bims-imicid 2023-07-09 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒07‒09
37 papers selected by
Dylan Ryan
University of Cambridge

SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.
Constitutively active autophagy in macrophages dampens inflammation through metabolic and post-transcriptional regulation of cytokine production.
Immunometabolic coevolution defines unique microenvironmental niches in ccRCC.
Loss of stearoyl-CoA desaturase 2 disrupts inflammatory response in macrophages.
Pharmacologic inhibition of glycolysis prevents the development of lupus by altering the gut microbiome in mice.
Sepsis-induced mitochondrial dysfunction: A narrative review.
Targeting 2-Oxoglutarate-Dependent Dioxygenases Promotes Metabolic Reprogramming That Protects against Lethal SARS-CoV-2 Infection in the K18-hACE2 Transgenic Mouse Model.
Diet, nutrient supply, and tumor immune responses.
Targeting the metabolism and immune system in pancreatic ductal adenocarcinoma: Insights and future directions.
Psoriasis immunometabolism: progress on metabolic biomarkers and targeted therapy.
ATF2 orchestrates macrophage differentiation and activation to promote antibacterial responses.
Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response.
T-cell Cholesterol Accumulation, Aging, and Atherosclerosis.
Extracellular Acidification Augments NLRP3-Mediated Inflammasome Signaling in Macrophages.
Immune regulation through tryptophan metabolism.
Lipid metabolism in regulation of B cell development and autoimmunity.
Fueling the fire of B cell activation.
Glycolytic Activation of CD14+ Intestinal Macrophages Contributes to the Inflammatory Responses via Exosomal Membrane Tumor Necrosis Factor in Crohn's Disease.
CD226 deficiency attenuates cardiac early pathological remodeling and dysfunction via decreasing inflammatory macrophage proportion and macrophage glycolysis in STZ-induced diabetic mice.
Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies.
Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis.
[Research progress on the effect of mitochondrial network remodeling on macrophages].
Determination of CAR T cell metabolism in an optimized protocol.
Diesel Exhaust Particle (DEP)-induced glucose intolerance is driven by an intestinal innate immune response and NLRP3 activation in mice.
Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.
Transcriptome analysis of human macrophages upon chikungunya virus (CHIKV) infection reveals regulation of distinct signaling and metabolic pathways during the early and late stages of infection.
A novel metabolic reprogramming strategy for the treatment of targeting to heart injury-mediated macrophages.
Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis-induced formation of neutrophil extracellular traps.
Selenium-Doped Mesoporous Bioactive Glass Regulates Macrophage Metabolism and Polarization by Scavenging ROS and Promotes Bone Regeneration In Vivo.
AMPK Drives Both Glycolytic and Oxidative Metabolism in T Cells During Graft-versus-host Disease.
Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages.
Elevated glutamate impedes anti-HIV-1 CD8 + T cell responses in HIV-1-infected individuals on antiretroviral therapy.
Innate activation of human neutrophils and neutrophil-like cells by the pro-inflammatory bacterial metabolite ADP-heptose and Helicobacter pylori.
The interplay between the DNA damage response and ectonucleotidases modulates tumor response to therapy.
Deep Phenotyping of the Lipidomic Response in COVID and non-COVID Sepsis.
Biosynthetic flexibility of Pseudomonas aeruginosa leads to hydroxylated 2-alkylquinolones with proinflammatory host response.
A targeted metabolomics approach for sepsis-induced ARDS and its subphenotypes.

Nature. 2023 Jul 05.

SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.

Chuansheng Guo, Zhiyuan You, Hao Shi, Yu Sun, Xingrong Du, Gustavo Palacios, Cliff Guy, Sujing Yuan, Nicole M Chapman, Seon Ah Lim, Xiang Sun, Jordy Saravia, Sherri Rankin, Yogesh Dhungana, Hongbo Chi.

Cancer cells evade T cell-mediated killing through tumour-immune interactions whose mechanisms are not well understood1,2. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours3. DC functions are orchestrated by pattern recognition receptors3-5, although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity6-8, but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour-cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T cell immunity, and overcomes therapeutic resistance to checkpoint blockade and T cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1s compete for glutamine uptake via the transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid in promoting cDC1 function. Further, glutamine signalling via FLCN impinges on TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner and phenocopies SLC38A2 deficiency by eliminating the anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1s that underpins tumour immune evasion, and reveal glutamine acquisition and signalling in cDC1s as limiting events for DC activation and putative targets for cancer treatment.

DOI: https://doi.org/10.1038/s41586-023-06299-8
Cell Rep. 2023 Jun 30. pii: S2211-1247(23)00719-2. [Epub ahead of print]42(7): 112708

Constitutively active autophagy in macrophages dampens inflammation through metabolic and post-transcriptional regulation of cytokine production.

Jinjin Xu, Lingjia Kong, Blayne A Oliver, Bihua Li, Elizabeth A Creasey, Gaelen Guzman, Monica Schenone, Kimberly L Carey, Steven A Carr, Daniel B Graham, Jacques Deguine, Ramnik J Xavier.

  Autophagy is an essential cellular process that is deeply integrated with innate immune signaling; however, studies that examine the impact of autophagic modulation in the context of inflammatory conditions are lacking. Here, using mice with a constitutively active variant of the autophagy gene Beclin1, we show that increased autophagy dampens cytokine production during a model of macrophage activation syndrome and in adherent-invasive Escherichia coli (AIEC) infection. Moreover, loss of functional autophagy through conditional deletion of Beclin1 in myeloid cells significantly enhances innate immunity in these contexts. We further analyzed primary macrophages from these animals with a combination of transcriptomics and proteomics to identify mechanistic targets downstream of autophagy. Our study reveals glutamine/glutathione metabolism and the RNF128/TBK1 axis as independent regulators of inflammation. Altogether, our work highlights increased autophagic flux as a potential approach to reduce inflammation and defines independent mechanistic cascades involved in this control.

Keywords:  CP: Immunology; RNF128; TBK1 signaling; autophagy; glutamine metabolism; glutathione metabolism; infection; inflammation; macrophages; proteogenomics

DOI:  https://doi.org/10.1016/j.celrep.2023.112708
Cell Metab. 2023 Jun 28. pii: S1550-4131(23)00215-2. [Epub ahead of print]

Immunometabolic coevolution defines unique microenvironmental niches in ccRCC.

Cerise Tang, Amy X Xie, Eric Minwei Liu, Fengshen Kuo, Minsoo Kim, Renzo G DiNatale, Mahdi Golkaram, Ying-Bei Chen, Sounak Gupta, Robert J Motzer, Paul Russo, Jonathan Coleman, Maria I Carlo, Martin H Voss, Ritesh R Kotecha, Chung-Han Lee, Wesley Tansey, Nikolaus Schultz, A Ari Hakimi, Ed Reznik.

  Tumor cell phenotypes and anti-tumor immune responses are shaped by local metabolite availability, but intratumoral metabolite heterogeneity (IMH) and its phenotypic consequences remain poorly understood. To study IMH, we profiled tumor/normal regions from clear cell renal cell carcinoma (ccRCC) patients. A common pattern of IMH transcended all patients, characterized by correlated fluctuations in the abundance of metabolites and processes associated with ferroptosis. Analysis of intratumoral metabolite-RNA covariation revealed that the immune composition of the microenvironment, especially the abundance of myeloid cells, drove intratumoral metabolite variation. Motivated by the strength of RNA-metabolite covariation and the clinical significance of RNA biomarkers in ccRCC, we inferred metabolomic profiles from the RNA sequencing data of ccRCC patients enrolled in 7 clinical trials, and we ultimately identifyied metabolite biomarkers associated with response to anti-angiogenic agents. Local metabolic phenotypes, therefore, emerge in tandem with the immune microenvironment, influence ongoing tumor evolution, and are associated with therapeutic sensitivity.

