with LPS increased cytokine production or inflammasome gene expression. Sulforaphane reduced TNF-α and IL-1β from monocytes in both groups, however inflammasome associated genes were only reduced in monocytes from obese subjects. Sulforaphane reduced cytokine production and inflammasome gene expression in ATMs.
CONCLUSION: NLRP3 inflammasome activation by PA is higher in obesity, which maybe driven by baseline activation of the NLRP3 inflammasome. Sulforaphane modulates inflammatory responses in immune cells and may play a role in reducing SI in obesity.

Keywords:  NLRP3; Obesity; Palmitic acid; Sulforaphane; interleukin 1 beta

DOI:  https://doi.org/10.1016/j.jnutbio.2022.108978
Arthritis Rheumatol. 2022 Mar 07.

Glutaminase 2 Promotes Interleukin-2 Production in CD4+ T cells by Supporting Antioxidant Defense.

Ryo Hisada, Nobuya Yoshida, Seo Yeon K Orite, Masataka Umeda, Catalina Burbano, Marc Scherlinger, Michihito Kono, Suzanne Krishfield, George C Tsokos.

OBJECTIVE: Glutaminase (GLS) isoenzymes GLS1 and GLS2 catalyze the first step of glutaminolysis. GLS1 is requisite for Th17 differentiation and its inhibition suppresses autoimmune disease in animals but the function of GLS2 is not known. The aim of this study was to investigate the role of GLS2 in CD4+ T cell function and systemic lupus erythematosus (SLE) pathogenesis.METHODS: We measured reactive oxygen species (ROS) levels, lipid peroxidation, and mitochondrial mass/polarization by flow cytometry, IL-2 production by dual luciferase assay, and CpG-DNA methylation of the Il-2 gene by real-time PCR. The impact of the overexpression of wild type GLS1 and GLS2, or mutated GLS2 at the PDZ domain-binding motif in CD4+ T cells was examined. Furthermore, GLS2 expression in CD4+ T cells from lupus-prone mice and patients with SLE was analyzed by Western blotting.
RESULTS: GLS2, but not GLS1, reduced ROS levels, lipid peroxidation and restored mitochondrial function in T cells. GLS2 promoted IL-2 production through the demethylation of the Il-2 promoter. Mutation of the PDZ domain-binding motif abated the ability of GLS2 to regulate IL-2 and ROS levels. In lupus-prone mice and patients with SLE, the expression of GLS2 was decreased in CD4+ T cells. Finally, GLS2 overexpression corrected ROS levels and restored IL-2 production by lupus CD4+ cells.
CONCLUSION: Our findings suggest that GLS2 has a crucial role in IL-2 production by CD4+ T cells by supporting the antioxidant defense and offer a new approach to correct IL-2 production by T cell in SLE.

DOI: https://doi.org/10.1002/art.42112
Atherosclerosis. 2022 Feb 23. pii: S0021-9150(22)00101-0. [Epub ahead of print]346 26-35

Transcriptome analysis revealed a two-step transformation of vascular smooth muscle cells to macrophage-like cells.

Zhong Zhang, Jiaxin Huang, Yan Wang, Wei Shen.

  BACKGROUND AND AIMS: It is known that vascular smooth muscle cells (VSMCs) represent a major part of the atherosclerotic plaque. In addition to forming fibrous cap cells that stabilize the atherosclerotic plaque, VSMCs trans-differentiate into macrophage-like cells that exacerbate the necrotic core. Here, we aim to address the question of how VSMCs are selected to perform distinct functions under a similar environmental stress, and how much cellular reprogramming happens during VSMC-to-macrophage-like transformation.METHODS: Single-cell RNA-Sequencing (scRNA-Seq) analysis, in vitro transcriptional and metabolic studies, and pathological sample examinations were performed to decipher the cellular reprogramming during VSMC-to-macrophage-like cell transformation.
RESULTS: By analyzing scRNA-Seq data of the atherosclerotic plaque, VSMC-derived macrophage-like cells were found to undergo a series promotion of lysosome-related and inflammation-related genes. In vitro transcriptional studies further confirmed that suppression of NOTCH signaling is the prerequisite for VSMCs to undergo sufficient genetic and metabolic reprogramming to a macrophage-like state and perform macrophage-like functions, while high-lipid treatment alone only promote VSMCs into a pro-inflammatory state without gain of lysosome-related functions. Mechanistic studies showed that NOTCH inhibition shifted VSMCs into a de-differentiated state by suppressing the developmental program, including key factor Myocd, leading to complete transformation into macrophage-like cells.
CONCLUSIONS: NOTCH, a signaling mediated by consistent cell contacts, prevents the complete transformation of VSMCs into macrophage-like cells under high lipid stress. We hope our study could offer some insights into the retarded VSMC-to-macrophage-like transformation observed in previous in vitro studies and clarify the cellular reprogramming underlying the VSMC-to-macrophage-like cell transformation.

