bims-imicid 2023-07-16 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–07–16
27 papers selected by
Dylan Ryan, University of Cambridge

CRAT links cholesterol metabolism to innate immune responses in the heart.
Proline is increased in allergic asthma and promotes airway remodeling.
Inhibitory IL-10-producing CD4+ T cells are T-bet-dependent and facilitate cytomegalovirus persistence via coexpression of arginase-1.
Itaconate attenuates autoimmune hepatitis via PI3K/AKT/mTOR pathway-mediated inhibition of dendritic cell maturation and autophagy.
Random forest and live single-cell metabolomics reveal metabolic profiles of human macrophages upon polarization.
STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2.
Succinate mediates inflammation-induced adrenocortical dysfunction.
α-Aminobutyric Acid Constrains Macrophage-Associated Inflammatory Diseases through Metabolic Reprogramming and Epigenetic Modification.
Mitochondrial Control for Healthy and Autoimmune T Cells.
Defining the metabolic signatures associated with human macrophage polarisation.
Effects of altered glycolysis levels on CD8+ T cell activation and function.
Combined cerebrospinal fluid metabolomic and cytokine profiling in tuberculosis meningitis reveals robust and prolonged changes in immunometabolic networks.
Tumor-associated macrophages: new insights on their metabolic regulation and their influence in cancer immunotherapy.
Contribution of Circulating Host and Microbial Tryptophan Metabolites Toward Ah Receptor Activation.
Implications of immunometabolism for smouldering MS pathology and therapy.
Glycolytic interference blocks influenza A virus propagation by impairing viral polymerase-driven synthesis of genomic vRNA.
Multimodal profiling of term human decidua demonstrates immune adaptations with pregravid obesity.
Metabolite-derived damage-associated molecular patterns in immunological diseases.
Lipopolysaccharide augments microglial GABA uptake by increasing GABA transporter-1 trafficking and bestrophin-1 expression.
Physiological role of cytokines in the regulation of mammalian metabolism.
Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection.
A unique inflammation-related mechanism by which high-fat diets induce depression-like behaviors in mice.
NLRP12 drives PANoptosis in response to heme.
Intermittent Fasting Modulates Immune Response by Generating Tregs via TGF-β Dependent Mechanisms in Obese Mice with Allergic Contact Dermatitis.
Alternative fatty acid desaturation pathways revealed by deep profiling of total fatty acids in RAW 264.7 cell line.
TCA cycle deficiency in multiple sclerosis.
Abnormal adenosine metabolism of neutrophils inhibits airway inflammation and remodeling in asthma model induced by Aspergillus fumigatus.

Nat Metab. 2023 Jul 13.

CRAT links cholesterol metabolism to innate immune responses in the heart.

Hua Mao, Aude Angelini, Shengyu Li, Guangyu Wang, Luge Li, Cam Patterson, Xinchun Pi, Liang Xie.

Chronic inflammation is associated with increased risk and poor prognosis of heart failure; however, the precise mechanism that provokes sustained inflammation in the failing heart remains elusive. Here we report that depletion of carnitine acetyltransferase (CRAT) promotes cholesterol catabolism through bile acid synthesis pathway in cardiomyocytes. Intracellular accumulation of bile acid or intermediate, 7α-hydroxyl-3-oxo-4-cholestenoic acid, induces mitochondrial DNA stress and triggers cGAS-STING-dependent type I interferon responses. Furthermore, type I interferon responses elicited by CRAT deficiency substantially increase AIM2 expression and AIM2-dependent inflammasome activation. Genetic deletion of cardiomyocyte CRAT in mice of both sexes results in myocardial inflammation and dilated cardiomyopathy, which can be reversed by combined depletion of caspase-1, cGAS or AIM2. Collectively, we identify a mechanism by which cardiac energy metabolism, cholesterol homeostasis and cardiomyocyte-intrinsic innate immune responses are interconnected via a CRAT-mediated bile acid synthesis pathway, which contributes to chronic myocardial inflammation and heart failure progression.

DOI: https://doi.org/10.1038/s42255-023-00844-5
JCI Insight. 2023 Jul 11. pii: e167395. [Epub ahead of print]

Proline is increased in allergic asthma and promotes airway remodeling.

Tingting Xu, Zhenzhen Wu, Qi Yuan, Xijie Zhang, Yanan Liu, Chaojie Wu, Meijuan Song, Jingjing Wu, Jingxian Jiang, Zhengxia Wang, Zhongqi Chen, Mingshun Zhang, Mao Huang, Ningfei Ji.

  Proline and its synthesis enzyme pyrroline-5-carboxylate reductase 1 (PYCR1) are implicated in epithelial-mesenchymal transition (EMT), yet how proline and PYCR1 function in allergic asthmatic airway remodeling via EMT has not yet been addressed. In the present study, increased levels of plasma proline and PYCR1 were observed in asthmatic patients. Similarly, proline and PYCR1 in lung tissues were higher in a murine allergic asthma model induced by house dust mites (HDMs). Pycr1 knockout (KO) decreased proline in lung tissues, with reduced airway remodeling and EMT. Mechanistically, loss of Pycr1 restrained HDM-induced EMT by modulating mitochondrial fission, metabolic reprogramming, and the AKT/mTOR1 and WNT3a/β-catenin signaling pathways in airway epithelial cells. Therapeutic inhibition of PYCR1 in wild-type mice disrupted HDM-induced airway inflammation and remodeling. Deprivation of exogeneous proline partially relieved HDM-induced airway remodeling to some extent. Collectively, this study illuminates that proline and PYCR1 involved with airway remodeling in allergic asthma could be viable targets for asthma treatment.