Keywords:  cancer metabolism; immune microenvironment; immunometabolism; imputation; intratumoral heterogeneity; metabolites; metabolomics; renal cell carcinoma; transcriptomics

DOI:  https://doi.org/10.1016/j.cmet.2023.06.005
mBio. 2023 Jul 07. e0092523

Loss of stearoyl-CoA desaturase 2 disrupts inflammatory response in macrophages.

Joseph B Lin, Amy Mora, Tzu Jui Wang, Andrea Santeford, Darksha Usmani, Marianne M Ligon, Indira U Mysorekar, Rajendra S Apte.

  Macrophages are innate immune cells that patrol tissues and are the first responders to detect infection. They orchestrate the host immune response in eliminating invading pathogens and the subsequent transition from inflammation to tissue repair. Macrophage dysfunction contributes to age-related pathologies, including low-grade inflammation in advanced age that is termed "inflammaging." Our laboratory has previously identified that macrophage expression of a fatty acid desaturase, stearoyl-CoA desaturase 2 (SCD2), declines with age. Herein, we delineate the precise cellular effects of SCD2 deficiency in murine macrophages. We found that deletion of Scd2 from macrophages dysregulated basal and bacterial lipopolysaccharide (LPS)-stimulated transcription of numerous inflammation-associated genes. Specifically, deletion of Scd2 from macrophages decreased basal and LPS-induced expression of Il1b transcript that corresponded to decreased production of precursor IL1B protein and release of mature IL1B. Furthermore, we identified disruptions in autophagy and depletion of unsaturated cardiolipins in SCD2-deficient macrophages. To assess the functional relevance of SCD2 in the macrophage response to infection, we challenged SCD2-deficient macrophages with uropathogenic Escherichia coli and found that there was impaired clearance of intracellular bacteria. This increased burden of intracellular bacteria was accompanied by increased release of pro-inflammatory cytokines IL6 and TNF but decreased IL1B. Taken together, these results indicate that macrophage expression of Scd2 is necessary for maintaining the macrophage response to inflammatory stimuli. This link between fatty acid metabolism and fundamental macrophage effector functions may potentially be relevant to diverse age-related pathologies. IMPORTANCE Macrophages are immune cells that respond to infection, but their dysfunction is implicated in many age-related diseases. Recent evidence showed that macrophage expression of a fatty acid enzyme, stearoyl-CoA desaturase 2, declines in aged organisms. In this work, we characterize the effects when stearoyl-CoA desaturase 2 is deficient in macrophages. We identify aspects of the macrophage inflammatory response to infection that may be affected when expression of a key fatty acid enzyme is decreased, and these findings may provide cellular insight into how macrophages contribute to age-related diseases.

Keywords:  IL1B; UPEC; cardiolipin; inflammaging; macrophage; stearoyl-CoA desaturase

DOI:  https://doi.org/10.1128/mbio.00925-23
iScience. 2023 Jul 21. 26(7): 107122

Pharmacologic inhibition of glycolysis prevents the development of lupus by altering the gut microbiome in mice.

Ahmed S Elshikha, Yong Ge, Josephine Brown, Nathalie Kanda, Mojgan Zadeh, Georges Abboud, Seung-Chul Choi, Gregg Silverman, Timothy J Garrett, William L Clapp, Mansour Mohamadzadeh, Laurence Morel.

  Gut dysbiosis has been associated with lupus pathogenesis, and fecal microbiota transfers (FMT) from lupus-prone mice shown to induce autoimmune activation into healthy mice. The immune cells of lupus patients exhibit an increased glucose metabolism and treatments with 2-deoxy-D-glucose (2DG), a glycolysis inhibitor, are therapeutic in lupus-prone mice. Here, we showed in two models of lupus with different etiologies that 2DG altered the composition of the fecal microbiome and associated metabolites. In both models, FMT from 2DG-treated mice protected lupus-prone mice of the same strain from the development of glomerulonephritis, reduced autoantibody production as well as the activation of CD4+ T cells and myeloid cells as compared to FMT from control mice. Thus, we demonstrated that the protective effect of glucose inhibition in lupus is transferable through the gut microbiota, directly linking alterations in immunometabolism to gut dysbiosis in the hosts.

Keywords:  Immune system disorder; Microbiome; Pharmaceutical science

DOI:  https://doi.org/10.1016/j.isci.2023.107122
World J Crit Care Med. 2023 Jun 09. 12(3): 139-152

Sepsis-induced mitochondrial dysfunction: A narrative review.

Wagner Nedel, Caroline Deutschendorf, Luis Valmor Cruz Portela.

  Sepsis represents a deranged and exaggerated systemic inflammatory response to infection and is associated with vascular and metabolic abnormalities that trigger systemic organic dysfunction. Mitochondrial function has been shown to be severely impaired during the early phase of critical illness, with a reduction in biogenesis, increased generation of reactive oxygen species and a decrease in adenosine triphosphate synthesis of up to 50%. Mitochondrial dysfunction can be assessed using mitochondrial DNA concentration and respirometry assays, particularly in peripheral mononuclear cells. Isolation of monocytes and lymphocytes seems to be the most promising strategy for measuring mitochondrial activity in clinical settings because of the ease of collection, sample processing, and clinical relevance of the association between metabolic alterations and deficient immune responses in mononuclear cells. Studies have reported alterations in these variables in patients with sepsis compared with healthy controls and non-septic patients. However, few studies have explored the association between mitochondrial dysfunction in immune mononuclear cells and unfavorable clinical outcomes. An improvement in mitochondrial parameters in sepsis could theoretically serve as a biomarker of clinical recovery and response to oxygen and vasopressor therapies as well as reveal unexplored pathophysiological mechanistic targets. These features highlight the need for further studies on mitochondrial metabolism in immune cells as a feasible tool to evaluate patients in intensive care settings. The evaluation of mitochondrial metabolism is a promising tool for the evaluation and management of critically ill patients, especially those with sepsis. In this article, we explore the pathophysiological aspects, main methods of measurement, and the main studies in this field.

Keywords:  Inflammation; Mitochondria; Mitochondrial dysfunction; Oxidative phosphorylation; Respirometry; Sepsis

DOI:  https://doi.org/10.5492/wjccm.v12.i3.139
Immunohorizons. 2023 Jul 01. 7(7): 528-542

Targeting 2-Oxoglutarate-Dependent Dioxygenases Promotes Metabolic Reprogramming That Protects against Lethal SARS-CoV-2 Infection in the K18-hACE2 Transgenic Mouse Model.

Forrest Jessop, Benjamin Schwarz, Eric Bohrnsen, Molly Miltko, Carl Shaia, Catharine M Bosio.

Dysregulation of host metabolism is a feature of lethal SARS-CoV-2 infection. Perturbations in α-ketoglutarate levels can elicit metabolic reprogramming through 2-oxoglutarate-dependent dioxygenases (2-ODDGs), leading to stabilization of the transcription factor HIF-1α. HIF1-α activation has been reported to promote antiviral mechanisms against SARS-CoV-2 through direct regulation of ACE2 expression (a receptor required for viral entry). However, given the numerous pathways HIF-1α serves to regulate it is possible that there are other undefined metabolic mechanisms contributing to the pathogenesis of SARS-CoV-2 independent of ACE2 downregulation. In this study, we used in vitro and in vivo models in which HIF-1α modulation of ACE2 expression was negated, allowing for isolated characterization of the host metabolic response within SARS-CoV-2 disease pathogenesis. We demonstrated that SARS-CoV-2 infection limited stabilization of HIF-1α and associated mitochondrial metabolic reprogramming by maintaining activity of the 2-ODDG prolyl hydroxylases. Inhibition of 2-ODDGs with dimethyloxalylglycine promoted HIF-1α stabilization following SARS-CoV-2 infection, and significantly increased survival among SARS-CoV-2-infected mice compared with vehicle controls. However, unlike previous reports, the mechanism by which activation of HIF-1α responses contributed to survival was not through impairment of viral replication. Rather, dimethyloxalylglycine treatment facilitated direct effects on host metabolism including increased glycolysis and resolution of dysregulated pools of metabolites, which correlated with reduced morbidity. Taken together, these data identify (to our knowledge) a novel function of α-ketoglutarate-sensing platforms, including those responsible for HIF-1α stabilization, in the resolution of SARS-CoV-2 infection and support targeting these metabolic nodes as a viable therapeutic strategy to limit disease severity during infection.