Keywords:  Atherosclerosis; Genetic reprogramming; Macrophage-like cells; Metabolic reprograming; NOTCH signaling; VSMC

DOI:  https://doi.org/10.1016/j.atherosclerosis.2022.02.021
Cell Death Differ. 2022 Mar 09.

The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis.

Chia George Hsu, Camila Lage Chávez, Chongyang Zhang, Mark Sowden, Chen Yan, Bradford C Berk.

Pyroptosis is a form of cell death triggered by the innate immune system that has been implicated in the pathogenesis of sepsis and acute lung injury. At the cellular level, pyroptosis is characterized by cell swelling, membrane rupture, and release of inflammatory cytokines, such as IL-1β. However, the role of endogenous lipids in pyroptosis remains underappreciated. We discovered that 4-hydroxynonenal (HNE), a major endogenous product of lipid peroxidation, inhibited pyroptosis and inflammasome activation. HNE at physiological concentrations (3 µM) blocked nigericin and ATP-induced cell death, as well as secretion of IL-1β, by mouse primary macrophages and human peripheral blood mononuclear cells. Treatment with HNE, or an increase of endogenous HNE by inhibiting glutathione peroxidase 4, reduced inflammasome activation in mouse models of acute lung injury and sepsis. Mechanistically, HNE inhibited the NLRP3 inflammasome activation independently of Nrf2 and NF-κB signaling, and had no effect on the NLRC4 or AIM2 inflammasome. Furthermore, HNE directly bound to NLRP3 and inhibited its interaction with NEK7. Our findings identify HNE as a novel, endogenous inhibitor of the NLRP3 inflammasome.

DOI: https://doi.org/10.1038/s41418-022-00966-5
Proc Natl Acad Sci U S A. 2022 Mar 15. 119(11): e2118300119

Epstein-Barr virus latency programs dynamically sensitize B cells to ferroptosis.

Eric M Burton, Jewel Voyer, Benjamin E Gewurz.

  SignificanceEpstein-Barr virus (EBV) contributes to Burkitt lymphoma and post-transplant lymphoproliferative disease (PTLD). EBV-transforming programs activate lipid metabolism to convert B cells into immortalized lymphoblastoid cell lines (LCL), a PTLD model. We found that stages of EBV transformation generate lipid reactive oxygen species (ROS) byproducts to varying degrees, and that a Burkitt-like phase of B cell outgrowth requires lipid ROS detoxification by glutathione peroxidase 4 and its cofactor glutathione. Perturbation of this redox defense in early stages of transformation or in Burkitt cells triggered ferroptosis, a programmed cell death pathway. LCLs were less dependent on this defense, a distinction tied to EBV latency programs. This highlights ferroptosis induction as a potential therapeutic approach for prevention or treatment of certain EBV+ lymphomas.

Keywords:  B lymphocyte; ferroptosis; lipid metabolism; oxidative stress; tumor virus

DOI:  https://doi.org/10.1073/pnas.2118300119
J Transl Autoimmun. 2022 ;5 100150

Metabolites and metabolic pathways associated with rheumatoid arthritis and systemic lupus erythematosus.

Nancy P Duarte-Delgado, Mónica P Cala, Alfonso Barreto, Luz-Stella Rodríguez C.

  Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are chronic autoimmune diseases that result from the combined influence of genetic and environmental factors that promotes the loss of tolerance to cellular components. The complexity of these diseases converts them into a major challenge at the diagnostic and treatment level. Therefore, it is convenient to implement the use of tools for a better understanding of the physiopathology of these diseases to propose reliable biomarkers. The "omics" disciplines like metabolomics and lipidomics allow to study RA and SLE in a higher degree of detail since they evaluate the metabolites and metabolic pathways involved in disease pathogenesis. This review has compiled the information of metabolomics and lipidomics studies where samples obtained from RA and SLE patients were evaluated to find the metabolites and pathways differences between patients and healthy controls. In both diseases, there is a decrease in several amino acids and oxidative stress-related metabolites like glutathione. These findings may be useful for functional metabolomics studies aiming to reprogram the metabolism in a disease setting to recover normal immune cell homeostasis and function.

Keywords:  Autoimmune tautology; Lipidomics; Metabolic pathways; Metabolites; Metabolomics; Rheumatoid arthritis; Systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.jtauto.2022.100150
Biomed Pharmacother. 2022 Mar 03. pii: S0753-3322(22)00157-3. [Epub ahead of print]148 112769

NOD1 splenic activation confers ferroptosis protection and reduces macrophage recruitment under pro-atherogenic conditions.

Victoria Fernández-García, Silvia González-Ramos, José Avendaño-Ortiz, Paloma Martín-Sanz, Carmen Delgado, Antonio Castrillo, Lisardo Boscá.

  The bioavailability and regulation of iron is essential for central biological functions in mammals. The role of this element in ferroptosis and the dysregulation of its metabolism contribute to diseases, ranging from anemia to infections, alterations in the immune system, inflammation and atherosclerosis. In this sense, monocytes and macrophages modulate iron metabolism and splenic function, while at the same time they can worsen the atherosclerotic process in pathological conditions. Since the nucleotide-binding oligomerization domain 1 (NOD1) has been linked to numerous disorders, including inflammatory and cardiovascular diseases, we investigated its role in iron homeostasis. The iron content was measured in various tissues of Apoe-/- and Apoe-/-Nod1-/- mice fed a high-fat diet (HFD) for 4 weeks, under normal or reduced splenic function after ligation of the splenic artery. In the absence of NOD1 the iron levels decreased in spleen, heart and liver regardless the splenic function. This iron decrease was accompanied by an increase in the recruitment of F4/80+-macrophages in the spleen through a CXCR2-dependent signaling, as deduced by the reduced recruitment after administration of a CXCR2 inhibitor. CXCR2 mediates monocyte/macrophage chemotaxis to areas of inflammation and accumulation of leukocytes in the atherosclerotic plaque. Moreover, in the absence of NOD1, inhibition of CXCR2 enhanced atheroma progression. NOD1 activation increased the levels of GPX4 and other iron and ferroptosis regulatory proteins in macrophages. Our findings highlight the preeminent role of NOD1 in iron homeostasis and ferroptosis. These results suggest promising avenues of investigation for the diagnosis and treatment of iron-related diseases directed by NOD1.

Keywords:  Atherosclerosis; CXCR2; Ferroptosis; Iron; Macrophages; NOD1

DOI:  https://doi.org/10.1016/j.biopha.2022.112769
Cancer Immunol Res. 2022 Mar 09. pii: canimm.0880.2021. [Epub ahead of print]

Circulating Tregs accumulate in omental tumors and acquire adipose-resident features.

Mingyong Liu, Dmytro Starenki, Christopher D Scharer, Aaron Silva-Sanchez, Patrick A Molina, Jennifer S Pollock, Sara J Cooper, Rebecca C Arend, Alexander F Rosenberg, Troy D Randall, Selene Meza-Perez.