Keywords:  Amino acid metabolism; Asthma; Metabolism; Pulmonology

DOI:  https://doi.org/10.1172/jci.insight.167395
Elife. 2023 Jul 13. pii: e79165. [Epub ahead of print]12

Inhibitory IL-10-producing CD4+ T cells are T-bet-dependent and facilitate cytomegalovirus persistence via coexpression of arginase-1.

Mathew Clement, Kristin Ladell, Kelly L Miners, Morgan Marsden, Lucy Chapman, Anna Cardus Figueras, Jake Scott, Robert Andrews, Simon Clare, Valeriia V Kriukova, Ksenia R Lupyr, Olga V Britanova, David R Withers, Simon A Jones, Dmitriy M Chudakov, David A Price, Ian R Humphreys.

  Inhibitory CD4+ T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity. However, the mechanisms that underpin the development of these regulatory cells, especially in the context of ongoing antigen exposure, have remained obscure. To address this knowledge gap, we undertook a comprehensive functional, phenotypic, and transcriptomic analysis of interleukin (IL)-10-producing CD4+ T cells induced by chronic infection with murine cytomegalovirus (MCMV). We identified these cells as clonally expanded and highly differentiated TH1-like cells that developed in a T-bet-dependent manner and coexpressed arginase-1 (Arg1), which promotes the catalytic breakdown of L-arginine. Mice lacking Arg1-expressing CD4+ T cells exhibited more robust antiviral immunity and were better able to control MCMV. Conditional deletion of T-bet in the CD4+ lineage suppressed the development of these inhibitory cells and also enhanced immune control of MCMV. Collectively, these data elucidated the ontogeny of IL-10-producing CD4+ T cells and revealed a previously unappreciated mechanism of immune regulation, whereby viral persistence was facilitated by the site-specific delivery of Arg1.

Keywords:  CD4+ T cells; IL-10; T-bet; arginase-1; cytomegalovirus; immunology; infectious disease; inflammation; mice; microbiology; viruses

DOI:  https://doi.org/10.7554/eLife.79165
Heliyon. 2023 Jul;9(7): e17551

Itaconate attenuates autoimmune hepatitis via PI3K/AKT/mTOR pathway-mediated inhibition of dendritic cell maturation and autophagy.

Qiyu Zhang, Yang Luo, Qiuxia Zheng, Haixia Zhao, Xiaofeng Wei, Xun Li.

  Autoimmune hepatitis (AIH) results from an autoimmune-mediated chronic inflammatory response against liver cells. Defective self-tolerance and dysfunctional dendritic cells (DCs) play a regulatory role in AIH. Itaconate has recently attracted attention in the field of immunometabolism because of its crucial role as an anti-inflammatory metabolite that negatively regulates the inflammatory response. However, the underlying mechanism of itaconate mediation of DCs in AIH remains unclear. In this study, we found that itaconate acts as an anti-inflammatory factor in the liver. Endogenous itaconate levels were significantly increased in mice with S100-induced AIH model and correlated with upregulation of the immune-responsive gene 1 expression. However, the anti-inflammatory response from endogenously itaconate may not represent the effects exogenously-produced itaconate. We investigated the anti-inflammatory response from exogenous itaconate in S100-induced AIH, and our results showed that itaconate treatment attenuated liver histopathological damage, hepatocyte apoptosis, aminotransferase elevation, and IL-6 production in the S100-induced AIH model. In addition, Itaconate decreased glycolysis to suppress the maturation of DCs in the liver and spleen of AIH models, thereby directly regulating differentiation of Th17 and Tregs in vivo. The percentage of Th17 cells among the CD4+ population were decreased and Tregs were increased (P < 0.05). Furthermore, Itaconate-induced bone marrow-derived monocytes suppressed CD4+cells proliferation. In vitro and in vivo, we found that itaconate suppressed autophagy via activating the PI3K/AKT/mTOR signalling pathway in bone marrow-derived DCs and liver tissues. We further investigated the function of Itaconate on DC-specific mTOR-deficient mice. mTOR-deficient DCs augmented inflammatory reactions in mTORDC-/- AIH mice and induced autophagy. MHY1485 (an agonist of mTOR) and itaconate significantly alleviated the inflammatory reaction and autophagy signalling. In conclusion, itaconate ameliorate liver inflammation in S100-induced AIH mice by regulating the PI3K/AKT/mTOR pathway to decrease DCs autophagy and maturation. These results provide insight useful for treating AIH.

Keywords:  Autoimmune hepatitis; Autophagy; Dendritic cell; Itaconate; PI3K/AKT/mTOR

DOI:  https://doi.org/10.1016/j.heliyon.2023.e17551
Biotechnol Bioeng. 2023 Jul 10.

Random forest and live single-cell metabolomics reveal metabolic profiles of human macrophages upon polarization.

Huaqi Tang, Ahmed Ali, Eman Abdelazem, Tom H M Ottenhoff, Ron M A Heeren, Alireza Mashaghi.

  Human macrophages are innate immune cells with diverse, functionally distinct phenotypes, namely, pro-inflammatory M1 and anti-inflammatory M2 macrophages. Both are involved in multiple physiological and pathological processes, including would healing, infection, and cancer. However, the metabolic differences between these phenotypes are largely unexplored at single-cell resolution. To address this knowledge gap, an untargeted live single-cell mass spectrometry-based metabolomic profiling coupled with a machine-learning data analysis approach was developed to investigate the metabolic profile of each phenotype at the single-cell level. Results show that M1 and M2 macrophages have distinct metabolic profiles, with differential levels of fatty acyls, glycerophospholipids, and sterol lipids, which are important components of plasma membrane and involved in multiple biological processes. Furthermore, we could discern several putatively annotated molecules that contribute to inflammatory response of macrophages. The combination of random forest and live single-cell metabolomics provided an in-depth profile of the metabolome of primary human M1 and M2 macrophages at the single-cell level for the first time, which will pave the way for future studies targeting the differentiation of other immune cells.