DOI: https://doi.org/10.4049/immunohorizons.2300048
Trends Cancer. 2023 Jul 01. pii: S2405-8033(23)00104-8. [Epub ahead of print]

Diet, nutrient supply, and tumor immune responses.

Claire L McIntyre, Ayantu Temesgen, Lydia Lynch.

  Nutrients are essential for cell function. Immune cells operating in the complex tumor microenvironment (TME), which has a unique nutrient composition, face challenges of adapting their metabolism to support effector functions. We discuss the impact of nutrient availability on immune function in the tumor, competition between immune cells and tumor cells for nutrients, and how this is altered by diet. Understanding which diets can promote antitumor immune responses could open a new era of treatment, where dietary modifications can be used as an adjunct to boost the success of existing cancer therapies.

Keywords:  T cells; cancer; diet; immune cells; metabolism; obesity

DOI:  https://doi.org/10.1016/j.trecan.2023.06.003
Cytokine Growth Factor Rev. 2023 Jun 30. pii: S1359-6101(23)00029-1. [Epub ahead of print]

Targeting the metabolism and immune system in pancreatic ductal adenocarcinoma: Insights and future directions.

Dhana Sekhar Reddy Bandi, Sujith Sarvesh, Batoul Farran, Ganji Purnachandra Nagaraju, Bassel F El-Rayes.

  Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), presents a challenging landscape due to its complex nature and the highly immunosuppressive tumor microenvironment (TME). This immunosuppression severely limits the effectiveness of immune-based therapies. Studies have revealed the critical role of immunometabolism in shaping the TME and influencing PDAC progression. Genetic alterations, lysosomal dysfunction, gut microbiome dysbiosis, and altered metabolic pathways have been shown to modulate immunometabolism in PDAC. These metabolic alterations can significantly impact immune cell functions, including T-cells, myeloid-derived suppressor cells (MDSCs), and macrophages, evading anti-tumor immunity. Advances in immunotherapy offer promising avenues for overcoming immunosuppressive TME and enhancing patient outcomes. This review highlights the challenges and opportunities for future research in this evolving field. By exploring the connections between immunometabolism, genetic alterations, and the microbiome in PDAC, it is possible to tailor novel approaches capable of improving immunotherapy outcomes and addressing the limitations posed by immunosuppressive TME. Ultimately, these insights may pave the way for improved treatment options and better outcomes for PDAC patients.

Keywords:  Immunometabolism; Immunotherapy; Metabolic pathways; Pancreatic ductal adenocarcinoma; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cytogfr.2023.06.006
Front Mol Biosci. 2023 ;10 1201912

Psoriasis immunometabolism: progress on metabolic biomarkers and targeted therapy.

Evangelia Sarandi, Sabine Krueger-Krasagakis, Dimitris Tsoukalas, Polytimi Sidiropoulou, George Evangelou, Maria Sifaki, Gottfried Rudofsky, Nikolaos Drakoulis, Aristidis Tsatsakis.

  Psoriasis is a common inflammatory disease that affects mainly the skin. However, the moderate to severe forms have been associated with several comorbidities, such as psoriatic arthritis, Crohn's disease, metabolic syndrome and cardiovascular disease. Keratinocytes and T helper cells are the dominant cell types involved in psoriasis development via a complex crosstalk between epithelial cells, peripheral immune cells and immune cells residing in the skin. Immunometabolism has emerged as a potent mechanism elucidating the aetiopathogenesis of psoriasis, offering novel specific targets to diagnose and treat psoriasis early. The present article discusses the metabolic reprogramming of activated T cells, tissue-resident memory T cells and keratinocytes in psoriatic skin, presenting associated metabolic biomarkers and therapeutic targets. In psoriatic phenotype, keratinocytes and activated T cells are glycolysis dependent and are characterized by disruptions in the TCA cycle, the amino acid metabolism and the fatty acid metabolism. Upregulation of the mammalian target of rapamycin (mTOR) results in hyperproliferation and cytokine secretion by immune cells and keratinocytes. Metabolic reprogramming through the inhibition of affected metabolic pathways and the dietary restoration of metabolic imbalances may thus present a potent therapeutic opportunity to achieve long-term management of psoriasis and improved quality of life with minimum adverse effects.

Keywords:  T cell; TCA; biomarkers; glycolysis; keratinocyte; lipid metabolism; metabolic targets; psoriasis

DOI:  https://doi.org/10.3389/fmolb.2023.1201912
J Leukoc Biol. 2023 Jul 04. pii: qiad076. [Epub ahead of print]

ATF2 orchestrates macrophage differentiation and activation to promote antibacterial responses.

Nusrah Rajabalee, Hannah Siushansian, Milani Weerapura, Stefania Berton, Fjolla Berbatovci, Breana Hooks, Michele Geoffrion, Dabo Yang, Mary-Ellen Harper, Katey Rayner, Alexandre Blais, Jim Sun.

  The differentiation and activation of macrophages are critical regulatory programs that are central to host inflammation and defense against pathogens. However, the transcriptional regulatory pathways involved in these programs are not well understood. Herein, we demonstrate that the activity and expression of Activating Transcription Factor 2 (ATF2) is precisely regulated during primary human monocyte to macrophage differentiation, and that its activation is linked to M1 polarization and antibacterial responses. Genetic perturbation experiments demonstrated that deletion of ATF2 (THP-ΔATF2) resulted in irregular and abnormal macrophage morphology, whereas macrophages overexpressing ATF2 (THP-ATF2) developed round and pancake-like morphology, resembling classically activated (M1) macrophages. Mechanistically, we show that ATF2 binds to the core promoter of PPM1A, a phosphatase that regulates monocyte-to-macrophage differentiation, to regulate its expression. Functionally, overexpression of ATF2 sensitized macrophages to M1 polarization, resulting in increased production of MHC Class II, IL-1β and IP-10, improved phagocytic capacity, and enhanced control of the intracellular pathogen Mycobacterium tuberculosis. Gene expression profiling revealed that overexpression of ATF2 reprogramed macrophages to promote antibacterial pathways enriched in chemokine signaling, metabolism and antigen presentation. Consistent with pathways analysis, metabolic profiling revealed that genetic overexpression or stimuli-induced activation of ATF2 alters the metabolic capacity of macrophages and primes these cells for glycolytic metabolism during M1 polarization or bacterial infection. Our findings reveal that ATF2 plays a central role during macrophage differentiation and M1 polarization to enhance the functional capacities of macrophages.

Keywords:   Mycobacterium tuberculosis ; ATF2; innate immunity; macrophage polarization; metabolic reprogramming; monocyte-to-macrophage differentiation; transcription factors

DOI:  https://doi.org/10.1093/jleuko/qiad076
Genes Dis. 2023 Jul;10(4): 1552-1563

Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response.

Wenchang Yang, Yaxin Wang, Tao Wang, Chengguo Li, Liang Shi, Peng Zhang, Yuping Yin, Kaixiong Tao, Ruidong Li.