Tumors that metastasize in the peritoneal cavity typically end up in the omental adipose tissue, a particularly immune-suppressive environment that includes specialized adipose-resident regulatory T cells (Tregs). Tregs rapidly accumulate in the omentum after tumor implantation and potently suppress anti-tumor immunity. However, it is unclear whether these Tregs are recruited from the circulation or derived from pre-existing adipose-resident Tregs by clonal expansion. Here we show that Tregs in tumor-bearing omenta predominantly have thymus-derived characteristics. Moreover, naïve tumor antigen-specific CD4+ T cells fail to differentiate into Tregs in tumor-bearing omenta. In fact, Tregs derived from the pre-tumor repertoire are sufficient to suppress anti-tumor immunity and promote tumor growth. However, tumor implantation in the omentum does not promote Treg clonal expansion, but instead leads to increased clonal diversity. Parabiosis experiments show that despite tissue-resident (non-circulating) characteristics of omental Tregs in naïve mice, tumor implantation promotes a rapid influx of circulating Tregs, many of which come from the spleen. Finally, we show that newly recruited Tregs rapidly acquire characteristics of adipose-resident Tregs in tumor-bearing omenta. These data demonstrate that most Tregs in omental tumors are recruited from the circulation and adapt to their environment by altering their homing, transcriptional and metabolic properties.

DOI: https://doi.org/10.1158/2326-6066.CIR-21-0880
Nat Cell Biol. 2022 Mar 07.

Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses.

Lei-Lei Chen, Carmen Morcelle, Zhou-Li Cheng, Xiufei Chen, Yanping Xu, Yajing Gao, Junbin Song, Zhijun Li, Matthew D Smith, Miao Shi, Yezhang Zhu, Neng Zhou, Meng Cheng, Chenxi He, Kwei-Yan Liu, Guoping Lu, Lei Zhang, Cheng Zhang, Jinye Zhang, Yiping Sun, Tuan Qi, Yingying Lyu, Zhi-Zhong Ren, Xian-Ming Tan, Jiayong Yin, Fei Lan, Ying Liu, Hui Yang, Maoxiang Qian, Caiwen Duan, Xing Chang, Yufeng Zhou, Li Shen, Albert S Baldwin, Kun-Liang Guan, Yue Xiong, Dan Ye.

As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.

DOI: https://doi.org/10.1038/s41556-022-00853-8
Vascul Pharmacol. 2022 Mar 07. pii: S1537-1891(22)00025-8. [Epub ahead of print] 106976

G6PD is a critical enabler of hypoxia-induced accumulation of macrophages and platelets in mice lungs and contributor to lung inflammation.

Ryota Hashimoto, Sachin A Gupte.

  Metabolic reprogramming-driven inflammation is emerging as central processes in the pathogenesis of pulmonary hypertension (PH). Although extensive work is ongoing to elucidate the role of inflammation in the remodeling of the pulmonary vasculature, the identity of macrophages and the role of increased glycolysis/glucose-6-phosphate dehydrogenase (G6PD) activity in fueling inflammation in the lung remains unclear. Our objective was to characterize inflammatory cell types in the lungs of hypoxic mice, a model of PH, and to investigate the effects of G6PD on hypoxia-induced accumulation of immunogenic/inflammatory cells in lungs. C57BL/6 mice were exposed to 10% O2. Our results revealed that hypoxia stimulated a time-dependent increase of CD11b+-cells in the bone marrow and blood. In the lung, hypoxia increased genes encoding M2a-macrophage markers. Unexpectedly, we also discovered that CD41+-platelets were the source of TNFα and that their numbers were increased in the lungs of hypoxic mice. Inhibition of G6PD activity with (3β,5α)-3,21-dihydroxypregnan-20-one suppressed (P < 0.05) expression of genes encoding CD163 and ARG-1 (M2a-macrophage marker) and CD41+TNFα+-platelets in lungs of hypoxic mice. Moreover, there were fewer CD41+TNFα+-platelets in lungs of hypoxic G6PD-deficient mice than their normoxic-controls. Collectively, these results reveal new observations that platelets secreting TNFα combined with macrophages potentially contribute to the pathogenesis of hypoxia-induced PH, and most importantly treatment of hypoxic mice with G6PD activity inhibitor decreased accumulation of the macrophages, platelets, and proinflammatory cytokines, in the lungs. Therefore, G6PD appears to be a good pharmacotherapeutic target to reduce lung inflammation.