Keywords:  human macrophages; phenotype classification; random forest; single-cell metabolomics

DOI:  https://doi.org/10.1002/bit.28494
Nat Cell Biol. 2023 Jul 13.

STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2.

Liting Zhang, Congqing Jiang, Yunhong Zhong, Kongliang Sun, Huiru Jing, Jiayu Song, Jun Xie, Yaru Zhou, Mao Tian, Chuchu Zhang, Xiaona Sun, Shaowei Wang, Xi Cheng, Yuelan Zhang, Wei Wei, Xiang Li, Bishi Fu, Pinghui Feng, Bing Wu, Hong-Bing Shu, Junjie Zhang.

Evasion of antitumour immunity is a hallmark of cancer. STING, a putative innate immune signalling adaptor, has a pivotal role in mounting antitumour immunity by coordinating innate sensing and adaptive immune surveillance in myeloid cells. STING is markedly silenced in various human malignancies and acts as a cell-intrinsic tumour suppressor. How STING exerts intrinsic antitumour activity remains unclear. Here, we report that STING restricts aerobic glycolysis independent of its innate immune function. Mechanistically, STING targets hexokinase II (HK2) to block its hexokinase activity. As such, STING inhibits HK2 to restrict tumour aerobic glycolysis and promote antitumour immunity in vivo. In human colorectal carcinoma samples, lactate, which can be used as a surrogate for aerobic glycolysis, is negatively correlated with STING expression level and antitumour immunity. Taken together, this study reveals that STING functions as a cell-intrinsic metabolic checkpoint that restricts aerobic glycolysis to promote antitumour immunity. These findings have important implications for the development of STING-based therapeutic modalities to improve antitumour immunotherapy.

DOI: https://doi.org/10.1038/s41556-023-01185-x
Elife. 2023 Jul 14. pii: e83064. [Epub ahead of print]12

Succinate mediates inflammation-induced adrenocortical dysfunction.

Ivona Mateska, Anke Witt, Eman Hagag, Anupam Sinha, Canelif Yilmaz, Evangelia Thanou, Na Sun, Ourania Kolliniati, Maria Patschin, Heba Abdelmegeed, Holger Henneicke, Waldemar Kanczkowski, Ben Wielockx, Christos Tsatsanis, Andreas Dahl, Axel Karl Walch, Ka Wan Li, Mirko Peitzsch, Triantafyllos Chavakis, Vasileia Ismini Alexaki.

  The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the adrenal cortex, thereby representing an endogenous feedback loop. However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH), although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation, in mice. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH), leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1β reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the SDHB promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis and enhance ROS production, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1β-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for the adrenal dysfunction in severe inflammation, but also offer a potential target for therapeutic intervention.

Keywords:  cell biology; immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.83064
Int J Mol Sci. 2023 Jun 21. pii: 10444. [Epub ahead of print]24(13):

α-Aminobutyric Acid Constrains Macrophage-Associated Inflammatory Diseases through Metabolic Reprogramming and Epigenetic Modification.

Fei Li, Yuting Xia, Shijie Yuan, Xiaorong Xie, Lin Li, Yuan Luo, Qiuyang Du, Yuqi Yuan, Ran He.

  Metabolites play critical roles in macrophage polarization and in their function in response to infection and inflammation. α-aminobutyric acid (AABA), a non-proteinogenic amino acid which can be generated from methionine, threonine, serine, and glycine, has not been studied extensively in relation to macrophage polarization and function. In this study, we aimed to investigate the immunomodulatory function of AABA in regulating M1 macrophage polarization and function in vitro and in vivo. We stimulated bone-marrow-derived macrophages with lipopolysaccharide (LPS) to generate M1 macrophages. Subsequently, we induced sepsis and colitis in mice, followed by treatment with AABA. We then analyzed the samples using ELISA, real-time PCR, Western blotting, flow cytometry, and histopathological analysis to evaluate cytokine secretion, inflammatory gene expression, macrophage activation, disease progression, and inflammation severity. Additionally, metabolomic and chromatin immunoprecipitation-qPCR were conducted to investigate the function of AABA on metabolic reprogramming and epigenetic modifications of M1 macrophages. Our results revealed that AABA inhibited M1 macrophage polarization and function, which led to prolonged survival in septic mice and reduced disease severity in colitis mice. Mechanically, AABA promoted oxidative phosphorylation (OXPHOS) and glutamine and arginine metabolism while inhibiting glycolysis. Moreover, AABA could increase the occupancy of trimethylation of histone H3K27 at the promoter regions of M1 macrophage-associated inflammatory genes, which contributed to the inhibition of M1 macrophage polarization. These findings suggest that AABA may have therapeutic potential for inflammatory diseases by regulating macrophage polarization and function through metabolic and epigenetic pathways.

Keywords:  EZH2; H3K27me3; inflammation; macrophage; metabolic reprogramming; α-aminobutyric acid

DOI:  https://doi.org/10.3390/ijms241310444
Cells. 2023 Jul 07. pii: 1800. [Epub ahead of print]12(13):

Mitochondrial Control for Healthy and Autoimmune T Cells.

Li Jia, Lei Zhang, Mengdi Liu, Huiyan Ji, Zhenke Wen, Chunhong Wang.

