bims-imicid 2023-07-30 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒07‒30
33 papers selected by
Dylan Ryan
University of Cambridge

Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α.
A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.
The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis.
Succinate signaling attenuates high-fat diet-induced metabolic disturbance and intestinal barrier dysfunction.
Purinergic receptor P2Y12 boosts autoimmune hepatitis through hexokinase 2-dependent glycolysis in T cells.
Myeloid-derived suppressor cells impair CD4+ T cell responses during chronic Staphylococcus aureus infection via lactate metabolism.
Single-cell transcriptomic landscape of immunometabolism reveals intervention candidates of ascorbate and aldarate metabolism, fatty-acid degradation and PUFA metabolism of T-cell subsets in healthy controls, psoriasis and psoriatic arthritis.
Macrophage Xanthine Oxidoreductase Links LPS Induced Lung Inflammatory Injury to NLRP3 Inflammasome Expression and Mitochondrial Respiration.
Immunometabolic control by Klebsiella pneumoniae.
Metabolism, metabolites, and macrophages in cancer.
ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis.
M2 Polarization and Inhibition of Host Cell Glycolysis Contributes Intracellular Survival of Salmonella Strains in Chicken Macrophage HD-11 Cells.
Therapeutically targeting essential metabolites to improve immunometabolism manipulation after liver transplantation for hepatocellular carcinoma.
The vitamin B5/coenzyme A axis: A target for immunomodulation?
The kynurenine pathway of tryptophan metabolism: a neglected therapeutic target of COVID-19 pathophysiology and immunotherapy.
Inflammatory and glycolytic programs underpin a primed blood neutrophil state in patients with pneumonia.
Metabolite-sensing GPCRs controlling interactions between adipose tissue and inflammation.
Interleukin-17 as a key player in neuroimmunometabolism.
Isotope tracing reveals bacterial catabolism of host-derived glutathione during Helicobacter pylori infection.
GDF15 ameliorates liver fibrosis by metabolic reprogramming of macrophages to acquire anti-inflammatory properties.
Mitochondria-related genes and metabolic profiles of innate and adaptive immune cells in primary Sjögren's syndrome.
Myeloid-specific ablation of Basp1 ameliorates diet-induced NASH in mice by attenuating pro-inflammatory signaling.
MTHFD2 Ablation in T Cells Protects against Heart Transplant Rejection by Perturbing IRF4/PD-1 Pathway through the Metabolic-epigenetic Nexus.
Effects of dietary rumen-protected choline supplementation to periparturient dairy cattle on inflammation, metabolism, and performance during an intramammary lipopolysaccharide challenge.
The Virulence Factor Macrophage Infectivity Potentiator (Mip) Influences Branched-Chain Amino Acid Metabolism and Pathogenicity of Legionella pneumophila.
Itaconate inhibits CD103+ TRM cells and alleviates hepatobiliary injury in mouse models of primary sclerosing cholangitis.
Implication of metabolism in the polarization of tumor-associated-macrophages: the mass spectrometry-based point of view.
IL4I1-catalyzed tryptophan metabolites mediate the anti-inflammatory function of cytokine-primed human muscle stem cells.
Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes.
Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation.
Metabolic reprogramming and altered cell envelope characteristics in a pentose phosphate pathway mutant increases MRSA resistance to β-lactam antibiotics.
The hepatic GABAergic system promotes liver macrophage M2 polarization and mediates HBV replication in mice.
Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.

Cell Metab. 2023 Jul 21. pii: S1550-4131(23)00251-6. [Epub ahead of print]

Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α.

Lijian Wu, Yiteng Jin, Xi Zhao, Kaiyang Tang, Yaoning Zhao, Linjie Tong, Xuerong Yu, Ke Xiong, Ce Luo, Jiajun Zhu, Fubing Wang, Zexian Zeng, Deng Pan.

  Metabolic reprogramming toward glycolysis is a hallmark of cancer malignancy. The molecular mechanisms by which the tumor glycolysis pathway promotes immune evasion remain to be elucidated. Here, by performing genome-wide CRISPR screens in murine tumor cells co-cultured with cytotoxic T cells (CTLs), we identified that deficiency of two important glycolysis enzymes, Glut1 (glucose transporter 1) and Gpi1 (glucose-6-phosphate isomerase 1), resulted in enhanced killing of tumor cells by CTLs. Mechanistically, Glut1 inactivation causes metabolic rewiring toward oxidative phosphorylation, which generates an excessive amount of reactive oxygen species (ROS). Accumulated ROS potentiate tumor cell death mediated by tumor necrosis factor alpha (TNF-α) in a caspase-8- and Fadd-dependent manner. Genetic and pharmacological inactivation of Glut1 sensitizes tumors to anti-tumor immunity and synergizes with anti-PD-1 therapy through the TNF-α pathway. The mechanistic interplay between tumor-intrinsic glycolysis and TNF-α-induced killing provides new therapeutic strategies to enhance anti-tumor immunity.

Keywords:  T cell-mediated killing; TNF-α; glycolysis; immune evasion

DOI:  https://doi.org/10.1016/j.cmet.2023.07.001
bioRxiv. 2023 Jul 07. pii: 2023.07.06.547932. [Epub ahead of print]

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.

Lynn Bonetti, Veronika Horkova, Joseph Longworth, Luana Guerra, Henry Kurniawan, Davide G Franchina, Leticia Soriano-Baguet, Melanie Grusdat, Sabine Spath, Eric Koncina, Anouk Ewen, Carole Binsfeld, Charlène Verschueren, Jean-Jacques Gérardy, Takumi Kobayashi, Catherine Dostert, Sophie Farinelle, Janika Härm, Ying Chen, Isaac S Harris, Philipp A Lang, Vasilis Vasiliou, Ari Waisman, Elisabeth Letellier, Burkhard Becher, Michel Mittelbronn, Dirk Brenner.

Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although Gclc ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with C. rodentium increases ROS, inhibits mitochondrial gene expression and mitochondrial function in Gclc-deficient Th17 cells. These mitochondrial deficits affect the PI3K/AKT/mTOR pathway, leading to reduced phosphorylation of the translation repressor 4E-BP1. As a consequence, the initiation of translation is restricted, resulting in decreased protein synthesis of IL-22. Loss of IL-22 results in poor bacterial clearance, enhanced intestinal damage, and high mortality. ROS-scavenging, reconstitution of IL-22 expression or IL-22 supplementation in vivo prevent the appearance of these pathologies. Our results demonstrate the existence of a previously unappreciated role for Th17 cell-intrinsic GSH coupling to promote mitochondrial function, IL-22 translation and signaling. These data reveal an axis that is essential for maintaining the integrity of the intestinal barrier and protecting it from damage caused by gastrointestinal infection.

DOI: https://doi.org/10.1101/2023.07.06.547932
Cell Metab. 2023 Jul 20. pii: S1550-4131(23)00250-4. [Epub ahead of print]

The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis.

Liraz Shmuel-Galia, Fiachra Humphries, Tim Vierbuchen, Zhaozhao Jiang, Nolan Santos, John Johnson, Boris Shklyar, Leonel Joannas, Nicholas Mustone, Shany Sherman, Doyle Ward, JeanMarie Houghton, Christina E Baer, Aisling O'Hara, Jorge Henao-Mejia, Kasper Hoebe, Katherine A Fitzgerald.

  This study reveals a previously uncharacterized mechanism to restrict intestinal inflammation via a regulatory RNA transcribed from a noncoding genomic locus. We identified a novel transcript of the lncRNA HOXA11os specifically expressed in the distal colon that is reduced to undetectable levels in colitis. HOXA11os is localized to mitochondria under basal conditions and interacts with a core subunit of complex 1 of the electron transport chain (ETC) to maintain its activity. Deficiency of HOXA11os in colonic myeloid cells results in complex I deficiency, dysfunctional oxidative phosphorylation (OXPHOS), and the production of mitochondrial reactive oxygen species (mtROS). As a result, HOXA11os-deficient mice develop spontaneous intestinal inflammation and are hypersusceptible to colitis. Collectively, these studies identify a new regulatory axis whereby a lncRNA maintains intestinal homeostasis and restricts inflammation in the colon through the regulation of complex I activity.