Keywords:  Blood; Bone marrow; Flow cytometry; Inflammation; Lung; Macrophages; Monocytes

DOI:  https://doi.org/10.1016/j.vph.2022.106976
Front Immunol. 2022 ;13 817572

Succinate/IL-1β Signaling Axis Promotes the Inflammatory Progression of Endothelial and Exacerbates Atherosclerosis.

Jingwen Xu, Yabing Zheng, Yaqing Zhao, Yujiao Zhang, Huilin Li, An Zhang, Xuehan Wang, Weizong Wang, Yinglong Hou, Jiangrong Wang.

  Inflammation is an important driver of atherosclerosis. Succinate is a new extracellular inflammatory alarm released by activated macrophages. Succinate is sensed by succinate receptor 1 (Sucnr1) and then transferred to effector cells. It is worth exploring whether succinate is capable of facilitating the inflammatory response in atherosclerosis. In this study, we firstly found that arterial serum of Coronary Heart Disease (CHD) patients contained significantly higher succinate and interleukin (IL)-1β than Health control (HC) subjects, and succinate was positively correlated with IL-1β. As demonstrated by the in vitro study, succinate/hypoxia-inducible factor 1α (Hif)-1α/IL-1β signal axis existed and significantly facilitated the inflammatory program in human umbilical vein endothelial cells (HUVECs). Under the coculture, activated macrophages released succinate, which would be transferred to HUVECs via Sucnr1 and then activate Hif-1α to produce a greater amount of IL-1β. Likewise, the aortic sinus's inflammatory phenotype was found to be more significant within Apoe-/- mice that were injected with succinate. Furthermore, Sucnr1 inhibitor (NF-56-EJ40) could significantly interrupt succinate/IL-1β signal in HUVECs and macrophages. As revealed by this study, glycolytic metabolism following the release of succinate could be found in atherosclerotic pathology, and succinate would drive succinate/IL-1β signal dependent on Sucnr1 and then exacerbate inflammatory responses. Sucnr1 might be a novel target for cutting off the transduction of succinate signal to prevent the inflammation of atherosclerosis.

Keywords:  Hif-1α; IL-1β; Sucnr1; atherosclerosis; inflammation; succinate

DOI:  https://doi.org/10.3389/fimmu.2022.817572
JCI Insight. 2022 Mar 08. pii: e153755. [Epub ahead of print]7(5):

Adipocyte-derived PGE2 is required for intermittent fasting-induced Treg proliferation and improvement of insulin sensitivity.

Chunqing Wang, Xing Zhang, Liping Luo, Yan Luo, Xin Yang, Xiaofeng Ding, Lu Wang, Huyen Le, Lily Elizabeth R Feldman, Xuebo Men, Cen Yan, Wendong Huang, Yingmei Feng, Feng Liu, Xuexian O Yang, Meilian Liu.

  The intermittent fasting (IF) diet has profound benefits for diabetes prevention. However, the precise mechanisms underlying IF's beneficial effects remain poorly defined. Here, we show that the expression levels of cyclooxygenase-2 (COX-2), an enzyme that produces prostaglandins, are suppressed in white adipose tissue (WAT) of obese humans. In addition, the expression of COX-2 in WAT is markedly upregulated by IF in obese mice. Adipocyte-specific depletion of COX-2 led to reduced fractions of CD4+Foxp3+ Tregs and a substantial decrease in the frequency of CD206+ macrophages, an increase in the abundance of γδT cells in WAT under normal chow diet conditions, and attenuation of IF-induced antiinflammatory and insulin-sensitizing effects, despite a similar antiobesity effect in obese mice. Mechanistically, adipocyte-derived prostaglandin E2 (PGE2) promoted Treg proliferation through the CaMKII pathway in vitro and rescued Treg populations in adipose tissue in COX-2-deficient mice. Ultimately, inactivation of Tregs by neutralizing anti-CD25 diminished IF-elicited antiinflammatory and insulin-sensitizing effects, and PGE2 restored the beneficial effects of IF in COX-2-KO mice. Collectively, our study reveals that adipocyte COX-2 is a key regulator of Treg proliferation and that adipocyte-derived PGE2 is essential for IF-elicited type 2 immune response and metabolic benefits.