  T cells are critical players in adaptive immunity, driving the tissue injury and organ damage of patients with autoimmune diseases. Consequently, investigations on T cell activation, differentiation, and function are valuable in uncovering the disease pathogenesis, thus exploring promising therapeutics for autoimmune diseases. In recent decades, accumulating studies have pinpointed immunometabolism as the fundamental determinant in controlling T cell fate. Specifically, mitochondria, as a hub of intracellular metabolism, connect glucose, lipid, and amino acid metabolic pathways. Herein, we summarize metabolic adaptations of mitochondrial oxidative phosphorylation and the relevant glucose, lipid, and amino acid metabolism during T cell activation, differentiation, and function. Further, we focused on current updates of the molecular bases for metabolic reprogramming in autoimmune T cells and advances in exploring metabolic-targeted therapeutics against autoimmune diseases. This might facilitate the in-depth understanding of autoimmune pathogeneses and the clinical management of autoimmune diseases.

Keywords:  T cells; autoimmunity; metabolic adaptation; mitochondria

DOI:  https://doi.org/10.3390/cells12131800
Biochem Soc Trans. 2023 Jul 14. pii: BST20220504. [Epub ahead of print]

Defining the metabolic signatures associated with human macrophage polarisation.

Adrián Povo-Retana, Rodrigo Landauro-Vera, Marco Fariñas, Sergio Sánchez-García, Carlota Alvarez-Lucena, Silvia Marin, Marta Cascante, Lisardo Boscá.

  Macrophages are essential components of the innate immune system that play both homeostatic roles in healthy organs, and host defence functions against pathogens after tissue injury. To accomplish their physiological role, macrophages display different profiles of gene expression, immune function, and metabolic phenotypes that allow these cells to participate in different steps of the inflammatory reaction, from the initiation to the resolution phase. In addition, significant differences exist in the phenotype of macrophages depending on the tissue in which they are present and on the mammalian species. From a metabolic point of view, macrophages are essentially glycolytic cells; however, their metabolic fluxes are dependent on the functional polarisation of these cells. This metabolic and cellular plasticity offers the possibility to interfere with the activity of macrophages to avoid harmful effects due to persistent activation or the release of molecules that delay tissue recovery after injury.

Keywords:  cell homeostasis; fibrosis; immunometabolism; inflammation; macrophages; monocytes

DOI:  https://doi.org/10.1042/BST20220504
Cell Death Dis. 2023 Jul 08. 14(7): 407

Effects of altered glycolysis levels on CD8+ T cell activation and function.

Jiaying Cao, Shan Liao, Feng Zeng, Qianjin Liao, Gengqiu Luo, Yanhong Zhou.

CD8+ T cells are an important component of the body's adaptive immune response. During viral or intracellular bacterial infections, CD8+ T cells are rapidly activated and differentiated to exert their immune function by producing cytokines. Alterations in the glycolysis of CD8+ T cells have an important effect on their activation and function, while glycolysis is important for CD8+ T cell functional failure and recovery. This paper summarizes the importance of CD8+ T cell glycolysis in the immune system. We discuss the link between glycolysis and CD8+ T cell activation, differentiation, and proliferation, and the effect of altered glycolysis on CD8+ T cell function. In addition, potential molecular targets to enhance and restore the immune function of CD8+ T cells by affecting glycolysis and the link between glycolysis and CD8+ T cell senescence are summarized. This review provides new insights into the relationship between glycolysis and CD8+ T cell function, and proposes novel strategies for immunotherapy by targeting glycolysis.

DOI: https://doi.org/10.1038/s41419-023-05937-3
medRxiv. 2023 Jun 29. pii: 2023.06.26.23291676. [Epub ahead of print]

Combined cerebrospinal fluid metabolomic and cytokine profiling in tuberculosis meningitis reveals robust and prolonged changes in immunometabolic networks.

Jeff Tomalka, Ashish Sharma, Alison G C Smith, Teona Avaliani, Mariam Gujabidze, Tinatin Bakuradze, Shorena Sabanadze, Dean P Jones, Zaza Avaliani, Maia Kipiani, Russell R Kempker, Jeffrey M Collins.

Much of the high mortality in tuberculosis meningitis (TBM) is attributable to excessive inflammation, making it imperative to identify targets for host-directed therapies that reduce pathologic inflammation and mortality. In this study, we investigate how cytokines and metabolites in the cerebral spinal fluid (CSF) associate with TBM at diagnosis and during TBM treatment. At diagnosis, TBM patients demonstrate significant increases versus controls of cytokines and chemokines that promote inflammation and cell migration including IL-17A, IL-2, TNFα, IFNγ, and IL-1β. Inflammatory immune signaling was strongly correlated with immunomodulatory metabolites including kynurenine, lactic acid, carnitine, tryptophan, and itaconate. Inflammatory immunometabolic networks were only partially reversed with two months of effective TBM treatment and remained significantly different versus control CSF. Together, these data highlight a critical role for host metabolism in regulating the inflammatory response to TBM and indicate the timeline for restoration of immune homeostasis in the CSF is prolonged.

DOI: https://doi.org/10.1101/2023.06.26.23291676
Front Immunol. 2023 ;14 1157291

Tumor-associated macrophages: new insights on their metabolic regulation and their influence in cancer immunotherapy.

Li Xiao, Qiao Wang, Hongling Peng.