Keywords:  IBD; Krebs cycle; OXPHOS; colitis; complex I; intestinal inflammation; lncRNA; mitochondria; mtROS; mucosal inflammation; ncRNA

DOI:  https://doi.org/10.1016/j.cmet.2023.06.019
Pharmacol Res. 2023 Jul 22. pii: S1043-6618(23)00221-9. [Epub ahead of print]194 106865

Succinate signaling attenuates high-fat diet-induced metabolic disturbance and intestinal barrier dysfunction.

Xuan Li, Guowen Huang, Yanan Zhang, Yuting Ren, Ruofan Zhang, Weiyun Zhu, Kaifan Yu.

  Succinate is a vital signaling metabolite produced by the host and gut microbiota. Succinate has been shown to regulate host metabolic homeostasis and inhibit obesity-associated inflammation in macrophages by engaging its cognate receptor, SUCNR1. However, the contribution of the succinate-SUCNR1 axis to intestinal barrier dysfunction in obesity remains unclear. In the present study, we explored the effects of succinate-SUCNR1 signaling on high-fat diet (HFD)-induced intestinal barrier dysfunction. Using a SUCNR1-deficient mouse model under HFD feeding conditions, we identified the effects of succinate-SUCNR1 axis on obesity-associated intestinal barrier impairment. Our results showed that HFD administration decreased goblet cell numbers and mucus production, promoted intestinal pro-inflammatory responses, induced gut microbiota composition imbalance, increased intestinal permeability, and caused mucosal barrier dysfunction. Dietary succinate supplementation was sufficient to activate a type 2 immune response, trigger the differentiation of barrier-promoting goblet cells, suppress intestinal inflammation, restore HFD-induced mucosal barrier impairment and intestinal dysbiosis, and eventually exert anti-obesity effects. However, SUNNR1-deficient mice failed to improve the intestinal barrier function and metabolic phenotype in HFD mice. Our data indicate the protective role of the succinate-SUCNR1 axis in HFD-induced intestinal barrier dysfunction.

Keywords:  Inflammation; Intestinal barrier; Microbiota; Obesity; SUCNR1; Succinate

DOI:  https://doi.org/10.1016/j.phrs.2023.106865
Int J Biol Sci. 2023 ;19(11): 3576-3594

Purinergic receptor P2Y12 boosts autoimmune hepatitis through hexokinase 2-dependent glycolysis in T cells.

Wei Zhuang, Xiucheng Liu, Guangyu Liu, Jie Lv, Hao Qin, Chun Wang, Ling Xie, Kaidireya Saimaier, Sanxing Han, Changjie Shi, Qiuhong Hua, Ru Zhang, Changsheng Du.

  Increasing evidence suggests that immunometabolism has started to unveil the role of metabolism in shaping immune function and autoimmune diseases. In this study, our data show that purinergic receptor P2Y12 (P2RY12) is highly expressed in concanavalin A (ConA)-induced immune hepatitis mouse model and serves as a potential metabolic regulator in promoting metabolic reprogramming from oxidative phosphorylation to glycolysis in T cells. P2RY12 deficiency or inhibition of P2RY12 with P2RY12 inhibitors (clopidogrel and ticagrelor) are proved to reduce the expression of inflammatory mediators, cause CD4+ and CD8+ effector T cells hypofunction and protect the ConA-induced immune hepatitis. A combined proteomics and metabolomics analysis revealed that P2RY12 deficiency causes redox imbalance and leads to reduced aerobic glycolysis by downregulating the expression of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway, indicating that HK2 might be a promising candidate for the treatment of diseases associated with T cell activation. Further analysis showed that P2RY12 prevents HK2 degradation by activating the PI3K/Akt pathway and inhibiting lysosomal degradation. Our findings highlight the importance of the function of P2RY12 for HK2 stability and metabolism in the regulation of T cell activation and suggest that P2RY12 might be a pivotal regulator of T cell metabolism in ConA-induced immune hepatitis.

Keywords:  HK2; P2RY12; T cell metabolism; autoimmune hepatitis; glycolysis

DOI:  https://doi.org/10.7150/ijbs.85133
Cell Mol Life Sci. 2023 Jul 22. 80(8): 221

Myeloid-derived suppressor cells impair CD4+ T cell responses during chronic Staphylococcus aureus infection via lactate metabolism.

Oliver Goldmann, Eva Medina.

  Staphylococcus aureus is an important cause of chronic infections resulting from the failure of the host to eliminate the pathogen. Effective S. aureus clearance requires CD4+ T cell-mediated immunity. We previously showed that myeloid-derived suppressor cells (MDSC) expand during staphylococcal infections and support infection chronicity by inhibiting CD4+ T cell responses. The aim of this study was to elucidate the mechanisms underlying the suppressive effect exerted by MDSC on CD4+ T cells during chronic S. aureus infection. It is well known that activated CD4+ T cells undergo metabolic reprogramming from oxidative metabolism to aerobic glycolysis to meet their increased bioenergetic requirements. In this process, pyruvate is largely transformed into lactate by lactate dehydrogenase with the concomitant regeneration of NAD+, which is necessary for continued glycolysis. The by-product lactate needs to be excreted to maintain the glycolytic flux. Using SCENITH (single-cell energetic metabolism by profiling translation inhibition), we demonstrated here that MDSC inhibit CD4+ T cell responses by interfering with their metabolic activity. MDSC are highly glycolytic and excrete large amount of lactate in the local environment that alters the transmembrane concentration gradient and prevent removal of lactate by activated CD4+ T. Accumulation of endogenous lactate impedes the regeneration of NAD+, inhibit NAD-dependent glycolytic enzymes and stop glycolysis. Together, the results of this study have uncovered a role for metabolism on MDSC suppression of CD4+ T cell responses. Thus, reestablishment of their metabolic activity may represent a mean to improve the functionality of CD4+ T cells during chronic S. aureus infection.

Keywords:  CD4+ T cells; Lactate; Myeloid-derived suppressor cells (MDSC); NAD+/NADH redox; SCENITH; Staphylococcus aureus

DOI:  https://doi.org/10.1007/s00018-023-04875-9
Front Immunol. 2023 ;14 1179877

Single-cell transcriptomic landscape of immunometabolism reveals intervention candidates of ascorbate and aldarate metabolism, fatty-acid degradation and PUFA metabolism of T-cell subsets in healthy controls, psoriasis and psoriatic arthritis.

Lu Peng, Ling Chen, Jianji Wan, Wenqi Liu, Shuang Lou, Zhu Shen.

  Introduction: The modulation of immunometabolic pathways is emerging as a promising therapeutic target for immune-mediated diseases. However, the immunometabolic features of psoriatic disease and the potential targets for immunometabolic intervention in the different T-cell subsets involved in its pathogenesis remain unclear.Methods: In this study, we analyzed circulating blood single-cell data from healthy controls (HC), psoriasis (PSO), and psoriatic arthritis (PSA) patients, and revealed their metabolic features of T-cell subsets: CD4+ central memory T cells (TCMs), CD8+ effective memory T cells (TEMs), regulatory T cells (Tregs), mucosal-associated invariant T cells (MAITs ), and γδ T cells. Pearson test was performed to determine the linkages between differential metabolic and inflammatory pathways. Based on these results, we also analyzed the potential impacts of biological antibodies on differential metabolic pathways by comparing the immunometabolism differences between PSA patients without and with biological treatment.
Results: Our results suggest that upregulation of ascorbate and aldarate metabolism, as well as fatty acid degradation, may enhance the immune suppression of Tregs. Enhanced metabolism of alpha-linolenic acid, linoleic acid, and arachidonic acid may inhibit the pro-inflammatory functions of CD4+ TCMs and CD8+ TEMs in PSO and PSA, and protect the immune suppression of Tregs in PSA. We propose that supporting ascorbic acid and fatty acid metabolic pathways may be an adjunctive reprogramming strategy with adalimumab and etanercept therapy.
Discussion: These findings not only provide insights into immunometabolism characteristics of psoriatic disease, but also offer preliminary options for the auxiliary treatment of psoriasis.