Keywords:  Adipose tissue; Innate immunity; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.153755
Cell Metab. 2022 Mar 07. pii: S1550-4131(22)00053-5. [Epub ahead of print]

A genome-scale gain-of-function CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T therapy.

Lupeng Ye, Jonathan J Park, Lei Peng, Quanjun Yang, Ryan D Chow, Matthew B Dong, Stanley Z Lam, Jianjian Guo, Erting Tang, Yueqi Zhang, Guangchuan Wang, Xiaoyun Dai, Yaying Du, Hyunu R Kim, Hanbing Cao, Youssef Errami, Paul Clark, Alexey Bersenev, Ruth R Montgomery, Sidi Chen.

  Chimeric antigen receptor (CAR)-T cell-based immunotherapy for cancer and immunological diseases has made great strides, but it still faces multiple hurdles. Finding the right molecular targets to engineer T cells toward a desired function has broad implications for the armamentarium of T cell-centered therapies. Here, we developed a dead-guide RNA (dgRNA)-based CRISPR activation screen in primary CD8+ T cells and identified gain-of-function (GOF) targets for CAR-T engineering. Targeted knockin or overexpression of a lead target, PRODH2, enhanced CAR-T-based killing and in vivo efficacy in multiple cancer models. Transcriptomics and metabolomics in CAR-T cells revealed that augmenting PRODH2 expression reshaped broad and distinct gene expression and metabolic programs. Mitochondrial, metabolic, and immunological analyses showed that PRODH2 engineering enhances the metabolic and immune functions of CAR-T cells against cancer. Together, these findings provide a system for identification of GOF immune boosters and demonstrate PRODH2 as a target to enhance CAR-T efficacy.

Keywords:  CAR-T; PRODH2; T cell CRISPR activation screen; T cell GOF screen; antitumor efficacy; dead-guide RNA; metabolism; mitochondria; proline metabolism

DOI:  https://doi.org/10.1016/j.cmet.2022.02.009
Sci Rep. 2022 Mar 09. 12(1): 4183

MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization.

Landon J Hansen, Rui Yang, Kristen Roso, Wenzhe Wang, Lee Chen, Qing Yang, Christopher J Pirozzi, Yiping He.

Glioblastoma (GBM) is a lethal brain cancer known for its potent immunosuppressive effects. Loss of Methylthioadenosine Phosphorylase (MTAP) expression, via gene deletion or epigenetic silencing, is one of the most common alterations in GBM. Here we show that MTAP loss in GBM cells is correlated with differential expression of immune regulatory genes. In silico analysis of gene expression profiles in GBM samples revealed that low MTAP expression is correlated with an increased proportion of M2 macrophages. Using in vitro macrophage models, we found that methylthioadenosine (MTA), the metabolite that accumulates as a result of MTAP loss in GBM cells, promotes the immunosuppressive alternative activation (M2) of macrophages. We show that this effect of MTA on macrophages is independent of IL4/IL3 signaling, is mediated by the adenosine A2B receptor, and can be pharmacologically reversed. This study suggests that MTAP loss in GBM cells may contribute to the immunosuppressive tumor microenvironment, and that MTAP status should be considered for characterizing GBM immune states and devising immunotherapy-based approaches for treating MTAP-null GBM.

DOI: https://doi.org/10.1038/s41598-022-07697-0
Curr Opin Pharmacol. 2022 Mar 08. pii: S1471-4892(22)00015-7. [Epub ahead of print]63 102191

Functional implications of neutrophil metabolism during ischemic tissue repair.

Enzo B Piccolo, Edward B Thorp, Ronen Sumagin.