  Tumor-associated macrophages (TAMs) are a dynamic and heterogeneous cell population of the tumor microenvironment (TME) that plays an essential role in tumor formation and progression. Cancer cells have a high metabolic demand for their rapid proliferation, survival, and progression. A comprehensive interpretation of pro-tumoral and antitumoral metabolic changes in TAMs is crucial for comprehending immune evasion mechanisms in cancer. The metabolic reprogramming of TAMs is a novel method for enhancing their antitumor effects. In this review, we provide an overview of the recent research on metabolic alterations of TAMs caused by TME, focusing primarily on glucose, amino acid, and fatty acid metabolism. In addition, this review discusses antitumor immunotherapies that influence the activity of TAMs by limiting their recruitment, triggering their depletion, and re-educate them, as well as metabolic profiles leading to an antitumoral phenotype. We highlighted the metabolic modulational roles of TAMs and their potential to enhance immunotherapy for cancer.

Keywords:  amino acid metabolism; fatty acid metabolism; glucose metabolism; immunotherapy; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2023.1157291
Int J Tryptophan Res. 2023 ;16 11786469231182510

Contribution of Circulating Host and Microbial Tryptophan Metabolites Toward Ah Receptor Activation.

Ethan W Morgan, Fangcong Dong, Andrew J Annalora, Iain A Murray, Trenton Wolfe, Reece Erickson, Krishne Gowda, Shantu G Amin, Kristina S Petersen, Penny M Kris-Etherton, Craig B Marcus, Seth T Walk, Andrew D Patterson, Gary H Perdew.

  The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that plays an integral role in homeostatic maintenance by regulating cellular functions such as cellular differentiation, metabolism, barrier function, and immune response. An important but poorly understood class of AHR activators are compounds derived from host and bacterial metabolism of tryptophan. The commensal bacteria of the gut microbiome are major producers of tryptophan metabolites known to activate the AHR, while the host also produces AHR activators through tryptophan metabolism. We used targeted mass spectrometry-based metabolite profiling to determine the presence and metabolic source of these metabolites in the sera of conventional mice, germ-free mice, and humans. Surprisingly, sera concentrations of many tryptophan metabolites are comparable between germ-free and conventional mice. Therefore, many major AHR-activating tryptophan metabolites in mouse sera are produced by the host, despite their presence in feces and mouse cecal contents. Here we present an investigation of AHR activation using a complex mixture of tryptophan metabolites to examine the biological relevance of circulating tryptophan metabolites. AHR activation is rarely studied in the context of a mixture at relevant concentrations, as we present here. The AHR activation potentials of individual and pooled metabolites were explored using cell-based assays, while ligand binding competition assays and ligand docking simulations were used to assess the detected metabolites as AHR agonists. The physiological and biomedical relevance of the identified metabolites was investigated in the context of a cell-based model for rheumatoid arthritis. We present data that reframe AHR biology to include the presence of a mixture of ubiquitous tryptophan metabolites, improving our understanding of homeostatic AHR activity and models of AHR-linked diseases.

Keywords:  Aryl hydrocarbon receptor; homeostasis; indole; kynurenine pathway; metabolomics; microbiome; tryptophan metabolism

DOI:  https://doi.org/10.1177/11786469231182510
Nat Rev Neurol. 2023 Jul 10.

Implications of immunometabolism for smouldering MS pathology and therapy.

Stefan Bittner, Katrin Pape, Luisa Klotz, Frauke Zipp.

Clinical symptom worsening in patients with multiple sclerosis (MS) is driven by inflammation compartmentalized within the CNS, which results in chronic neuronal damage owing to insufficient repair mechanisms. The term 'smouldering inflammation' summarizes the biological aspects underlying this chronic, non-relapsing and immune-mediated mechanism of disease progression. Smouldering inflammation is likely to be shaped and sustained by local factors in the CNS that account for the persistence of this inflammatory response and explain why current treatments for MS do not sufficiently target this process. Local factors that affect the metabolic properties of glial cells and neurons include cytokines, pH value, lactate levels and nutrient availability. This Review summarizes current knowledge of the local inflammatory microenvironment in smouldering inflammation and how it interacts with the metabolism of tissue-resident immune cells, thereby promoting inflammatory niches within the CNS. The discussion highlights environmental and lifestyle factors that are increasingly recognized as capable of altering immune cell metabolism and potentially responsible for smouldering pathology in the CNS. Currently approved MS therapies that target metabolic pathways are also discussed, along with their potential for preventing the processes that contribute to smouldering inflammation and thereby to progressive neurodegenerative damage in MS.

DOI: https://doi.org/10.1038/s41582-023-00839-6
PLoS Pathog. 2023 Jul;19(7): e1010986

Glycolytic interference blocks influenza A virus propagation by impairing viral polymerase-driven synthesis of genomic vRNA.

Jens Kleinehr, Michael Schöfbänker, Katharina Daniel, Franziska Günl, Fakry Fahmy Mohamed, Josua Janowski, Linda Brunotte, Yvonne Boergeling, Marie Liebmann, Matthias Behrens, Andrea Gerdemann, Luisa Klotz, Melanie Esselen, Hans-Ulrich Humpf, Stephan Ludwig, Eike R Hrincius.