Keywords:  TCM; TEM; Treg; immunometabolism; psoriasis; psoriatic arthritis; single-cell transcriptomics

DOI:  https://doi.org/10.3389/fimmu.2023.1179877
bioRxiv. 2023 Jul 21. pii: 2023.07.21.550055. [Epub ahead of print]

Macrophage Xanthine Oxidoreductase Links LPS Induced Lung Inflammatory Injury to NLRP3 Inflammasome Expression and Mitochondrial Respiration.

Mehdi A Fini, Jenifer A Monks, Min Li, Evgenia Gerasimovskaya, Petr Paucek, Kepeng Wang, Maria G Frid, Steven C Pugliese, Donna Bratton, Yen-Rei Yu, David Irwin, Michael Karin, Richard M Wright, Kurt R Stenmark.

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) remain poorly treated inflammatory lung disorders. Both reactive oxygen species (ROS) and macrophages are involved in the pathogenesis of ALI/ARDS. Xanthine oxidoreductase (XOR) is an ROS generator that plays a central role in the inflammation that contributes to ALI. To elucidate the role of macrophage-specific XOR in endotoxin induced ALI, we developed a conditional myeloid specific XOR knockout in mice. Myeloid specific ablation of XOR in LPS insufflated mice markedly attenuated lung injury demonstrating the essential role of XOR in this response. Macrophages from myeloid specific XOR knockout exhibited loss of inflammatory activation and increased expression of anti-inflammatory genes/proteins. Transcriptional profiling of whole lung tissue of LPS insufflated XOR fl/fl//LysM-Cre mice demonstrated an important role for XOR in expression and activation of the NLRP3 inflammasome and acquisition of a glycolytic phenotype by inflammatory macrophages. These results identify XOR as an unexpected link between macrophage redox status, mitochondrial respiration and inflammatory activation.

DOI: https://doi.org/10.1101/2023.07.21.550055
Immunometabolism (Cobham). 2023 Jul;5(3): e00028

Immunometabolic control by Klebsiella pneumoniae.

Alice Prince, Tania Wong Fok Lung.

  Klebsiella pneumoniae is a common Gram-negative pathogen associated with community-acquired and healthcare-associated infections. Its ability to acquire genetic elements resulted in its rapid development of resistance to virtually all antimicrobial agents. Once infection is established, K. pneumoniae is able to evade the host immune response and perhaps more importantly, undergo metabolic rewiring to optimize its ability to maintain infection. K. pneumoniae lipopolysaccharide and capsular polysaccharide are central factors in the induction and evasion of immune clearance. Less well understood is the importance of immunometabolism, the intersection between cellular metabolism and immune function, in the host response to K. pneumoniae infection. Bacterial metabolism itself is perceived as a metabolic stress to the host, altering the microenvironment at the site of infection. In this review, we will discuss the metabolic responses induced by K. pneumoniae, particularly in response to stimulation with the metabolically active bacteria versus pathogen-associated molecular patterns alone, and their implications in shaping the nature of the immune response and the infection outcome. A better understanding of the immunometabolic response to K. pneumoniae may help identify new targets for therapeutic intervention in the treatment of multidrug-resistant bacterial infections.

Keywords:  Klebsiella pneumoniae; antimicrobial resistance; immunometabolism; metabolic reprogramming; pulmonary infection; resistance; tolerance

DOI:  https://doi.org/10.1097/IN9.0000000000000028
J Hematol Oncol. 2023 07 25. 16(1): 80

Metabolism, metabolites, and macrophages in cancer.

Mengyuan Li, Yuhan Yang, Liting Xiong, Ping Jiang, Junjie Wang, Chunxiao Li.

  Tumour-associated macrophages (TAMs) are crucial components of the tumour microenvironment and play a significant role in tumour development and drug resistance by creating an immunosuppressive microenvironment. Macrophages are essential components of both the innate and adaptive immune systems and contribute to pathogen resistance and the regulation of organism homeostasis. Macrophage function and polarization are closely linked to altered metabolism. Generally, M1 macrophages rely primarily on aerobic glycolysis, whereas M2 macrophages depend on oxidative metabolism. Metabolic studies have revealed that the metabolic signature of TAMs and metabolites in the tumour microenvironment regulate the function and polarization of TAMs. However, the precise effects of metabolic reprogramming on tumours and TAMs remain incompletely understood. In this review, we discuss the impact of metabolic pathways on macrophage function and polarization as well as potential strategies for reprogramming macrophage metabolism in cancer treatment.

Keywords:  Cancer; Metabolism; Metabolism reprogramming; Tumour microenvironment; Tumour-associated macrophages

DOI:  https://doi.org/10.1186/s13045-023-01478-6
Clin Immunol. 2023 Jul 20. pii: S1521-6616(23)00461-8. [Epub ahead of print]254 109698

ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis.

Tiantian Liu, Zhenliang Wen, Lujing Shao, Yun Cui, Xiaomeng Tang, Huijie Miao, Jingyi Shi, Linlin Jiang, Shuyun Feng, Yilin Zhao, Hong Zhang, Qiming Liang, Dechang Chen, Yucai Zhang, Chunxia Wang.

  Strengthened glycolysis is crucial for the macrophage pro-inflammatory response during sepsis. Activating transcription factor 4 (ATF4) plays an important role in regulating glucose and lipid metabolic homeostasis in hepatocytes and adipocytes. However, its immunometabolic role in macrophage during sepsis remains largely unknown. In the present study, we found that the expression of ATF4 in peripheral blood mononuclear cells (PBMCs) was increased and associated with glucose metabolism in septic patients. Atf4 knockdown specifically decreased LPS-induced spleen macrophages and serum pro-inflammatory cytokines levels in mice. Moreover, Atf4 knockdown partially blocked LPS-induced pro-inflammatory cytokines, lactate accumulation and glycolytic capacity in RAW264.7. Mechanically, ATF4 binds to the promoter region of hexokinase II (HK2), and interacts with hypoxia inducible factor-1α (HIF-1α) and stabilizes HIF-1α through ubiquitination modification in response to LPS. Furthermore, ATF4-HIF-1α-HK2-glycolysis axis launches pro-inflammatory response in macrophage depending on the activation of mammalian target of rapamycin (mTOR). Importantly, Atf4 overexpression improves the decreased level of pro-inflammatory cytokines and lactate secretion and HK2 expression in LPS-induced tolerant macrophages. In conclusion, we propose a novel function of ATF4 as a crucial glycolytic activator contributing to pro-inflammatory response and improving immune tolerant in macrophage involved in sepsis. So, ATF4 could be a potential new target for immunotherapy of sepsis.

Keywords:  Activating transcription factor 4; Glycolysis; Hexokinase II; Hypoxia inducible factor-1α; Pro-inflammatory response; sepsis

DOI:  https://doi.org/10.1016/j.clim.2023.109698
Microorganisms. 2023 Jul 19. pii: 1838. [Epub ahead of print]11(7):

M2 Polarization and Inhibition of Host Cell Glycolysis Contributes Intracellular Survival of Salmonella Strains in Chicken Macrophage HD-11 Cells.

Haiqi He, Kenneth J Genovese, Ryan J Arsenault, Christina L Swaggerty, Casey N Johnson, J Allen Byrd, Michael H Kogut.

  Salmonella enterica is a group of facultative, gram-negative bacteria. Recently, new evidence indicated that Salmonella could reprogram the host metabolism to increase energy or metabolites available for intracellular replication. In this study, using a chicken-specific kinomic immunometabolism peptide array analysis, we found that infection by S. Enteritidis induced significant phosphorylation changes in many key proteins of the glycolytic pathway in chicken macrophage HD-11 cells, indicating a shift in glycolysis caused by Salmonella infection. Nitric oxide production and changes of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) represented by extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), respectively, were measured in chicken macrophages infected with three Salmonella strains (S. Enteritidis, S. Heidelberg, and S. Senftenberg). The infection reduced glycolysis and enhanced OXPHOS in chicken macrophages as indicated by changes of ECAR and OCR. Salmonella strains differentially affected macrophage polarization and glycolysis. Among three strains tested, S. Enteritidis was most effective in downregulating glycolysis and promoting M2 polarization as measured by ECAR, ORC, and NO production; while S. Senftenberg did not alter glycolysis and may promote M1 polarization. Our results suggested that downregulation of host cell glycolysis and increase of M2 polarization of macrophages may contribute to increased intracellular survival of S. Enteritidis.