  Inflammatory bowel disease (IBD) is a chronic relapsing gastrointestinal disorder, while the treatment effect is not satisfactory. Immune responsive gene 1 (IRG1) is a highly expressed gene in macrophage in response to inflammatory response and catalyzes the production of itaconate. Studies have reported that IRG1/itaconate has a significant antioxidant effect. This study aimed to investigate the effect and mechanism of IRG1/itaconate on dextran sulfate sodium (DSS)-induced colitis in vivo and in vitro. In vivo experiments, we found IRG1/itaconate exerted protective effects against acute colitis by increasing mice weight, the length of colon, reducing disease activity index and colonic inflammation. Meanwhile, IRG1 deletion aggravated the macrophages/CD4+/CD8+ T-cell accumulation, and increased the release of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-6, the activation of nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, and gasdermin D (GSDMD) mediated pyroptosis. Four-octyl itaconate (4-OI), a derivative of itaconate, attenuated these changes, therefore relieved DSS-induced colitis. In vitro experiment, we found 4-OI inhibited the reactive oxygen species production, thereby inhibiting the activation of MAPK/NF-κB signaling pathway in RAW264.7 and murine bone-marrow-derived macrophages. Simultaneously, we found 4-OI inhibited caspase1/GSDMD-mediated pyroptosis to reduce the release of cytokines. Finally, we found anti-TNF-α agent reduced the severity of DSS-induced colitis and inhibited gasdermin E (GSDME)-mediated pyroptosis in vivo. Meanwhile, our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-α in vitro. Taken together, IRG1/itaconate exerted a protective role in DSS-induced colitis by inhibiting inflammatory response and GSDMD/GSDME-mediated pyroptosis, which could be a promising candidate for IBD therapy.

Keywords:  Colitis; Gasdermin D; Gasdermin E; IRG1; Inflammation

DOI:  https://doi.org/10.1016/j.gendis.2022.05.039
Curr Atheroscler Rep. 2023 Jul 03.

T-cell Cholesterol Accumulation, Aging, and Atherosclerosis.

Venetia Bazioti, Benedek Halmos, Marit Westerterp.

  PURPOSE OF REVIEW: The majority of leukocytes in advanced human atherosclerotic plaques are T-cells. T-cell subsets exert pro- or anti-atherogenic effects largely via the cytokines they secrete. Tregulatory cells (Tregs) are anti-inflammatory, but may lose these properties during atherosclerosis, proposed to be downstream of cholesterol accumulation. Aged T-cells also accumulate cholesterol. The effects of T-cell cholesterol accumulation on T-cell fate and atherosclerosis are not uniform.RECENT FINDINGS: T-cell cholesterol accumulation enhances differentiation into pro-atherogenic cytotoxic T-cells and boosts their killing capacity, depending on the localization and extent of cholesterol accumulation. Excessive cholesterol accumulation induces T-cell exhaustion or T-cell apoptosis, the latter decreasing atherosclerosis but impairing T-cell functionality in terms of killing capacity and proliferation. This may explain the compromised T-cell functionality in aged T-cells and T-cells from CVD patients. The extent of T-cell cholesterol accumulation and its cellular localization determine T-cell fate and downstream effects on atherosclerosis and T-cell functionality.

Keywords:  ABC transporters; Atherosclerosis; CVD; Cholesterol; T-cell

DOI:  https://doi.org/10.1007/s11883-023-01125-y
Immune Netw. 2023 Jun;23(3): e23

Extracellular Acidification Augments NLRP3-Mediated Inflammasome Signaling in Macrophages.

Byeong Jun Chae, Kyung-Seo Lee, Inhwa Hwang, Je-Wook Yu.

  Inflammation is a series of host defense processes in response to microbial infection and tissue injury. Inflammatory processes frequently cause extracellular acidification in the inflamed region through increased glycolysis and lactate secretion. Therefore, the immune cells infiltrating the inflamed region encounter an acidic microenvironment. Extracellular acidosis can modulate the innate immune response of macrophages; however, its role for inflammasome signaling still remains elusive. In the present study, we demonstrated that macrophages exposed to an acidic microenvironment exhibited enhanced caspase-1 processing and IL-1β secretion compared with those under physiological pH. Moreover, exposure to an acidic pH increased the ability of macrophages to assemble the NLR family pyrin domain containing 3 (NLRP3) inflammasome in response to an NLRP3 agonist. This acidosis-mediated augmentation of NLRP3 inflammasome activation occurred in bone marrow-derived macrophages but not in bone marrow-derived neutrophils. Notably, exposure to an acidic environment caused a reduction in the intracellular pH of macrophages but not neutrophils. Concordantly, macrophages, but not neutrophils, exhibited NLRP3 agonist-mediated translocation of chloride intracellular channel protein 1 (CLIC1) into their plasma membranes under an acidic microenvironment. Collectively, our results demonstrate that extracellular acidosis during inflammation can increase the sensitivity of NLRP3 inflammasome formation and activation in a CLIC1-dependent manner. Thus, CLIC1 may be a potential therapeutic target for NLRP3 inflammasome-mediated pathological conditions.

Keywords:  Acidosis; Chloride channels; Inflammasome; Inflammation; NLR family, pyrin domain-containing 3 protein (NLRP3)

DOI:  https://doi.org/10.4110/in.2023.23.e23
Exp Mol Med. 2023 Jul 03.

Immune regulation through tryptophan metabolism.

Su-Kil Seo, Byungsuk Kwon.

Amino acids are fundamental units of molecular components that are essential for sustaining life; however, their metabolism is closely interconnected to the control systems of cell function. Tryptophan (Trp) is an essential amino acid catabolized by complex metabolic pathways. Several of the resulting Trp metabolites are bioactive and play central roles in physiology and pathophysiology. Additionally, various physiological functions of Trp metabolites are mutually regulated by the gut microbiota and intestine to coordinately maintain intestinal homeostasis and symbiosis under steady state conditions and during the immune response to pathogens and xenotoxins. Cancer and inflammatory diseases are associated with dysbiosis- and host-related aberrant Trp metabolism and inactivation of the aryl hydrocarbon receptor (AHR), which is a receptor of several Trp metabolites. In this review, we focus on the mechanisms through which Trp metabolism converges to AHR activation for the modulation of immune function and restoration of tissue homeostasis and how these processes can be targeted using therapeutic approaches for cancer and inflammatory and autoimmune diseases.

DOI: https://doi.org/10.1038/s12276-023-01028-7
Cytokine Growth Factor Rev. 2023 Jun 30. pii: S1359-6101(23)00027-8. [Epub ahead of print]

Lipid metabolism in regulation of B cell development and autoimmunity.

Xing Ji, Liang Wu, Tony Marion, Yubin Luo.

  B cells play an important role in adaptive immunity and participate in the process of humoral immunity mainly by secreting antibodies. The entire development and differentiation process of B cells occurs in multiple microenvironments and is regulated by a variety of environmental factors and immune signals. Differentiation biases or disfunction of B cells participate in the process of many autoimmune diseases. Emerging studies report the impact of altered metabolism in B cell biology, including lipid metabolism. Here, we discuss how extracellular lipid environment and metabolites, membrane lipid-related components, and lipid synthesis and catabolism programs coordinate B cell biology and describe the crosstalk of lipid metabolic programs with signal transduction pathways and transcription factors. We conclude with a summary of therapeutic targets for B cell lipid metabolism and signaling in autoimmune diseases and discuss important future directions.

Keywords:  Autoimmune diseases; B cell biology; Cholesterol derivatives; Fatty acids; Lipid synthesis and catabolism; Sphingomyelin metabolites

DOI:  https://doi.org/10.1016/j.cytogfr.2023.06.008
Sci Immunol. 2023 Jul 14. 8(85): eadj4913

Fueling the fire of B cell activation.

Patricia M Sikorski, Linda L Kusner.

Antigen activated naïve B cells undergoing germinal center responses have distinct metabolic requirements.

DOI: https://doi.org/10.1126/sciimmunol.adj4913
Inflamm Bowel Dis. 2023 Jul 05. pii: izad117. [Epub ahead of print]

Glycolytic Activation of CD14+ Intestinal Macrophages Contributes to the Inflammatory Responses via Exosomal Membrane Tumor Necrosis Factor in Crohn's Disease.

Ziwei Zeng, Sijing Cheng, Xuanna Li, Huashan Liu, Jinxin Lin, Zhenxing Liang, Xuanhui Liu, Chao Cao, Shujuan Li, Xiaowen He, Liang Kang, Xiaojian Wu, Xiaobin Zheng.