Influenza A virus (IAV), like any other virus, provokes considerable modifications of its host cell's metabolism. This includes a substantial increase in the uptake as well as the metabolization of glucose. Although it is known for quite some time that suppression of glucose metabolism restricts virus replication, the exact molecular impact on the viral life cycle remained enigmatic so far. Using 2-deoxy-d-glucose (2-DG) we examined how well inhibition of glycolysis is tolerated by host cells and which step of the IAV life cycle is affected. We observed that effects induced by 2-DG are reversible and that cells can cope with relatively high concentrations of the inhibitor by compensating the loss of glycolytic activity by upregulating other metabolic pathways. Moreover, mass spectrometry data provided information on various metabolic modifications induced by either the virus or agents interfering with glycolysis. In the presence of 2-DG viral titers were significantly reduced in a dose-dependent manner. The supplementation of direct or indirect glycolysis metabolites led to a partial or almost complete reversion of the inhibitory effect of 2-DG on viral growth and demonstrated that indeed the inhibition of glycolysis and not of N-linked glycosylation was responsible for the observed phenotype. Importantly, we could show via conventional and strand-specific qPCR that the treatment with 2-DG led to a prolonged phase of viral mRNA synthesis while the accumulation of genomic vRNA was strongly reduced. At the same time, minigenome assays showed no signs of a general reduction of replicative capacity of the viral polymerase. Therefore, our data suggest that the significant reduction in IAV replication by glycolytic interference occurs mainly due to an impairment of the dynamic regulation of the viral polymerase which conveys the transition of the enzyme's function from transcription to replication.

DOI: https://doi.org/10.1371/journal.ppat.1010986
Cell Rep. 2023 Jul 10. pii: S2211-1247(23)00780-5. [Epub ahead of print]42(7): 112769

Multimodal profiling of term human decidua demonstrates immune adaptations with pregravid obesity.

Suhas Sureshchandra, Brianna M Doratt, Heather True, Norma Mendoza, Monica Rincon, Nicole E Marshall, Ilhem Messaoudi.

  Leukocyte diversity of the first-trimester maternal-fetal interface has been extensively described; however, the immunological landscape of the term decidua remains poorly understood. We therefore profiled human leukocytes from term decidua collected via scheduled cesarean delivery. Relative to the first trimester, our analyses show a shift from NK cells and macrophages to T cells and enhanced immune activation. Although circulating and decidual T cells are phenotypically distinct, they demonstrate significant clonotype sharing. We also report significant diversity within decidual macrophages, the frequency of which positively correlates with pregravid maternal body mass index. Interestingly, the ability of decidual macrophages to respond to bacterial ligands is reduced with pregravid obesity, suggestive of skewing toward immunoregulation as a possible mechanism to safeguard the fetus against excessive maternal inflammation. These findings are a resource for future studies investigating pathological conditions that compromise fetal health and reproductive success.

Keywords:  CP: Immunology; TCR; decidua; human; macrophages; maternal-fetal interface; obesity

DOI:  https://doi.org/10.1016/j.celrep.2023.112769
FEBS J. 2023 Jul 11.

Metabolite-derived damage-associated molecular patterns in immunological diseases.

Na Kang, Zhenglin Ji, Yuxin Li, Ji Gao, Xinfeng Wu, Xiaoyang Zhang, Qinghui Duan, Can Zhu, Yue Xu, Luyao Wen, Xiaofei Shi, Wanli Liu.

  Damage-associated molecular patterns (DAMPs) are typically derived from the endogenous elements of necrosis cells and can trigger inflammatory responses by activating DAMPs-sensing receptors on immune cells. Failure to clear DAMPs may lead to persistent inflammation, thereby contributing to the pathogenesis of immunological diseases. This review focuses on a newly recognized class of DAMPs derived from lipid, glucose, nucleotide, and amino acid metabolic pathways, which are then termed as metabolite-derived DAMPs. This review summarizes the reported molecular mechanisms of these metabolite-derived DAMPs in exacerbating inflammation responses, which may attribute to the pathology of certain types of immunological diseases. Additionally, this review also highlights both direct and indirect clinical interventions that have been explored to mitigate the pathological effects of these DAMPs. By summarizing our current understanding of metabolite-derived DAMPs, this review aims to inspire future thoughts and endeavors on targeted medicinal interventions and the development of therapies for immunological diseases.

Keywords:  DAMPs; amino acid metabolism; glucose metabolism; immunological diseases; lipid metabolism; nucleotide metabolism

DOI:  https://doi.org/10.1111/febs.16902
Glia. 2023 Jul 10.

Lipopolysaccharide augments microglial GABA uptake by increasing GABA transporter-1 trafficking and bestrophin-1 expression.

Michael Di Palma, Myriam Catalano, Carmela Serpe, Mariassunta De Luca, Lucia Monaco, Karl Kunzelmann, Cristina Limatola, Fiorenzo Conti, Giorgia Fattorini.

  Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the brain, affects numerous immune cell functions. Microglia, the brain's resident innate immune cells, regulate GABA signaling through GABA receptors and express the complete GABAergic machinery for GABA synthesis, uptake, and release. Here, the use of primary microglial cell cultures and ex vivo brain tissue sections allowed for demonstrating that treatment with lipopolysaccharide (LPS) increased microglial GABA uptake as well as GABA transporter (GAT)-1 trafficking. This effect was not entirely abolished by treatment with GAT inhibitors (GAT-Is). Notably, LPS also induced microglial upregulation of bestrophin-1 (BEST-1), a Ca2+ -activated Cl- channel permeable to GABA. Combined administration of GAT-Is and a BEST-1 inhibitor completely abolished LPS-induced microglial GABA uptake. Interestingly, increased microglial GAT-1 membrane turnover via syntaxin 1A was detected in LPS-treated cultures after BEST-1 blockade. Altogether, these findings provided evidence for a novel mechanism through which LPS may trigger the inflammatory response by directly altering microglial GABA clearance and identified the GAT-1/BEST-1 interplay as a potential novel mechanism involved in brain inflammation.

Keywords:  GABA; GABA transporter 1; LPS; bestrophin-1; inflammation; microglial cells

DOI:  https://doi.org/10.1002/glia.24437
Trends Immunol. 2023 Jul 07. pii: S1471-4906(23)00110-2. [Epub ahead of print]

Physiological role of cytokines in the regulation of mammalian metabolism.