Keywords:  Salmonella; Salmonella intracellular survival; chicken macrophage cell; foodborne pathogens; glycolysis; macrophage polarization; nitric oxide

DOI:  https://doi.org/10.3390/microorganisms11071838
Front Immunol. 2023 ;14 1211126

Therapeutically targeting essential metabolites to improve immunometabolism manipulation after liver transplantation for hepatocellular carcinoma.

Wenhui Zhang, Yu Zhao, Qiang He, Ren Lang.

  Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy worldwide and is associated with a poor prognosis. Sophisticated molecular mechanisms and biological characteristics need to be explored to gain a better understanding of HCC. The role of metabolites in cancer immunometabolism has been widely recognized as a hallmark of cancer in the tumor microenvironment (TME). Recent studies have focused on metabolites that are derived from carbohydrate, lipid, and protein metabolism, because alterations in these may contribute to HCC progression, ischemia-reperfusion (IR) injury during liver transplantation (LT), and post-LT rejection. Immune cells play a central role in the HCC microenvironment and the duration of IR or rejection. They shape immune responses through metabolite modifications and by engaging in complex crosstalk with tumor cells. A growing number of publications suggest that immune cell functions in the TME are closely linked to metabolic changes. In this review, we summarize recent findings on the primary metabolites in the TME and post-LT metabolism and relate these studies to HCC development, IR injury, and post-LT rejection. Our understanding of aberrant metabolism and metabolite targeting based on regulatory metabolic pathways may provide a novel strategy to enhance immunometabolism manipulation by reprogramming cell metabolism.

Keywords:  hepatocellular carcinoma (HCC); immunometabolism; ischemia-reperfusion (IR) injury; lipid metabolism; liver transplantation (LT); succinate

DOI:  https://doi.org/10.3389/fimmu.2023.1211126
Eur J Immunol. 2023 Jul 22. e2350435

The vitamin B5/coenzyme A axis: A target for immunomodulation?

Miallot Richard, Millet Virginie, Galland Franck, Naquet Philippe.

  Coenzyme A (CoA) serves as a vital cofactor in numerous enzymatic reactions involved in energy production, lipid metabolism, and synthesis of essential molecules. Dysregulation of CoA-dependent metabolic pathways can contribute to chronic diseases, such as inflammatory diseases, obesity, diabetes, cancer, and cardiovascular disorders. Additionally, CoA influences immune cell activation by modulating the metabolism of these cells, thereby affecting their proliferation, differentiation, and effector functions. Targeting CoA metabolism presents a promising avenue for therapeutic intervention, as it can potentially restore metabolic balance, mitigate chronic inflammation, and enhance immune cell function. This might ultimately improve the management and outcomes for these diseases. This review will more specifically focus on the contribution of pathways regulating the availability of the CoA precursor Vitamin B5/pantothenate in vivo and modulating the development of Th17-mediated inflammation, CD8-dependent anti-tumor immunity but also tissue repair processes in chronic inflammatory or degenerative diseases.

Keywords:  Coenzyme A; Inflammation; Tissue repair; Tumor immunity; Vitamin B5

DOI:  https://doi.org/10.1002/eji.202350435
Biosci Rep. 2023 Jul 24. pii: BSR20230595. [Epub ahead of print]

The kynurenine pathway of tryptophan metabolism: a neglected therapeutic target of COVID-19 pathophysiology and immunotherapy.

Abdulla Abu-Bakr Badawy.

  SARS-CoV-2 (COVID-19) exerts profound changes in the kynurenine (Kyn) pathway (KP) of tryptophan (Trp) metabolism that may underpin its pathophysiology. The KP is the main source of the vital cellular effector NAD+ and intermediate metabolites that modulate immune and neuronal functions. Trp metabolism is the top pathway influenced by COVID-19. Sixteen studies established virus-induced activation of the KP mediated mainly by induction of indoleamine 2,3-dioxygenase (IDO1) in most affected tissues and of IDO2 in lung by the increased release of proinflammatory cytokines, but could additionally involve increased flux of plasma free Trp and induction of Trp 2,3-dioxygenase (TDO) by cortisol. The major Kyn metabolite targeted by COVID-19 is kynurenic acid (KA), the Kyn metabolite with the greatest affinity for the aryl hydrocarbon receptor (AhR), which is also activated by COVID-19. AhR activation initiates two important series of events: a vicious circle involving IDO1 induction, KA accumulation and further AhR activation, and activation of poly (ADP-ribose) polymerase (PARP) leading to NAD+ depletion and cell death. The virus further deprives the host of NAD+ by inhibiting its main biosynthetic pathway from quinolinic acid, while simultaneously acquiring NAD+ by promoting its synthesis from nicotinamide in the salvage pathway. Additionally, the protective effects of sirtuin 1 are minimised by the PARP activation. KP dysfunction may also underpin the mood and neurological disorders acutely and during "long COVID". More studies of potential effects of vaccination therapy on the KP are required and exploration of therapeutic strategies involving modulation of the KP changes are proposed.

Keywords:  Aryl hydrocarbon receptor; Indoleamine 2,3-dioxygenase; Kynurenic acid; Poly (ADP-ribose) polymerase; Proinflammatory cytokines; Tryptophan 2,3-dioxygenase

DOI:  https://doi.org/10.1042/BSR20230595
iScience. 2023 Jul 21. 26(7): 107181

Inflammatory and glycolytic programs underpin a primed blood neutrophil state in patients with pneumonia.

Alex R Schuurman, Joe M Butler, Erik H A Michels, Natasja A Otto, Xanthe Brands, Bastiaan W Haak, Fabrice Uhel, Augustijn M Klarenbeek, Daniël R Faber, Bauke V Schomakers, Michel van Weeghel, Alex F de Vos, Brendon P Scicluna, Riekelt H Houtkooper, W Joost Wiersinga, Tom van der Poll.

  Neutrophils are potent immune cells with key antimicrobial functions. Previous in vitro work has shown that neutrophil effector functions are mainly fueled by intracellular glycolysis. Little is known about the state of neutrophils still in the circulation in patients during infection. Here, we combined flow cytometry, stimulation assays, transcriptomics, and metabolomics to investigate the link between inflammatory and metabolic pathways in blood neutrophils of patients with community-acquired pneumonia. Patients' neutrophils, relative to neutrophils from age- and sex- matched controls, showed increased degranulation upon ex vivo stimulation, and portrayed distinct upregulation of inflammatory transcriptional programs. This neutrophil phenotype was accompanied by a high-energy state with increased intracellular ATP content, and transcriptomic and metabolic upregulation of glycolysis and glycogenolysis. One month after hospital admission, these metabolic and transcriptomic changes were largely normalized. These data elucidate the molecular programs that underpin a balanced, yet primed state of blood neutrophils during pneumonia.

Keywords:  Health sciences; Immunology; Medicine

DOI:  https://doi.org/10.1016/j.isci.2023.107181
Front Endocrinol (Lausanne). 2023 ;14 1197102

Metabolite-sensing GPCRs controlling interactions between adipose tissue and inflammation.

Elaine M Duncan, Luca Vita, Bethany Dibnah, Brian D Hudson.

  Metabolic disorders including obesity, diabetes and non-alcoholic steatohepatitis are a group of conditions characterised by chronic low-grade inflammation of metabolic tissues. There is now a growing appreciation that various metabolites released from adipose tissue serve as key signalling mediators, influencing this interaction with inflammation. G protein-coupled receptors (GPCRs) are the largest family of signal transduction proteins and most historically successful drug targets. The signalling pathways for several key adipose metabolites are mediated through GPCRs expressed both on the adipocytes themselves and on infiltrating macrophages. These include three main groups of GPCRs: the FFA4 receptor, which is activated by long chain free fatty acids; the HCA2 and HCA3 receptors, activated by hydroxy carboxylic acids; and the succinate receptor. Understanding the roles these metabolites and their receptors play in metabolic-immune interactions is critical to establishing how these GPCRs may be exploited for the treatment of metabolic disorders.