  BACKGROUND: Macrophage (Mφ) activation plays a critical role in the inflammatory response. Activated Mφ go through profound reprogramming of cellular metabolism. However, changes in their intracellular energy metabolism and its effect on inflammatory responses in Crohn's disease (CD) remain currently unclear. The aim of this study is to explore metabolic signatures of CD14+ Mφ and their potential role in CD pathogenesis as well as the underlying mechanisms.METHODS: CD14+ Mφ were isolated from peripheral blood or intestinal tissues of CD patients and control subjects. Real-time flux measurements and enzyme-linked immunosorbent assay were used to determine the inflammatory states of Mφ and metabolic signatures. Multiple metabolic routes were suppressed to determine their relevance to cytokine production.
RESULTS: Intestinal CD14+ Mφ in CD patients exhibited activated glycolysis compared with those in control patients. Specifically, macrophagic glycolysis in CD largely induced inflammatory cytokine release. The intestinal inflammatory microenvironment in CD elicited abnormal glycolysis in Mφ. Mechanistically, CD14+ Mφ derived exosomes expressed membrane tumor necrosis factor (TNF), which engaged TNFR2 and triggered glycolytic activation via TNF/nuclear factor κB autocrine and paracrine signaling. Importantly, clinically applicable anti-TNF antibodies effectively prevented exosomal membrane TNF-induced glycolytic activation in CD14+ Mφ.
CONCLUSIONS: CD14+ Mφ take part in CD pathogenesis by inducing glycolytic activation via membrane TNF-mediated exosomal autocrine and paracrine signaling. These results provide novel insights into pathogenesis of CD and enhance understanding of the mechanisms of anti-TNF agents.

Keywords:  Crohn’s disease; exosome; glycolytic activation; macrophages

DOI:  https://doi.org/10.1093/ibd/izad117
FASEB J. 2023 Aug;37(8): e23047

CD226 deficiency attenuates cardiac early pathological remodeling and dysfunction via decreasing inflammatory macrophage proportion and macrophage glycolysis in STZ-induced diabetic mice.

Yongli Hou, Yazhen Wang, Kang Tang, Yan Yang, Yiwei Wang, Ruiyan Liu, Bin Wu, Xutao Chen, Zhaoyue Fu, Feng Zhao, Lihua Chen.

  Diabetic cardiomyopathy (DCM) is one of the main complications in type I diabetic patients. Activated macrophage is critical for directing the process of inflammation during the development of DCM. The present study focused on the roles of CD226 on macrophage function during the DCM progression. It has been found that the number of cardiac macrophages in the hearts of streptozocin (STZ)-induced diabetes mice was significantly increased compared with that in non-diabetes mice, and the expression level of CD226 on cardiac macrophages in STZ-induced diabetes mice was higher than that in non-diabetes mice. CD226 deficiency attenuated the diabetes-induced cardiac dysfunction and decreased the proportion of CD86+ F4/80+ macrophages in the diabetic hearts. Notably, adoptive transfer of Cd226-/- - bone marrow derived macrophages (BMDMs) alleviated diabetes-induced cardiac dysfunction, which may be due to the attenuated migration capacity of Cd226-/- -BMDM under high glucose stimulation. Furthermore, CD226 deficiency decreased the macrophage glycolysis accompanying by the downregulated hexokinase 2 (HK2) and lactate dehydrogenase A (LDH-A) expression. Taken together, these findings revealed the pathogenic roles of CD226 played in the process of DCM and provided a basis for the treatment of DCM.

Keywords:  CD226; diabetic cardiomyopathy; glycolysis; immune metabolism; macrophage

DOI:  https://doi.org/10.1096/fj.202300424RR
J Immunother Cancer. 2023 06;pii: e006287. [Epub ahead of print]11(6):

Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies.

Ernesto Lopez, Rajesh Karattil, Francesco Nannini, Gordon Weng-Kit Cheung, Lilian Denzler, Felipe Galvez-Cancino, Sergio Quezada, Martin A Pule.

  BACKGROUND: Chimeric antigen receptor (CAR) T cells have shown remarkable results against B-cell malignancies, but only a minority of patients have long-term remission. The metabolic requirements of both tumor cells and activated T cells result in production of lactate. The export of lactate is facilitated by expression of monocarboxylate transporter (MCTs). CAR T cells express high levels of MCT-1 and MCT-4 on activation, while certain tumors predominantly express MCT-1.METHODS: Here, we studied the combination of CD19-specific CAR T-cell therapy with pharmacological blockade of MCT-1 against B-cell lymphoma.
RESULTS: MCT-1 inhibition with small molecules AZD3965 or AR-C155858 induced CAR T-cell metabolic rewiring but their effector function and phenotype remained unchanged, suggesting CAR T cells are insensitive to MCT-1 inhibition. Moreover, improved cytotoxicity in vitro and antitumoral control on mouse models was found with the combination of CAR T cells and MCT-1 blockade.
CONCLUSION: This work highlights the potential of selective targeting of lactate metabolism via MCT-1 in combination with CAR T cells therapies against B-cell malignancies.

Keywords:  Immunotherapy; Metabolic Networks and Pathways; Receptors, Chimeric Antigen; T-Lymphocytes

DOI:  https://doi.org/10.1136/jitc-2022-006287
PLoS One. 2023 ;18(7): e0286525

Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis.

Brooks P Leitner, Won D Lee, Wanling Zhu, Xinyi Zhang, Rafael C Gaspar, Zongyu Li, Joshua D Rabinowitz, Rachel J Perry.

Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and 13C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine's contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine's contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis.

DOI: https://doi.org/10.1371/journal.pone.0286525
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2023 Jul;39(7): 656-662

[Research progress on the effect of mitochondrial network remodeling on macrophages].

Lianlian Zhu, Xiangmin Kong, Wei Zhu.

Remodeling of the mitochondrial network is an important process in the maintenance of cellular homeostasis and is closely related to mitochondrial function. Interactions between the biogenesis of new mitochondria and the clearance of damaged mitochondria (mitophagy) is an important manifestation of mitochondrial network remodeling. Mitochondrial fission and fusion act as a bridge between biogenesis and mitophagy. In recent years, the importance of these processes has been described in a variety of tissues and cell types and under a variety of conditions. For example, robust remodeling of the mitochondrial network has been reported during the polarization and effector function of macrophages. Previous studies have also revealed the important role of mitochondrial morphological structure and metabolic changes in regulating the function of macrophages. Therefore, the processes that regulate remodeling of the mitochondrial network also play a crucial role in the immune response of macrophages. In this paper, we focus on the molecular mechanisms of mitochondrial regeneration, fission, fusion, and mitophagy in the process of mitochondrial network remodeling, and integrate these mechanisms to investigate their biological roles in macrophage polarization, inflammasome activation, and efferocytosis.
Front Bioeng Biotechnol. 2023 ;11 1207576

Determination of CAR T cell metabolism in an optimized protocol.

Sandy Joaquina, Christopher Forcados, Benjamin Caulier, Else Marit Inderberg, Sébastien Wälchli.

  Adoptive transfer of T cells modified to express chimeric antigenic receptors (CAR) has emerged as a solution to cure refractory malignancies. However, although CAR T cell treatment of haematological cancers has now shown impressive improvement in outcome, solid tumours have been more challenging to control. The latter type is protected by a strong tumour microenvironment (TME) which might impact cellular therapeutic treatments. Indeed, the milieu around the tumour can become particularly inhibitory to T cells by directly affecting their metabolism. Consequently, the therapeutic cells become physically impeded before being able to attack the tumour. It is therefore extremely important to understand the mechanism behind this metabolic break in order to develop TME-resistant CAR T cells. Historically, the measurement of cellular metabolism has been performed at a low throughput which only permitted a limited number of measurements. However, this has been changed by the introduction of real-time technologies which have lately become more popular to study CAR T cell quality. Unfortunately, the published protocols lack uniformity and their interpretation become confusing. We herein tested the essential parameters to perform a metabolic study on CAR T cells and propose a check list of factors that should be set in order to draw sound conclusion.