Immune cell mobilization and their accumulation in the extravascular space is a key consequence of tissue injury. Maladaptive trafficking and immune activation following reperfusion of ischemic tissue can exacerbate tissue repair. After ischemic injury such as myocardial infarction (MI), PMNs are the first cells to arrive at the sites of insult and their response is critical for the sequential progression of ischemia from inflammation to resolution and finally to tissue repair. However, PMN-induced inflammation can also be detrimental to cardiac function and ultimately lead to heart failure. In this review, we highlight the role of PMNs during key cellular and molecular events of ischemic heart failure. We address new research on PMN metabolism, and how this orchestrates diverse functions such as PMN chemotaxis, degranulation, and phagocytosis. Particular focus is given to PMN metabolism regulation by mitochondrial function and mTOR kinase activity.

DOI: https://doi.org/10.1016/j.coph.2022.102191
Int J Mol Sci. 2022 Feb 27. pii: 2629. [Epub ahead of print]23(5):

Modulatory Effects of Fractalkine on Inflammatory Response and Iron Metabolism of Lipopolysaccharide and Lipoteichoic Acid-Activated THP-1 Macrophages.

Edina Pandur, Kitti Tamási, Ramóna Pap, Gergely Jánosa, Katalin Sipos.

  Fractalkine (CX3CL1) acts as a chemokine as well as a regulator of iron metabolism. Fractalkine binds CX3CR1, the fractalkine receptor on the surface of monocytes/macrophages regulating different intracellular signalling pathways such as mitogen-activated protein kinase (MAPK), phospholipase C (PLC) and NFκB contributing to the production of pro-inflammatory cytokine synthesis, and the regulation of cell growth, differentiation, proliferation and metabolism. In this study, we focused on the modulatory effects of fractalkine on the immune response and on the iron metabolism of Escherichia coli and Pseudomonas aeruginosa lipopolysaccharides (LPS) and Staphylococcus aureus lipoteichoic acid (LTA) activated THP-1 cells to get a deeper insight into the role of soluble fractalkine in the regulation of the innate immune system. Pro-inflammatory cytokine secretions of the fractalkine-treated, LPS/LTA-treated, and co-treated THP-1 cells were determined using ELISArray and ELISA measurements. We analysed the protein expression levels of signalling molecules regulated by CX3CR1 as well as hepcidin, the major iron regulatory hormone, the iron transporters, the iron storage proteins and mitochondrial iron utilization. The results showed that fractalkine treatment alone did not affect the pro-inflammatory cytokine secretion, but it was proposed to act as a regulator of the iron metabolism of THP-1 cells. In the case of two different LPS and one type of LTA with fractalkine co-treatments, fractalkine was able to alter the levels of signalling proteins (NFκB, PSTAT3, Nrf2/Keap-1) regulating the expression of pro-inflammatory cytokines as well as hepcidin, and the iron storage and utilization of the THP-1 cells.

Keywords:  cell signalling; cytokine; fractalkine; inflammation; iron metabolism; lipopolysaccharide; lipoteichoic acid; macrophage

DOI:  https://doi.org/10.3390/ijms23052629
Acta Pharm Sin B. 2022 Feb 28.

Suppressing fatty acid synthase by type I interferon and chemical inhibitors as a broad spectrum anti-viral strategy against SARS-CoV-2.

Saba R Aliyari, Amir Ali Ghaffari, Olivier Pernet, Kislay Parvatiyar, Yao Wang, Hoda Gerami, Ann-Jay Tong, Laurent Vergnes, Armin Takallou, Adel Zhang, Xiaochao Wei, Linda D Chilin, Yuntao Wu, Clay F Semenkovich, Karen Reue, Stephen T Smale, Benhur Lee, Genhong Cheng.

  SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism. Overexpression of FASN or the addition of its downstream product, palmitate, increased viral infection while knockout or knockdown of FASN reduced infection. More importantly, pharmacological inhibitors of FASN effectively blocked infections with a broad range of viruses, including SARS-CoV-2 and its variants of concern. Thus, our studies not only suggest that downregulation of metabolic genes may present an antiviral strategy by type I interferon, but they also introduce the potential for FASN inhibitors to have a therapeutic application in combating emerging infectious diseases such as COVID-19.