Axel de Baat, Beckey Trinh, Helga Ellingsgaard, Marc Y Donath.

  The innate cytokine system is involved in the response to excessive food intake. In this review, we highlight recent advances in our understanding of the physiological role of three prominent cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), in mammalian metabolic regulation. This recent research highlights the pleiotropic and context-dependent functions in the immune-metabolic interplay. IL-1β is activated in response to overloaded mitochondrial metabolism, stimulates insulin secretion, and allocates energy to immune cells. IL-6 is released by contracting skeletal muscle and adipose tissue and directs energy from storing tissues to consuming tissues. TNF induces insulin resistance and prevents ketogenesis. Additionally, the therapeutic potential of modulating the activity of each cytokine is discussed.

Keywords:  cytokine; diabetes; humans; insulin; metabolism; obesity

DOI:  https://doi.org/10.1016/j.it.2023.06.002
bioRxiv. 2023 Jun 26. pii: 2023.06.25.546471. [Epub ahead of print]

Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection.

Luisella Spiga, Ryan T Fansler, Yasiru R Perera, Nicolas G Shealy, Matthew J Munneke, Teresa P Torres, Holly E David, Andrew Lemoff, Xinchun Ran, Katrina L Richardson, Nicholas Pudlo, Eric C Martens, Zhongyue J Yang, Eric P Skaar, Mariana X Byndloss, Walter J Chazin, Wenhan Zhu.

During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients such as iron. Pathogens scavenge iron using siderophores, which is counteracted by the host using lipocalin-2, a protein that sequesters iron-laden siderophores, including enterobactin. Although the host and pathogens compete for iron in the presence of gut commensal bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron in the inflamed gut by utilizing siderophores produced by other bacteria including Salmonella, via a secreted siderophore-binding lipoprotein termed XusB. Notably, XusB-bound siderophores are less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella , allowing the pathogen to evade nutritional immunity. As the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the interactions between pathogen and host nutritional immunity.

DOI: https://doi.org/10.1101/2023.06.25.546471
J Affect Disord. 2023 Jul 10. pii: S0165-0327(23)00841-8. [Epub ahead of print]

A unique inflammation-related mechanism by which high-fat diets induce depression-like behaviors in mice.

Haining Yu, Bixian Yu, Xiuyuan Qin, Weiguang Shan.

   BACKGROUND: High-fat diet (HFD) consumption is an important reason for promoting depression, but the mechanism is unclear. The present study aims to explore the relationship between metabolic disturbance and HFD-induced depression-like behaviors.
METHODS: Depression models were established by HFD consumption and chronic unpredictable mild stress (CUMS) in mice. Enzyme-linked immunosorbent assay, western blotting, real-time polymerase chain reaction, gas chromatography and metabolomic analysis were undertaken to investigate the 5-hydroxytryptamine (5-HT) system, neuroinflammation and to identify altered lipid metabolic pathways.
RESULTS: Depression-like behaviors, impaired 5-HT neurotransmission and disordered lipid metabolism were observed upon HFD consumption. Despite a similar reduction of high-density lipoprotein cholesterol in CUMS and HFD group, high levels of body low-density lipoprotein cholesterol in the HFD group could help distinguish HFD from CUMS. Levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and inflammation-related metabolites were increased in HFD mice, so a link between depression and inflammation was postulated. Different metabolites were enriched in the two groups. The linoleic acid (LA) metabolic pathway and expression of fatty acid desaturase (FADS)1 and FADS2 (key enzymes in LA metabolic pathway) were enhanced significantly in HFD mice compared with the control group.
LIMITATIONS: Causality analyses for HFD and inflammation-related features were not undertaken.
CONCLUSIONS: HFD-induced depression-like behaviors was characterized by more severely disordered metabolism of lipids (especially in the LA metabolic pathway) and increased levels of inflammatory mediators, which might be the reasons for the disturbance of serotonergic system in hippocampus.

Keywords:  Depression; High-fat diet; Inflammation; Linoleic acid; Lipid metabolism

DOI:  https://doi.org/10.1016/j.jad.2023.07.005
Trends Immunol. 2023 Jul 07. pii: S1471-4906(23)00132-1. [Epub ahead of print]

NLRP12 drives PANoptosis in response to heme.

Fiona D R Henkel, Luke A J O'Neill.

PANoptosomes are large cell death-inducing complexes that drive a type of cell death called PANoptosis during infection and inflammation. Sundaram and colleagues recently identified NLRP12 as a PANoptosome that induces PANoptosis in response to heme, TNF, and pathogen-associated molecular patterns (PAMPs), indicating a role for NLRP12 in hemolytic and inflammatory diseases.

DOI: https://doi.org/10.1016/j.it.2023.06.008
Biomol Ther (Seoul). 2023 Jul 10.

Intermittent Fasting Modulates Immune Response by Generating Tregs via TGF-β Dependent Mechanisms in Obese Mice with Allergic Contact Dermatitis.

Sang-Chul Han, Jung-Il Kang, Youn Kyung Choi, Hye-Jin Boo, Weon-Jong Yoon, Hee-Kyoung Kang, Eun-Sook Yoo.