Keywords:  CAR T cell; Seahorse XF96; cancer therapy; immunotherapy; metabolim

DOI:  https://doi.org/10.3389/fbioe.2023.1207576
Part Fibre Toxicol. 2023 07 03. 20(1): 25

Diesel Exhaust Particle (DEP)-induced glucose intolerance is driven by an intestinal innate immune response and NLRP3 activation in mice.

Angela J T Bosch, Theresa V Rohm, Shefaa AlAsfoor, Andy J Y Low, Zora Baumann, Neena Parayil, Faiza Noreen, Julien Roux, Daniel T Meier, Claudia Cavelti-Weder.

  BACKGROUND: We previously found that air pollution particles reaching the gastrointestinal tract elicit gut inflammation as shown by up-regulated gene expression of pro-inflammatory cytokines and monocyte/macrophage markers. This inflammatory response was associated with beta-cell dysfunction and glucose intolerance. So far, it remains unclear whether gut inflammatory changes upon oral air pollution exposure are causally linked to the development of diabetes. Hence, our aim was to assess the role of immune cells in mediating glucose intolerance instigated by orally administered air pollutants.METHODS: To assess immune-mediated mechanisms underlying air pollution-induced glucose intolerance, we administered diesel exhaust particles (DEP; NIST 1650b, 12 µg five days/week) or phosphate-buffered saline (PBS) via gavage for up to 10 months to wild-type mice and mice with genetic or pharmacological depletion of innate or adaptive immune cells. We performed unbiased RNA-sequencing of intestinal macrophages to elucidate signaling pathways that could be pharmacologically targeted and applied an in vitro approach to confirm these pathways.
RESULTS: Oral exposure to air pollution particles induced an interferon and inflammatory signature in colon macrophages together with a decrease of CCR2- anti-inflammatory/resident macrophages. Depletion of macrophages, NLRP3 or IL-1β protected mice from air pollution-induced glucose intolerance. On the contrary, Rag2-/- mice lacking adaptive immune cells developed pronounced gut inflammation and glucose intolerance upon oral DEP exposure.
CONCLUSION: In mice, oral exposure to air pollution particles triggers an immune-mediated response in intestinal macrophages that contributes to the development of a diabetes-like phenotype. These findings point towards new pharmacologic targets in diabetes instigated by air pollution particles.

Keywords:  Air pollution; Diesel exhaust particles; Gastrointestinal tract; Glucose metabolism; Gut exposure; IL-1β; Innate immune response; Macrophages; Metabolic disease; NLRP3

DOI:  https://doi.org/10.1186/s12989-023-00536-8
Nat Cell Biol. 2023 Jul 03.

Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.

Tao Zhang, Daichao Xu, Jianping Liu, Min Wang, Li-Juan Duan, Min Liu, Huyan Meng, Yuan Zhuang, Huibing Wang, Yingnan Wang, Mingming Lv, Zhengyi Zhang, Jia Hu, Linyu Shi, Rui Guo, Xingxing Xie, Hui Liu, Emily Erickson, Yaru Wang, Wenyu Yu, Fabin Dang, Dongxian Guan, Cong Jiang, Xiaoming Dai, Hiroyuki Inuzuka, Peiqiang Yan, Jingchao Wang, Mrigya Babuta, Gewei Lian, Zhenbo Tu, Ji Miao, Gyongyi Szabo, Guo-Hua Fong, Antoine E Karnoub, Yu-Ru Lee, Lifeng Pan, William G Kaelin, Junying Yuan, Wenyi Wei.

The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα-TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN-pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1.

DOI: https://doi.org/10.1038/s41556-023-01170-4
Heliyon. 2023 Jun;9(6): e17158

Transcriptome analysis of human macrophages upon chikungunya virus (CHIKV) infection reveals regulation of distinct signaling and metabolic pathways during the early and late stages of infection.

Priyanshu Srivastava, Sakshi Chaudhary, Surbhi Malhotra, Binuja Varma, Sujatha Sunil.

  Macrophages are efficient reservoirs for viruses that enable the viruses to survive over a longer period of infection. Alphaviruses such as chikungunya virus (CHIKV) are known to persist in macrophages even after the acute febrile phase. The viral particles replicate in macrophages at a very low level over extended period of time and are localized in tissues that are often less accessible by treatment. Comprehensive experimental studies are thus needed to characterize the CHIKV-induced modulation of host genes in these myeloid lineage cells and in one such pursuit, we obtained global transcriptomes of a human macrophage cell line infected with CHIKV, over its early and late timepoints of infection. We analyzed the pathways, especially immune related, perturbed over these timepoints and observed several host factors to be differentially expressed in infected macrophages in a time-dependent manner. We postulate that these pathways may play crucial roles in the persistence of CHIKV in macrophages.

Keywords:  CHIKV; Macrophages; Metabolic pathways; Transcriptome

DOI:  https://doi.org/10.1016/j.heliyon.2023.e17158
Int Immunopharmacol. 2023 Jul 01. pii: S1567-5769(23)00700-2. [Epub ahead of print]122 110377

A novel metabolic reprogramming strategy for the treatment of targeting to heart injury-mediated macrophages.

ShuRui Chen, Xiang Luo, Yu Sun, Wen Jin, Rongrong He.

  M1 macrophages polarization has been reported as the direct risk of acute myocardial infarction (AMI) occurrence and worsen AMI prognosis, especially for hyperinflammation-associated AMI. However, clinic treatments remain challenges, including off-target and side-effects. The development of enzyme mimetics could provide effective treatments for a wide variety of diseases. Herein, nanomaterials were used to create artificial hybrid nanozymes. In this study, we synthesized in situ zeolitic imidazolate framework nanozyme (ZIF-8zyme) with anti-oxidative and anti-inflammatory ability to repair microenvironment via reprogramming M1 macrophages polarization. In vitro study reported that a metabolic reprogramming strategy that the improvement of glucose import and glycolysis with ZIF-8zyme via inhibiting ROS levels led to a metabolic crisis within the macrophages. ZIF-8zyme shifted the polarization of M1 macrophages toward higher production of M2 phenotype, decreased proinflammatory cytokines secretion, and promoted significant survival of cardiomyocytes under hyperinflammation condition. Moreover, ZIF-8zyme elicits more potent macrophages-polarizing effects under hyperinflammation condition. Therefore, metabolic reprogramming strategy based on ZIF-8zyme is a promising AMI therapy, especially for hyperinflammation-associated AMI.

Keywords:  Acute myocardial infarction; Macrophages polarization; ROS; ZIF-8zyme

DOI:  https://doi.org/10.1016/j.intimp.2023.110377
Clin Transl Med. 2023 Jul;13(7): e1325

Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis-induced formation of neutrophil extracellular traps.

Tingting Lv, Xiaofeng Xiong, Wei Yan, Mei Liu, Hongwei Xu, Qin He.

  BACKGROUND: Mitochondria play central roles in metabolic diseases including nonalcoholic steatohepatitis (NASH). However, how mitochondria regulate NASH progression remains largely unknown. Our previous findings demonstrate that mitochondrial general control of amino acid synthesis 5 like 1 (GCN5L1) is associated with mitochondrial metabolism. Nevertheless, the roles of GCN5L1 in NASH are unclear.AIMS AND METHODS: The GCN5L1 expression was detected in the fatty livers of NASH patients and animals. Hepatocyte-specific GCN5L1 deficiency or overexpression mice were used to induce NASH models by feeding with a high-fat/high-cholesterol or methionine-choline deficient diet. The molecular mechanisms underlying GCN5L1-regulated NASH were further explored and verified in mice.
RESULTS AND CONCLUSIONS: GCN5L1 expression was increased in NASH patients. Upregulated GCN5L1 level was also illustrated in NASH mice. Mice with hepatocyte-specific GCN5L1 conditional knockout improved the inflammatory response compared to GCN5L1flox/flox mice. However, overexpression of mitochondrial GCN5L1 augmented the inflammatory response. Mechanically, GCN5L1 acetylated CypD and enhanced its binding with ATP5B, which induced the opening of mitochondrial permeability transition pores and the release of mitochondrial ROS into the cytoplasm. The increased ROS promoted ferroptosis of hepatocytes and induced accumulation of high mobility group box 1 in the microenvironment, which recruited neutrophils and induced the generation of neutrophil extracellular traps (NETs). NETs block impaired GCN5L1-induced NASH progression. Furthermore, the upregulation of GCN5L1 in NASH was contributed by lipid overload-induced endoplasmic reticulum stress. Together, mitochondrial GCN5L1 has a vital function in promoting NASH progression by regulating oxidative metabolism and the hepatic inflammatory microenvironment. Thus, GCN5L1 might be a potential intervention target in NASH treatment.