Keywords:  G protein-coupled receptor; adipose; free fatty acid; hydroxy carboxylic acids; inflammation; metabolite signalling; succinate

DOI:  https://doi.org/10.3389/fendo.2023.1197102
Nat Metab. 2023 Jul;5(7): 1088-1100

Interleukin-17 as a key player in neuroimmunometabolism.

Aaron Douglas, Brenneth Stevens, Lydia Lynch.

In mammals, interleukin (IL)-17 cytokines are produced by innate and adaptive lymphocytes. However, the IL-17 family has widespread expression throughout evolution, dating as far back as cnidaria, molluscs and worms, which predate lymphocytes. The evolutionary conservation of IL-17 suggests that it is involved in innate defence strategies, but also that this cytokine family has a fundamental role beyond typical host defence. Throughout evolution, IL-17 seems to have a major function in homeostatic maintenance at barrier sites. Most recently, a pivotal role has been identified for IL-17 in regulating cellular metabolism, neuroimmunology and tissue physiology, particularly in adipose tissue. Here we review the emerging role of IL-17 signalling in regulating metabolic processes, which may shine a light on the evolutionary role of IL-17 beyond typical immune responses. We propose that IL-17 helps to coordinate the cross-talk among the nervous, endocrine and immune systems for whole-body energy homeostasis as a key player in neuroimmunometabolism.

DOI: https://doi.org/10.1038/s42255-023-00846-3
PLoS Pathog. 2023 Jul 26. 19(7): e1011526

Isotope tracing reveals bacterial catabolism of host-derived glutathione during Helicobacter pylori infection.

Maia J Baskerville, Yekaterina Kovalyova, Raquel Mejías-Luque, Markus Gerhard, Stavroula K Hatzios.

Mammalian cells synthesize the antioxidant glutathione (GSH) to shield cellular biomolecules from oxidative damage. Certain bacteria, including the gastric pathogen Helicobacter pylori, can perturb host GSH homeostasis. H. pylori infection significantly decreases GSH levels in host tissues, which has been attributed to the accumulation of reactive oxygen species in infected cells. However, the precise mechanism of H. pylori-induced GSH depletion remains unknown, and tools for studying this process during infection are limited. We developed an isotope-tracing approach to quantitatively monitor host-derived GSH in H. pylori-infected cells by mass spectrometry. Using this method, we determined that H. pylori catabolizes reduced GSH from gastric cells using γ-glutamyl transpeptidase (gGT), an enzyme that hydrolyzes GSH to glutamate and cysteinylglycine (Cys-Gly). gGT is an established virulence factor with immunomodulatory properties that is required for H. pylori colonization in vivo. We found that H. pylori internalizes Cys-Gly in a gGT-dependent manner and that Cys-Gly production during H. pylori infection is coupled to the depletion of intracellular GSH from infected cells. Consistent with bacterial catabolism of host GSH, levels of oxidized GSH did not increase during H. pylori infection, and exogenous antioxidants were unable to restore the GSH content of infected cells. Altogether, our results indicate that H. pylori-induced GSH depletion proceeds via an oxidation-independent mechanism driven by the bacterial enzyme gGT, which fortifies bacterial acquisition of nutrients from the host. Additionally, our work establishes a method for tracking the metabolic fate of host-derived GSH during infection.

DOI: https://doi.org/10.1371/journal.ppat.1011526
Cell Mol Gastroenterol Hepatol. 2023 Jul 25. pii: S2352-345X(23)00139-X. [Epub ahead of print]

GDF15 ameliorates liver fibrosis by metabolic reprogramming of macrophages to acquire anti-inflammatory properties.

Xiaolei Li, Qian Huai, Cheng Zhu, Xu Zhang, Wentao Xu, Hanren Dai, Hua Wang.

  BACKGROUND&AIMS: Liver fibrosis/cirrhosis is significant health burden worldwide, resulting in liver failure or cancer and accounting for many deaths each year. The pathogenesis of liver fibrosis is very complex, which makes treatment challenging. GDF15, a cysteine knot protein belonging to the transforming growth factor-beta superfamily, has been shown to play a protective role after tissue injury and to promote a negative energy balance during obesity and diabetes. However, paucity of literature is available about GDF15 function in liver fibrosis. This study aimed to investigate the immunomodulatory role and therapeutic potential of GDF15 in progression of hepatic fibrosis.METHODS: GDF15 expression was studied in patients with fibrosis/cirrhosis and in 2 murine models of liver fibrosis, including mice treated with carbon tetrachloride (CCl4)- or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. GDF15 involvement in the pathogenesis of liver fibrosis was assessed in Gdf15 knockout mouse using both CCl4- and DDC diet experimental models. We used the CCl4- and/or DDC diet-induced liver fibrosis model to examine the antifibrotic and anti-inflammatory effects of AAV8-mediated GDF15 overexpression in hepatocytes or recombinant mouse GDF15.
RESULTS: GDF15 expression is decreased in the liver of animal models and patients with liver fibrosis/cirrhosis compared with those without liver disease. In vivo studies showed that GDF15 deficiency aggravated CCl4- and DDC diet-induced liver fibrosis, while GDF15 overexpression mediated by AAV8 or its recombinant protein alleviated CCl4- and/or DDC diet-induced liver fibrosis. In Gdf15 knockout mice, the intrahepatic microenvironment that developed during fibrosis showed relatively more inflammation, as demonstrated by enhanced infiltration of monocytes and neutrophils and increased expression of proinflammatory factors, which could be diminished by AAV8-mediated GDF15 overexpression in hepatocytes. Intriguingly, GDF15 exerts its effects by metabolic reprogramming macrophages to acquire oxidative phosphorylation (OXPHOS)-dependent anti-inflammatory functional fate. Furthermore, adoptive transfer of GDF15-preprogrammed macrophages to mouse models of liver fibrosis induced by CCl4 attenuated inflammation and alleviated the progression of liver fibrosis.
CONCLUSION: GDF15 ameliorates liver fibrosis via modulation of liver macrophages. Our data implicate the importance of the liver microenvironment in macrophage programming during liver fibrosis and suggest GDF15 that is a potentially attractive therapeutic target for the treatment of patients with liver fibrosis.

Keywords:  GDF15; immunometabolism; inflammation; liver fibrosis; macrophage; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.jcmgh.2023.07.009
Front Immunol. 2023 ;14 1156774

Mitochondria-related genes and metabolic profiles of innate and adaptive immune cells in primary Sjögren's syndrome.

Danyang Luo, Lei Li, Yicheng Wu, Yi Yang, Yulin Ye, Jiawei Hu, Yiming Gao, Naiyan Zeng, Xiaochun Fei, Ning Li, Liting Jiang.

  Background: Primary Sjogren's syndrome (pSS) is a prototypical systemic autoimmune disease characterised by lymphocyte infiltration and immune-complex deposition in multiple organs. The specific distribution of immune cell populations and their relationship with mitochondria remain unknown.Methods: Histological analysis was performed to assess the specific distribution of innate and adaptive immune cell populations in labial salivary gland (LSG) samples from 30 patients with pSS and 13 patients with non-pSS. The ultrastructural morphometric features of mitochondria within immune cells were observed under the transmission electron microscope (TEM). RNA sequencing was performed on LSG samples from 40 patients with pSS and 7 non-pSS patients. The Single-sample Gene Set Enrichment Analysis (ssGSEA), ESTIMATE, and CIBERSORT algorithms and Pearson correlation coefficients were used to examine the relationship between mitochondria-related genes and immune infiltration. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify the mitochondria-specific genes and the related pathways based on the immune cell types.
Results: HE staining revealed a massive infiltration of plasma cells with abundant immunoglobulin protein distributed around phenotypically normal-appearing acinar and ductal tissues of patients with pSS. Immunohistochemical analyses revealed that innate immune cells (macrophages, eosinophils and NK cells) were distributed throughout the glandular tissue. Dominant adaptive immune cell infiltration composed of B cells, CD4+T cells and CD8+ T cells or ectopic lymphoid follicle-like structures were observed in the LSGs of patients with pSS. TEM validated the swelling of mitochondria with disorganised cristae in some lymphocytes that had invaded the glandular tissue. Subsequently, bioinformatic analysis revealed that innate and adaptive immune cells were associated with different mitochondrial metabolism pathways. Mitochondrial electron transport and respiratory chain complexes in the glandular microenvironment were positively correlated with innate immune cells, whereas amino acid and nucleic acid metabolism were negatively correlated with adaptive immune cells. In addition, mitochondrial biogenesis and mitochondrial apoptosis in the glandular microenvironment were closely associated with adaptive immune cells.
Conclusion: Innate and adaptive immune cells have distinct distribution profiles in the salivary gland tissues of patients with pSS and are associated with different mitochondrial metabolic pathways, which may contribute to disease progression.