  People with obesity maintain low levels of inflammation; therefore, their exposure to foreign antigens can trigger an excessive immune response. In people with obesity or allergic contact dermatitis (ACD), symptoms are exacerbated by a reduction in the number of regulatory T cells (Tregs) and IL-10/TGF-β-modified macrophages (M2 macrophages) at the inflammatory site. Benefits of intermittent fasting (IF) have been demonstrated for many diseases; however, the immune responses regulated by macrophages and CD4+T cells in obese ACD animal models are poorly understood. Therefore, we investigated whether IF suppresses inflammatory responses and upregulates the generation of Tregs and M2 macrophages in experimental ACD animal models of obese mice. The IF regimen relieved various ACD symptoms in inflamed and adipose tissues. We showed that the IF regimen upregulates Treg generation in a TGF-β-dependent manner and induces CD4+T cell hypo-responsiveness. IF-M2 macrophages, which strongly express TGF-β and inhibit CD4+T cell proliferation, directly regulated Treg differentiation from CD4+T cells. These results indicate that the IF regimen enhances the TGF-β-producing ability of M2 macrophages and that the development of Tregs keeps mice healthy against ACD exacerbated by obesity. Therefore, the IF regimen may ameliorate inflammatory immune disorders caused by obesity.

Keywords:  Allergic contact dermatitis; Inflammation; Intermittent fasting; M2 macrophage; Obesity; Regulatory T cells

DOI:  https://doi.org/10.4062/biomolther.2023.053
J Lipid Res. 2023 Jul 10. pii: S0022-2275(23)00083-4. [Epub ahead of print] 100410

Alternative fatty acid desaturation pathways revealed by deep profiling of total fatty acids in RAW 264.7 cell line.

Tian Xia, Xue Jin, Donghui Zhang, Jitong Wang, Ruijun Jian, Hang Yin, Yu Xia.

  In-depth structural characterization of lipids provides a new means to investigate lipid metabolism. In this study, we have conducted deep proﬁling of total fatty acids (FAs) from RAW 264.7 macrophages by utilizing charge-tagging Paterno-B u¨chi derivatization of carbon-carbon double bond (C=C) and reversed-phase liquid chromatography-tandem mass spectrometry. A series of FAs exhibiting unusual site(s) of unsaturation was unearthed, with their identities being confirmed by observing anticipated compositional alterations upon desaturase inhibition. The data reveal that FADS2 Δ6-desaturation can generate n-11 C=C in the odd-chain monounsaturated fatty acids (MUFAs) as well as n-10 and n-12 families of even-chain MUFAs. SCD1 Δ9-desaturation yields n-6, n-8, and n-10 of odd-chain MUFAs, as well as n-5, n-7, and n-9 families of even-chain MUFAs. Besides n-3 and n-6 families of polyunsaturated fatty acids (PUFAs), the presence of n-7 and n-9 families of PUFAs indicates that the n-7 and n-9 isomers of FA 18:1 can be utilized as substrates for further desaturation and elongation. The n-7 and n-9 families of PUFAs identiﬁed in RAW 264.7 macrophages are noteworthy because their C=C modiﬁcations are achieved exclusively via de novo lipogenesis. Our discovery outlines the metabolic plasticity in fatty acid desaturation which constitutes an unexplored rewiring in RAW264.7 macrophages.

Keywords:  Paternò–Büchi reaction; RAW 264.7 macrophage; Unsaturated fatty acids; double bond location isomers; mass spectrometry

DOI:  https://doi.org/10.1016/j.jlr.2023.100410
Nat Metab. 2023 Jul 10.

TCA cycle deficiency in multiple sclerosis.

Swadha Mishra, Fabian den Brave, Thomas Becker.

DOI: https://doi.org/10.1038/s42255-023-00840-9
BMC Pulm Med. 2023 Jul 14. 23(1): 258

Abnormal adenosine metabolism of neutrophils inhibits airway inflammation and remodeling in asthma model induced by Aspergillus fumigatus.

Ting-Ting Liu, Yue-Li Wang, Zhi Zhang, Li-Xin Jia, Jing Zhang, Shuai Zheng, Zhi-Hua Chen, Hua-Hao Shen, Chun-Mei Piao, Jie Du.

   BACKGROUND: Neutrophils consume a large amount of energy when performing their functions. Compared with other white blood cells, neutrophils contain few mitochondria and mainly rely on glycolysis and gluconeogenesis to produce ATP. The inflammatory site is hypoxic and nutrient poor. Our aim is to study the role of abnormal adenosine metabolism of neutrophils in the asthmatic airway inflammation microenvironment.
METHOD: In this study, an asthma model was established by intratracheal instillation of Aspergillus fumigatus extract in Ecto-5'-Nucleotidase (CD73) gene-knockout and wild-type mice. Multiple analyses from bronchoalveolar lavage fluid (BALF) were used to determine the levels of cytokines and chemokines. Immunohistochemistry was used to detect subcutaneous fibrosis and inflammatory cell infiltration. Finally, adenosine 5'-(α, β-methylene) diphosphate (APCP), a CD73 inhibitor, was pumped subcutaneously before Aspergillus attack to observe the infiltration of inflammatory cells and subcutaneous fibrosis to clarify its therapeutic effect.
RESULT: PAS staining showed that CD73 knockout inhibited pulmonary epithelial cell proliferation and bronchial fibrosis induced by Aspergillus extract. The genetic knockdownof CD73 significantly reduced the production of Th2 cytokines, interleukin (IL)-4, IL-6, IL-13, chemokine (C-C motif) ligand 5 (CCL5), eosinophil chemokine, neutrophil IL-17, and granulocyte colony-stimulating factor (G-CSF). In addition, exogenous adenosine supplementation increased airway inflammation. Finally, the CD73 inhibitor APCP was administered to reduce inflammation and subcutaneous fibrosis.
CONCLUSION: Elevated adenosine metabolism plays an inflammatory role in asthma, and CD73 could be a potential therapeutic target for asthma.

Keywords:  Adenosine; Asthma; CD73; Metabolism

DOI:  https://doi.org/10.1186/s12890-023-02553-x