Keywords:  C75; COVID-19; Cerulenin; FASN; Fatty acid synthase; IFN-I; SARS-CoV-2; TVB-3166

DOI:  https://doi.org/10.1016/j.apsb.2022.02.019
Int J Mol Sci. 2022 Feb 26. pii: 2584. [Epub ahead of print]23(5):

Mycobacterium tuberculosis Acetyltransferase Suppresses Oxidative Stress by Inducing Peroxisome Formation in Macrophages.

Ananyaashree Behera, Preeti Jain, Geetanjali Ganguli, Mainak Biswas, Avinash Padhi, Kali Prasad Pattanaik, Barsa Nayak, Süleyman Ergün, Kristine Hagens, Natalja Redinger, Mohd Saqib, Bibhuti B Mishra, Ulrich E Schaible, Srikanth Karnati, Avinash Sonawane.

  Mycobacterium tuberculosis (Mtb) inhibits host oxidative stress responses facilitating its survival in macrophages; however, the underlying molecular mechanisms are poorly understood. Here, we identified a Mtb acetyltransferase (Rv3034c) as a novel counter actor of macrophage oxidative stress responses by inducing peroxisome formation. An inducible Rv3034c deletion mutant of Mtb failed to induce peroxisome biogenesis, expression of the peroxisomal β-oxidation pathway intermediates (ACOX1, ACAA1, MFP2) in macrophages, resulting in reduced intracellular survival compared to the parental strain. This reduced virulence phenotype was rescued by repletion of Rv3034c. Peroxisome induction depended on the interaction between Rv3034c and the macrophage mannose receptor (MR). Interaction between Rv3034c and MR induced expression of the peroxisomal biogenesis proteins PEX5p, PEX13p, PEX14p, PEX11β, PEX19p, the peroxisomal membrane lipid transporter ABCD3, and catalase. Expression of PEX14p and ABCD3 was also enhanced in lungs from Mtb aerosol-infected mice. This is the first report that peroxisome-mediated control of ROS balance is essential for innate immune responses to Mtb but can be counteracted by the mycobacterial acetyltransferase Rv3034c. Thus, peroxisomes represent interesting targets for host-directed therapeutics to tuberculosis.

Keywords:  Mycobacterium tuberculosis; Rv3034c; acetyltransferase; macrophages; oxidative stress; peroxisome

DOI:  https://doi.org/10.3390/ijms23052584
Sci Rep. 2022 Mar 08. 12(1): 4131

Targeted metabolomics analysis of serum and Mycobacterium tuberculosis antigen-stimulated blood cultures of pediatric patients with active and latent tuberculosis.

Druszczynska Magdalena, Seweryn Michal, Sieczkowska Marta, Kowalewska-Pietrzak Magdalena, Pankowska Anna, Godkowicz Magdalena, Szewczyk Rafał.

Profound tuberculosis (TB)-induced metabolic changes reflected in the blood metabolomic profile may provide an opportunity to identify specific markers of Mycobacterium tuberculosis infection. Using targeted liquid chromatography tandem mass spectrometry, we compared the levels of 30 small metabolites, including amino acids and derivatives, and small organic compounds in serum and M.tb antigen-stimulated whole blood cultures of active TB children, latent TB (LTBI) children, nonmycobacterial pneumonia (NMP) children, and healthy controls (HCs) to assess their potential as biomarkers of childhood TB. We found elevated levels of leucine and kynurenine combined with reduced concentrations of citrulline and glutamine in serum and blood cultures of TB and LTBI groups. LTBI status was additionally associated with a decrease in valine levels in blood cultures. The NMP metabolite profile was characterized by an increase in citrulline and glutamine and a decrease in leucine, kynurenine and valine concentrations. The highest discriminatory potential for identifying M.tb infection was observed for leucine detected in serum and kynurenine in stimulated blood cultures. The use of targeted metabolomics may reveal metabolic changes in M.tb-infected children, and the obtained results are a proof of principle of the usefulness of metabolites in the auxiliary diagnosis of TB in children.

DOI: https://doi.org/10.1038/s41598-022-08201-4