Keywords:  RNA sequencing; Sjogren’s syndrome; immune cell; mitochondria; mitochondrial metabolism; transcriptomics

DOI:  https://doi.org/10.3389/fimmu.2023.1156774
Hepatology. 2023 Jul 25.

Myeloid-specific ablation of Basp1 ameliorates diet-induced NASH in mice by attenuating pro-inflammatory signaling.

Ziyi Meng, Linkang Zhou, Sungki Hong, Xiaoxue Qiu, Zhimin Chen, Tongyu Liu, Ken Inoki, Jiandie D Lin.

Nonalcoholic steatohepatitis (NASH) represents a severe stage of fatty liver disease characterized by hepatocyte injury, inflammation, and liver fibrosis. Myeloid-derived innate immune cells, such as macrophages and dendritic cells, play an important role in host defense and disease pathogenesis. Despite this, the nature of transcriptomic reprogramming of myeloid cells in NASH liver and its contribution to disease progression remain incompletely defined. In this study, we performed bulk and single-cell RNA sequencing analysis to delineate the landscape of macrophage and dendritic cell transcriptomes in healthy and NASH liver. Our analysis uncovered cell type-specific patterns of transcriptomic reprogramming upon diet-induced NASH. We identified Brain abundant membrane attached signal protein 1 (Basp1) as a myeloid-enriched gene that is markedly induced in mouse and human NASH liver. Myeloid-specific inactivation of Basp1 attenuates the severity of diet-induced NASH pathologies as shown by reduced hepatocyte injury and liver fibrosis in mice. Mechanistically, cultured macrophages lacking Basp1 exhibited diminished response to pro-inflammatory stimuli, impaired NLRP3 inflammasome activation, and reduced cytokine secretion. Together, these findings uncover Basp1 as a critical regulator of myeloid inflammatory signaling that underlies NASH pathogenesis.

DOI: https://doi.org/10.1097/HEP.0000000000000537
J Heart Lung Transplant. 2023 Jul 24. pii: S1053-2498(23)01940-X. [Epub ahead of print]

MTHFD2 Ablation in T Cells Protects against Heart Transplant Rejection by Perturbing IRF4/PD-1 Pathway through the Metabolic-epigenetic Nexus.

Yuan Li, Zhang Chen, Jikai Cui, Jizhang Yu, Yuqing Niu, Shuan Ran, Song Wang, Weicong Ye, Heng Xu, Xi Zhang, Jie Wu, Jiahong Xia.

  BACKGROUND: One-carbon metabolism supports the activation, proliferation, and function of multiple immune cells. However, researchers have not clearly determined whether and how one-carbon metabolic enzymes contribute to heart transplant rejection.METHODS: We investigated the dynamic metabolic adaptation in grafts during heart transplant rejection by conducting transcriptomics, metabolomics and single-cell RNA sequencing studies of cardiac tissue from human and mouse heart transplant recipients. We also assessed the expression of the one-carbon metabolic enzyme MTHFD2 in cardiac grafts by immunofluorescence and flow cytometry assays. Then we constructed a murine heart transplant model with T cell-specific Mthfd2 knockout mice, analyzed T cells function by flow cytometry assays and enzyme-linked immunospot assays, and studied the mechanism by Cleavage Under Targets and Tagmentation assays. Finally, we studied the effect of a pharmacological inhibitor of MTHFD2 in humanized skin transplant model.
RESULTS: We revealed that the one-carbon metabolism enzyme MTHFD2 was a hallmark of alloreactive T cells and was linked to T cell proliferation and function after exposure to alloantigen. And, Mthfd2 ablation prevented murine heart transplant rejection. Mechanistically, we found Mthfd2 ablation affected the IRF4/PD-1 pathway through a metabolic-epigenetic mechanism involving H3K4me3. Furthermore, we found that inhibiting MTHFD2 attenuated human allograft rejection in a humanized skin transplant model.
CONCLUSIONS: These data show that the one-carbon metabolic enzyme MTHFD2 serves as a metabolic checkpoint of alloreactive T cells and suggest that it may be a potential therapeutic target for heart transplant rejection.

Keywords:  Heart transplant rejection; IRF4; MTHFD2; One-carbon metabolism; T cells

DOI:  https://doi.org/10.1016/j.healun.2023.07.009
J Dairy Sci. 2023 Jul 25. pii: S0022-0302(23)00428-9. [Epub ahead of print]

Effects of dietary rumen-protected choline supplementation to periparturient dairy cattle on inflammation, metabolism, and performance during an intramammary lipopolysaccharide challenge.

T H Swartz, B J Bradford, L K Mamedova, K A Estes.

  Recent studies have suggested that dietary rumen-protected choline (RPC) supplementation can modulate immune function, attenuate inflammation, and improve performance in periparturient dairy cattle; however, this has yet to be evaluated during a mastitis challenge. Therefore, the objective of this study was to examine the effects of supplementation and dose of RPC on metabolism, inflammation, and performance during an intramammary lipopolysaccharide (LPS) challenge. Parous Holstein cows (parity, mean ± SD, 1.9 ± 1.1 at enrollment) were blocked by calving month and randomly assigned within block to receive either 45 g/d of RPC (20.4 g/d of choline ions; CHOL45, n = 18), 30 g/d of RPC (13.6 g/d of choline ions; CHOL30, n = 21), or no RPC (CON, n = 19) as a top-dress starting 24 d before expected calving until 21 d postpartum. Cows were alternately assigned within treatment group to either receive an intramammary LPS challenge (200 μg in each rear quarter; Escherichia coli O111:B4) or not at 17 DIM. Before the challenge, CHOL45 and CHOL30 cows produced 3.4 and 3.8 (±1.2 SED) kg/d more milk than CON, respectively. Dietary RPC supplementation did not mitigate the milk loss associated with the intramammary LPS challenge; however, CHOL45 and CHOL30 cows produced 3.1 and 3.5 (±1.4 SED) kg/d more milk than CON, respectively in the carryover period (22 to 84 DIM). Dietary RPC supplementation enhanced plasma β-hydroxybutyrate (BHB) concentrations before the LPS challenge, and increased plasma nonesterified fatty acids (NEFA) and acetylcarnitine concentrations during the LPS challenge, potentially reflecting greater adipose tissue mobilization, fatty acid transport and oxidation. Aside from trimethylamine N-oxide and sarcosine, which were increased in CHOL45-LPS as compared with CON-LPS, most other choline metabolite concentrations in plasma were unaffected by treatment, likely because more choline was being secreted in milk. Plasma lactic acid concentrations were decreased in CHOL45-LPS and CHOL30-LPS as compared with CON-LPS, suggesting a reduction in glycolysis or an enhancement in the flux through the lactic acid cycle to support gluconeogenesis. Plasma concentrations of fumaric acid, a byproduct of AA catabolism and the urea cycle, were increased in both choline groups as compared with CON-LPS during the LPS challenge. Cows in the CHOL45 group had greater plasma antioxidant potential before the LPS challenge and reduced plasma methionine sulfoxide concentrations during the LPS challenge compared with CON-LPS, suggesting an improvement in oxidant status. Nevertheless, concentrations of inflammatory markers such as haptoglobin and tumor necrosis factor α (TNFα) were not affected by treatment. Taken together, our data suggest that the effects of dietary RPC supplementation on milk yield could be mediated through metabolic pathways and are unlikely to be related to the resolution of inflammation in periparturient dairy cattle. Lastly, dose responses to dietary RPC supplementation were not found for various economically important outcomes including milk yield, limiting the justification for feeding a greater dietary RPC dose in industry.