Keywords:  GCN5L1; ferroptosis; mitochondrial permeability transition pores; neutrophil extracellular traps; nonalcoholic steatohepatitis

DOI:  https://doi.org/10.1002/ctm2.1325
ACS Appl Mater Interfaces. 2023 Jul 05.

Selenium-Doped Mesoporous Bioactive Glass Regulates Macrophage Metabolism and Polarization by Scavenging ROS and Promotes Bone Regeneration In Vivo.

Ding Chen, Zitian Liang, Zhikang Su, Jiangyong Huang, Yixing Pi, Yuanting Ouyang, Tao Luo, Lvhua Guo.

  Bone regeneration is complex and involves multiple cells and systems, with macrophage-mediated immune regulation being critical for the development and regulation of inflammation, angiogenesis, and osteogenesis. Biomaterials with modified physical and chemical properties (e.g., modified wettability and morphology) effectively regulate macrophage polarization. This study proposes a novel approach to macrophage-polarization induction and -metabolism regulation through selenium (Se) doping. We synthesized Se-doped mesoporous bioactive glass (Se-MBG) and demonstrated its macrophage-polarization regulation toward M2 and its enhancement of the macrophage oxidative phosphorylation metabolism. The underlying mechanism is the effective scavenging of excessive intracellular reactive oxygen species (ROS) by the Se-MBG extracts through the promotion of peroxide-scavenging enzyme glutathione peroxidase 4 expression in the macrophages; this, in turn, improves the mitochondrial function. Printed Se-MBG scaffolds were implanted into rats with critical-sized skull defects to evaluate their immunomodulatory and bone regeneration capacity in vivo. The Se-MBG scaffolds demonstrated excellent immunomodulatory function and robust bone regeneration capacity. Macrophage depletion with clodronate liposomes impaired the Se-MBG-scaffold bone regeneration effect. Se-mediated immunomodulation, which targets ROS scavenging to regulate macrophage metabolic profiles and mitochondrial function, is a promising concept for future effective biomaterials for bone regeneration and immunomodulation.

Keywords:  ROS scavenging; bone regeneration; mitochondrial function; osteoimmunomodulation; selenium-doped mesoporous bioactive glass

DOI:  https://doi.org/10.1021/acsami.3c03446
bioRxiv. 2023 Jun 13. pii: 2023.06.12.544686. [Epub ahead of print]

AMPK Drives Both Glycolytic and Oxidative Metabolism in T Cells During Graft-versus-host Disease.

Archana Ramgopal, Erica L Braverman, Lee-Kai Sun, Darlene Monlish, Christopher Wittmann, Manda J Ramsey, Richard Caitley, William Hawse, Craig A Byersdorfer.

Allogeneic T cells reprogram their metabolism during acute graft-versus-host disease (GVHD) in a process reliant on the cellular energy sensor AMP-activated protein kinase (AMPK). Deletion of AMPK in donor T cells limits GVHD but still preserves homeostatic reconstitution and graft-versus-leukemia (GVL) effects. In the current studies, murine T cells lacking AMPK decreased oxidative metabolism at early timepoints post-transplant and were also unable to mediate a compensatory increase in glycolysis following inhibition of the electron transport chain. Human T cells lacking AMPK gave similar results, with glycolytic compensation impaired both in vitro and following expansion in vivo in a modified model of GVHD. Immunoprecipitation of proteins from day 7 allogeneic T cells, using an antibody specific to phosphorylated AMPK targets, recovered lower levels of multiple glycolysis-related proteins including the glycolytic enzymes aldolase, enolase, pyruvate kinase M (PKM), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Functionally, murine T cells lacking AMPK exhibited impaired aldolase activity following anti-CD3/CD28 stimulation and a decrease in GAPDH activity on day 7 post-transplant. Importantly, these changes in glycolysis correlated with an impaired ability of AMPK KO T cells to produce significant amounts of interferon gamma (IFNγ) upon antigenic re-stimulation. Together these data highlight a significant role for AMPK in controlling oxidative and glycolytic metabolism in both murine and human T cells during GVHD and endorse further study of AMPK inhibition as a potential target for future clinical therapies.KEY POINTS: AMPK plays a key role in driving both and oxidative and glycolytic metabolism in T cells during graft-versus-host disease (GVHD)Absence of AMPK simultaneously impairs both glycolytic enzyme activity, most notably by aldolase, and interferon gamma (IFNγ) production.

DOI: https://doi.org/10.1101/2023.06.12.544686
Nat Commun. 2023 07 03. 14(1): 3902

Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages.

Marko Groeger, Koji Matsuo, Emad Heidary Arash, Ashley Pereira, Dounia Le Guillou, Cindy Pino, Kayque A Telles-Silva, Jacquelyn J Maher, Edward C Hsiao, Holger Willenbring.

Hepatic insulin resistance is recognized as a driver of type 2 diabetes and fatty liver disease but specific therapies are lacking. Here we explore the potential of human induced pluripotent stem cells (iPSCs) for modeling hepatic insulin resistance in vitro, with a focus on resolving the controversy about the impact of inflammation in the absence of steatosis. For this, we establish the complex insulin signaling cascade and the multiple inter-dependent functions constituting hepatic glucose metabolism in iPSC-derived hepatocytes (iPSC-Heps). Co-culture of these insulin-sensitive iPSC-Heps with isogenic iPSC-derived pro-inflammatory macrophages induces glucose output by preventing insulin from inhibiting gluconeogenesis and glycogenolysis and activating glycolysis. Screening identifies TNFα and IL1β as the mediators of insulin resistance in iPSC-Heps. Neutralizing these cytokines together restores insulin sensitivity in iPSC-Heps more effectively than individual inhibition, reflecting specific effects on insulin signaling and glucose metabolism mediated by NF-κB or JNK. These results show that inflammation is sufficient to induce hepatic insulin resistance and establish a human iPSC-based in vitro model to mechanistically dissect and therapeutically target this metabolic disease driver.

DOI: https://doi.org/10.1038/s41467-023-39311-w
Commun Biol. 2023 Jul 07. 6(1): 696

Elevated glutamate impedes anti-HIV-1 CD8 + T cell responses in HIV-1-infected individuals on antiretroviral therapy.

You-Yuan Wang, Cheng Zhen, Wei Hu, Hui-Huang Huang, Yan-Jun Li, Ming-Ju Zhou, Jing Li, Yu-Long Fu, Peng Zhang, Xiao-Yu Li, Tao Yang, Jin-Wen Song, Xing Fan, Jun Zou, Si-Run Meng, Ya-Qin Qin, Yan-Mei Jiao, Ruonan Xu, Ji-Yuan Zhang, Chun-Bao Zhou, Jin-Hong Yuan, Lei Huang, Ming Shi, Liang Cheng, Fu-Sheng Wang, Chao Zhang.

CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.

DOI: https://doi.org/10.1038/s42003-023-04975-z
Int J Med Microbiol. 2023 Jun 28. pii: S1438-4221(23)00013-9. [Epub ahead of print]313(4): 151585

Innate activation of human neutrophils and neutrophil-like cells by the pro-inflammatory bacterial metabolite ADP-heptose and Helicobacter pylori.

Larissa Faass, Martina Hauke, Saskia C Stein, Christine Josenhans.

  Lipopolysaccharide inner core heptose metabolites, including ADP-heptose, play a substantial role in the activation of cell-autonomous innate immune responses in eukaryotic cells, via the ALPK1-TIFA signaling pathway, as demonstrated for various pathogenic bacteria. The important role of LPS heptose metabolites during Helicobacter pylori infection of the human gastric niche has been demonstrated for gastric epithelial cells and macrophages, while the role of heptose metabolites on human neutrophils has not been investigated. In this study, we aimed to gain a better understanding of the activation potential of bacterial heptose metabolites for human neutrophil cells. To do so, we used pure ADP-heptose and, as a bacterial model, H. pylori, which can transport heptose metabolites into the human host cell via the Cag Type 4 Secretion System (CagT4SS). Main questions were how bacterial heptose metabolites impact on the pro-inflammatory activation, alone and in the bacterial context, and how they influence maturation of human neutrophils. Results of the present study demonstrated that neutrophils respond with high sensitivity to pure heptose metabolites, and that global regulation networks and neutrophil maturation are influenced by heptose exposure. Furthermore, activation of human neutrophils by live H. pylori is strongly impacted by the presence of LPS heptose metabolites and the functionality of its CagT4SS. Similar activities were determined in cell culture neutrophils of different maturation states and in human primary neutrophils. In conclusion, we demonstrated that specific heptose metabolites or bacteria producing heptoses exhibit a strong activity on cell-autonomous innate responses of human neutrophils.

Keywords:  Bacterial heptose metabolites; Chronic infection; Helicobacter pylori; Inflammation; Innate immune activation; Neutrophils

DOI:  https://doi.org/10.1016/j.ijmm.2023.151585
Sci Immunol. 2023 Jul 14. 8(85): eabq3015

The interplay between the DNA damage response and ectonucleotidases modulates tumor response to therapy.

John Stagg, Encouse Golden, Erik Wennerberg, Sandra Demaria.

The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.

DOI: https://doi.org/10.1126/sciimmunol.abq3015
bioRxiv. 2023 Jun 02. pii: 2023.06.02.543298. [Epub ahead of print]

Deep Phenotyping of the Lipidomic Response in COVID and non-COVID Sepsis.

Hu Meng, Arjun Sengupta, Emanuela Ricciotti, Antonijo Mrčela, Divij Mathew, Liudmila L Mazaleuskaya, Soumita Ghosh, Thomas G Brooks, Alexandra P Turner, Alessa Soares Schanoski, Nicholas F Lahens, Ai Wen Tan, Ashley Woolfork, Greg Grant, Katalin Susztak, Andrew G Letizia, Stuart C Sealfon, E John Wherry, Krzysztof Laudanski, Aalim M Weljie, Nuala B Meyer, Garret A FitzGerald.

Lipids may influence cellular penetrance by pathogens and the immune response that they evoke. Here we find a broad based lipidomic storm driven predominantly by secretory (s) phospholipase A 2 (sPLA 2 ) dependent eicosanoid production occurs in patients with sepsis of viral and bacterial origin and relates to disease severity in COVID-19. Elevations in the cyclooxygenase (COX) products of arachidonic acid (AA), PGD 2 and PGI 2 , and the AA lipoxygenase (LOX) product, 12-HETE, and a reduction in the high abundance lipids, ChoE 18:3, LPC-O-16:0 and PC-O-30:0 exhibit relative specificity for COVID-19 amongst such patients, correlate with the inflammatory response and link to disease severity. Linoleic acid (LA) binds directly to SARS-CoV-2 and both LA and its di-HOME products reflect disease severity in COVID-19. AA and LA metabolites and LPC-O-16:0 linked variably to the immune response. These studies yield prognostic biomarkers and therapeutic targets for patients with sepsis, including COVID-19. An interactive purpose built interactive network analysis tool was developed, allowing the community to interrogate connections across these multiomic data and generate novel hypotheses.

DOI: https://doi.org/10.1101/2023.06.02.543298
Commun Chem. 2023 Jul 03. 6(1): 138

Biosynthetic flexibility of Pseudomonas aeruginosa leads to hydroxylated 2-alkylquinolones with proinflammatory host response.

Viktoriia Savchenko, Dávid Szamosvári, Yifan Bao, Marc Pignitter, Thomas Böttcher.

The human pathogen Pseudomonas aeruginosa produces various 4(1H)-quinolones with diverse functions. Among these, 2-nonyl-4(1H)-quinolone (NQ) and its N-oxide (NQNO) belong to the main metabolites. Their biosynthesis involves substrates from the fatty acid metabolism and we hypothesized that oxidized fatty acids could be responsible for a so far undetected class of metabolites. We developed a divergent synthesis strategy for 2'-hydroxy (2'-OH) and 2'-oxo- substituted quinolones and N-oxides and demonstrated for the first time that 2'-OH-NQ and 2'-OH-NQNO but not the corresponding 2'-oxo compounds are naturally produced by PAO1 and PA14 strains of P. aeruginosa. The main metabolite 2'-OH-NQ is produced even in concentrations comparable to NQ. Exogenous availability of β-hydroxydecanoic acid can further increase the production of 2'-OH-NQ. In contrast to NQ, 2'-OH-NQ potently induced the cytokine IL-8 in a human cell line at 100 nм, suggesting a potential role in host immune modulation.

DOI: https://doi.org/10.1038/s42004-023-00937-y
Crit Care. 2023 07 05. 27(1): 263

A targeted metabolomics approach for sepsis-induced ARDS and its subphenotypes.

Youjin Chang, Hyun Ju Yoo, Su Jung Kim, Kwangha Lee, Chae-Man Lim, Sang-Bum Hong, Younsuck Koh, Jin Won Huh.

  BACKGROUND: Acute respiratory distress syndrome (ARDS) is etiologically and clinically a heterogeneous disease. Its diagnostic characteristics and subtype classification, and the application of these features to treatment, have been of considerable interest. Metabolomics is becoming important for identifying ARDS biology and distinguishing its subtypes. This study aimed to identify metabolites that could distinguish sepsis-induced ARDS patients from non-ARDS controls, using a targeted metabolomics approach, and to identify whether sepsis-induced direct and sepsis-induced indirect ARDS are metabolically distinct groups, and if so, confirm their metabolites and associated pathways.METHODS: This study retrospectively analyzed 54 samples of ARDS patients from a sepsis registry that was prospectively collected from March 2011 to February 2018, along with 30 non-ARDS controls. The cohort was divided into direct and indirect ARDS. Metabolite concentrations of five analyte classes (energy metabolism, free fatty acids, amino acids, phospholipids, sphingolipids) were measured using liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry by targeted metabolomics.
RESULTS: In total, 186 metabolites were detected. Among them, 102 metabolites could differentiate sepsis-induced ARDS patients from the non-ARDS controls, while 14 metabolites could discriminate sepsis-induced ARDS subphenotypes. Using partial least-squares discriminant analysis, we showed that sepsis-induced ARDS patients were metabolically distinct from the non-ARDS controls. The main distinguishing metabolites were lysophosphatidylethanolamine (lysoPE) plasmalogen, PE plasmalogens, and phosphatidylcholines (PCs). Sepsis-induced direct and indirect ARDS were also metabolically distinct subgroups, with differences in lysoPCs. Glycerophospholipid and sphingolipid metabolism were the most significant metabolic pathways involved in sepsis-induced ARDS biology and in sepsis-induced direct/indirect ARDS, respectively.
CONCLUSION: Our study demonstrated a marked difference in metabolic patterns between sepsis-induced ARDS patients and non-ARDS controls, and between sepsis-induced direct and indirect ARDS subpheonotypes. The identified metabolites and pathways can provide clues relevant to the diagnosis and treatment of individuals with ARDS.

Keywords:  Adult; Biomarkers; Metabolomics; Pathways; Respiratory distress syndrome; Sepsis

DOI:  https://doi.org/10.1186/s13054-023-04552-0