Keywords:  inflammation; mastitis; metabolomics; methyl donor

DOI:  https://doi.org/10.3168/jds.2023-23259
Metabolites. 2023 Jul 11. pii: 834. [Epub ahead of print]13(7):

The Virulence Factor Macrophage Infectivity Potentiator (Mip) Influences Branched-Chain Amino Acid Metabolism and Pathogenicity of Legionella pneumophila.

Fabian Nikolka, Mustafa Safa Karagöz, Mohamed Zakaria Nassef, Karsten Hiller, Michael Steinert, Thekla Cordes.

  Legionella pneumophila (Lp) is a common etiological agent of bacterial pneumonia that causes Legionnaires' disease (LD). The bacterial membrane-associated virulence factor macrophage infectivity potentiator (Mip) exhibits peptidyl-prolyl-cis/trans-isomerase (PPIase) activity and contributes to the intra- and extracellular pathogenicity of Lp. Though Mip influences disease outcome, little is known about the metabolic consequences of altered Mip activity during infections. Here, we established a metabolic workflow and applied mass spectrometry approaches to decipher how Mip activity influences metabolism and pathogenicity. Impaired Mip activity in genetically engineered Lp strains decreases intracellular replication in cellular infection assays, confirming the contribution of Mip for Lp pathogenicity. We observed that genetic and chemical alteration of Mip using the PPIase inhibitors rapamycin and FK506 induces metabolic reprogramming in Lp, specifically branched-chain amino acid (BCAA) metabolism. Rapamycin also inhibits PPIase activity of mammalian FK506 binding proteins, and we observed that rapamycin induces a distinct metabolic signature in human macrophages compared to bacteria, suggesting potential involvement of Mip in normal bacteria and in infection. Our metabolic studies link Mip to alterations in BCAA metabolism and may help to decipher novel disease mechanisms associated with LD.

Keywords:  Legionella pneumophila; branched-chain amino acid; infection model; macrophage; macrophage infectivity potentiator (Mip); mass spectrometry; metabolism; tracing; virulence factor

DOI:  https://doi.org/10.3390/metabo13070834
Hepatology. 2023 Jul 26.

Itaconate inhibits CD103+ TRM cells and alleviates hepatobiliary injury in mouse models of primary sclerosing cholangitis.

Yikang Li, Bo Li, Xiao Xiao, Qiwei Qian, Rui Wang, Zhuwan Lyu, Ruiling Chen, NaNa Cui, Yiyan Ou, Xiting Pu, Qi Miao, Qixia Wang, Min Lian, M Eric Gershwin, Ruqi Tang, Xiong Ma, Zhengrui You.

BACKGROUND AIMS: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease characterized by infiltration of intrahepatic tissue-resident memory CD8+ T cells (TRM). Itaconate has demonstrated therapeutic potential in modulating inflammation. An unmet need for PSC is the reduction of biliary inflammation, and we hypothesized that itaconate may directly modulate pathogenic TRM.METHODS: The numbers of intrahepatic CD103+ TRM were evaluated by immunofluorescence in PSC (n = 32) and serum levels of itaconate in PSC (n = 64), primary biliary cholangitis (PBC) (n = 60), autoimmune hepatitis (AIH) (n = 49), and healthy controls (n = 109) were determined by LC-MS/MS. Additionally, the frequencies and immunophenotypes of intrahepatic TRM using explants from PSC (n = 5) and healthy donors (n = 6) were quantitated by flow cytometry. The immunomodulatory properties of 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) on CD103+ TRM were studied in vitro. Finally, the therapeutic potential of itaconate was studied by administration of 4-OI and deficiency of immune-responsive gene 1(Irg1, encodes the aconitate decarboxylase producing itaconate) in murine models of PSC.
RESULTS: Intrahepatic CD103+ TRM was significantly expanded in PSC and was positively correlated with disease severity. Serum itaconate levels decreased in PSC. Importantly, 4-OI inhibited the induction and effector functions of CD103+ TRM in vitro. Mechanistically, 4-OI blocked DNA demethylation of RUNX3 in CD8+T cells. Moreover, 4-OI reduced intrahepatic CD103+ TRM and ameliorated liver injury in murine models of PSC.
CONCLUSIONS: Itaconate exerted immunomodulatory activity on CD103+ TRM in both in vitro and murine PSC models. Our study suggests that targeting pathogenic CD103+ TRM with itaconate has therapeutic potential in PSC.

DOI: https://doi.org/10.1097/HEP.0000000000000549
Front Immunol. 2023 ;14 1193235

Implication of metabolism in the polarization of tumor-associated-macrophages: the mass spectrometry-based point of view.

Giulia De Simone, Cristiana Soldani, Aurelia Morabito, Barbara Franceschini, Fabrizio Ferlan, Guido Costa, Roberta Pastorelli, Matteo Donadon, Laura Brunelli.

  Tumor-associated macrophages (TAMs) represent one of the main tumor-infiltrating immune cell types and are generally categorized into either of two functionally contrasting subtypes, namely classical activated M1 macrophages and alternatively activated M2 macrophages. TAMs showed different activation states that can be represent by the two extremes of the complex profile of macrophages biology, the M1-like phenotype (pro-inflammatory activity) and the M2-like phenotype (anti-inflammatory activity). Based on the tumor type, and grades, TAMs can acquire different functions and properties; usually, the M1-like phenotype is typical of early tumor stages and is associated to an anti-tumor activity, while M2-like phenotype has a pro-inflammatory activity and is related to a poor patients' prognosis. The classification of macrophages into M1/M2 groups based on well-defined stimuli does not model the infinitely more complex tissue milieu where macrophages (potentially of different origin) would be exposed to multiple signals in different sequential order. This review aims to summarize the recent mass spectrometry-based (MS-based) metabolomics findings about the modifications of metabolism in TAMs polarization in different tumors. The published data shows that MS-based metabolomics is a promising tool to help better understanding TAMs metabolic phenotypes, although it is still poorly applied for TAMs metabolism. The knowledge of key metabolic alterations in TAMs is an essential step for discovering TAMs polarization novel biomarkers and developing novel therapeutic approaches targeting TAM metabolism to repolarize TAMs towards their anti-tumor phenotype.

Keywords:  TAM polarization; mass spectrometry; metabolism; prognostic markers; tumor associated macrophages (TAMs)

DOI:  https://doi.org/10.3389/fimmu.2023.1193235
Cell Death Discov. 2023 Jul 28. 9(1): 269

IL4I1-catalyzed tryptophan metabolites mediate the anti-inflammatory function of cytokine-primed human muscle stem cells.

Muqiu Zuo, Jiankai Fang, Peiqing Huang, Shisong Liu, Pengbo Hou, Shiqing Wang, Zhanhong Liu, Chao Feng, Lijuan Cao, Peishan Li, Yufang Shi, Changshun Shao.

Muscle stem cells (MuSCs) have been demonstrated to exert impressive therapeutic efficacy in disease settings through orchestrating inflammatory microenvironments. Nevertheless, the mechanisms underlying the immunoregulatory property of MuSCs remain largely uncharacterized. Here, we showed that interleukin-4-induced-1 (IL4I1), an essential enzyme that catalyzes indole metabolism in humans, was highly expressed in human MuSCs exposed to IFN-γ and TNF-α. Functionally, the MuSCs were found to inhibit the infiltration of neutrophils into sites of inflammation in a IL4I1-dependent manner and thus ameliorate acute lung injury in mice. Mechanistically, the indole metabolites, including indole-3-pyruvic acid (I3P) and indole-3-aldehyde (I3A), produced by IL4I1, acted as ligands to activate aryl hydrocarbon receptor (AHR), leading to augmented expression of TNF-stimulated gene 6 (TSG-6) in inflammatory cytokine-primed MuSCs. Furthermore, I3P administration alone suppressed neutrophil infiltration into damaged lungs. I3P could also reduce the level of reactive oxygen species in neutrophils. Therefore, our study has uncovered a novel mechanism by which MuSCs acquire their immunoregulatory property and may help to develop or optimize MuSC-based therapies for inflammatory diseases.

DOI: https://doi.org/10.1038/s41420-023-01568-x
Sci Transl Med. 2023 07 26. 15(706): eabn4722

Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes.

Inflammatory Arthritis Microbiome Consortium (IAMC) investigators group

Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis.

DOI: https://doi.org/10.1126/scitranslmed.abn4722
iScience. 2023 Jul 21. 26(7): 107230

Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation.

Vugar Azizov, Michel Hübner, Michael Frech, Jörg Hofmann, Marketa Kubankova, Dennis Lapuente, Matthias Tenbusch, Jochen Guck, Georg Schett, Mario M Zaiss.

  Alcohol is among the most widely consumed dietary substances. Excessive alcohol consumption damages the liver, heart, and brain. Alcohol also has strong immunoregulatory properties. Here, we report how alcohol impairs T cell function via acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Upon alcohol consumption, acetate, the metabolite of alcohol, accumulates in lymphoid organs. T cells exposed to acetate, exhibit increased acetylation of cortactin. Acetylation of cortactin inhibits filamentous actin binding and hence reduces T cell migration, immune synapse formation and activation. While mutated, acetylation-resistant cortactin rescues the acetate-induced inhibition of T cell migration, primary mouse cortactin knockout T cells exhibited impaired migration. Acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in T cells in vitro and in vivo in an influenza infection model in mice. Together these findings reveal cortactin as a possible target for mitigation of T cell driven autoimmune diseases.

Keywords:  Immunology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.107230
PLoS Pathog. 2023 Jul 24. 19(7): e1011536

Metabolic reprogramming and altered cell envelope characteristics in a pentose phosphate pathway mutant increases MRSA resistance to β-lactam antibiotics.

Merve S Zeden, Laura A Gallagher, Emilio Bueno, Aaron C Nolan, Jongsam Ahn, Dhananjay Shinde, Fareha Razvi, Margaret Sladek, Órla Burke, Eoghan O'Neill, Paul D Fey, Felipe Cava, Vinai C Thomas, James P O'Gara.

Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In Staphylococcus aureus the role of the pentose phosphate pathway (PPP) remains largely unexplored. Mutation of the 6-phosphogluconolactonase gene pgl, which encodes the only non-essential enzyme in the oxidative phase of the PPP, significantly increased MRSA resistance to β-lactam antibiotics, particularly in chemically defined media with physiologically-relevant concentrations of glucose, and reduced oxacillin (OX)-induced lysis. Expression of the methicillin-resistance penicillin binding protein 2a and peptidoglycan architecture were unaffected. Carbon tracing and metabolomics revealed extensive metabolic reprogramming in the pgl mutant including increased flux to glycolysis, the TCA cycle, and several cell envelope precursors, which was consistent with increased β-lactam resistance. Morphologically, pgl mutant cells were smaller than wild-type with a thicker cell wall and ruffled surface when grown in OX. The pgl mutation reduced resistance to Congo Red, sulfamethoxazole and oxidative stress, and increased resistance to targocil, fosfomycin and vancomycin. Levels of lipoteichoic acids (LTAs) were significantly reduced in pgl, which may limit cell lysis, while the surface charge of pgl cells was significantly more positive. A vraG mutation in pgl reversed the increased OX resistance phenotype, and partially restored wild-type surface charge, but not LTA levels. Mutations in vraF or graRS from the VraFG/GraRS complex that regulates DltABCD-mediated d-alanylation of teichoic acids (which in turn controls β-lactam resistance and surface charge), also restored wild-type OX susceptibility. Collectively these data show that reduced levels of LTAs and OX-induced lysis combined with a VraFG/GraRS-dependent increase in cell surface positive charge are accompanied by significantly increased OX resistance in an MRSA pgl mutant. (266 words).

DOI: https://doi.org/10.1371/journal.ppat.1011536
Antiviral Res. 2023 Jul 24. pii: S0166-3542(23)00158-4. [Epub ahead of print] 105680

The hepatic GABAergic system promotes liver macrophage M2 polarization and mediates HBV replication in mice.

Ziyou Bao, Xiaotong Chen, Yan Li, Wenshan Jiang, Di Pan, Lushun Ma, Yunxiao Wu, Yunling Chen, Chaojia Chen, Liyuan Wang, Songbo Zhao, Tixiao Wang, Wei-Yang Lu, Chunhong Ma, Shuanglian Wang.

  Macrophages display functional phenotypic plasticity. Hepatitis B virus (HBV) infection induces polarizations of liver macrophages either to M1-like pro-inflammatory phenotype or to M2-like anti-inflammatory phenotype. Gamma-aminobutyric acid (GABA) signaling exists in various non-neuronal cells including hepatocytes and some immune cells. Here we report that macrophages express functional GABAergic signaling components and activation of type A GABA receptors (GABAARs) promotes M2-polarization thus advancing HBV replication. Notably, intraperitoneal injection of GABA or the GABAAR agonist muscimol increased HBV replication in HBV-carrier mice that were generated by hydrodynamical injection of adeno-associated virus/HBV1.2 plasmids (pAAV/HBV1.2). The GABA-augmented HBV replication in HBV-carrier mice was significantly reduced by the GABAAR inhibitor picrotoxin although picrotoxin had no significant effect on serum HBsAg levels in control HBV-carrier mice. Depletion of liver macrophages by liposomal clodronate treatment also significantly reduced the GABA-augmented HBV replication. Yet adoptive transfer of liver macrophages isolated from GABA-treated donor HBV-carrier mice into the liposomal clodronate-pretreated recipient HBV-carrier mice restored HBV replication. Moreover, GABA or muscimol treatment increased the expression of "M2" cytokines in macrophages, but had no direct effect on HBV replication in the HepG2.2.15 cells, HBV1.3-transfected Huh7, HepG2, or HepaRG cells, or HBV-infected Huh7-NTCP cells. Taken together, these results suggest that increasing GABA signaling in the liver promotes HBV replication in HBV-carrier mice by suppressing the immunity of liver macrophages, but not by increasing the susceptibility of hepatocytes to HBV infection. Our study shows that a previously unknown GABAergic system in liver macrophage has an essential role in HBV replication.

Keywords:  GABA; GABA(A) receptor; HBV replication; Liver macrophages; Macrophage polarization

DOI:  https://doi.org/10.1016/j.antiviral.2023.105680
Nat Commun. 2023 07 25. 14(1): 4101

Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.

Liming Yu, Lin Xu, Haiyan Chu, Jun Peng, Anastasia Sacharidou, Hsi-Hsien Hsieh, Ada Weinstock, Sohaib Khan, Liqian Ma, José Gabriel Barcia Durán, Jeffrey McDonald, Erik R Nelson, Sunghee Park, Donald P McDonnell, Kathryn J Moore, Lily Jun-Shen Huang, Edward A Fisher, Chieko Mineo, Linzhang Huang, Philip W Shaul.

Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular inflammation is poorly understood. Here we show in male mice that hypercholesterolemia-driven endothelial activation, monocyte recruitment and atherosclerotic lesion formation are promoted by a crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol (27HC). The pro-atherogenic actions of macrophage-derived 27HC require endothelial estrogen receptor alpha (ERα) and disassociation of the cytoplasmic scaffolding protein septin 11 from ERα, leading to extranuclear ERα- and septin 11-dependent activation of NF-κB. Furthermore, pharmacologic inhibition of cyp27a1, which generates 27HC, affords atheroprotection by reducing endothelial activation and monocyte recruitment. These findings demonstrate cell-to-cell communication by 27HC, and identify a major causal linkage between the hypercholesterolemia and vascular inflammation that partner to promote atherosclerosis. Interventions interrupting this linkage may provide the means to blunt vascular inflammation without impairing host defense to combat the risk of atherosclerotic cardiovascular disease that remains despite lipid-lowering therapies.

DOI: https://doi.org/10.1038/s41467-023-39586-z