bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2023‒05‒14
27 papers selected by
Dylan Ryan
University of Cambridge

  1. Cell Rep. 2023 May 06. pii: S2211-1247(23)00482-5. [Epub ahead of print]42(5): 112471
      T helper type 2 (Th2) cytokine-activated M2 macrophages contribute to inflammation resolution and wound healing. This study shows that IL-4-primed macrophages exhibit a stronger response to lipopolysaccharide stimulation while maintaining M2 signature gene expression. Metabolic divergence between canonical M2 and non-canonical proinflammatory-prone M2 (M2INF) macrophages occurs after the IL-4Rα/Stat6 axis. Glycolysis supports Hif-1α stabilization and proinflammatory phenotype of M2INF macrophages. Inhibiting glycolysis blunts Hif-1α accumulation and M2INF phenotype. Wdr5-dependent H3K4me3 mediates the long-lasting effect of IL-4, with Wdr5 knockdown inhibiting M2INF macrophages. Our results also show that the induction of M2INF macrophages by IL-4 intraperitoneal injection and transferring of M2INF macrophages confer a survival advantage against bacterial infection in vivo. In conclusion, our findings highlight the previously neglected non-canonical role of M2INF macrophages and broaden our understanding of IL-4-mediated physiological changes. These results have immediate implications for how Th2-skewed infections could redirect disease progression in response to pathogen infection.
    Keywords:  CP: Immunology; CP: Metabolism; Hif1α; IL-4; M2 macrophage; epigenetics; glycolysis; trained immunity
  2. bioRxiv. 2023 Apr 25. pii: 2023.04.21.537859. [Epub ahead of print]
      Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8 + CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.Statement of Significance: Adenosine is well known to inhibit T cell function and substantial effort has focused on inhibiting adenosine generation and signaling. Here, we show that exhausted T cells are suppressed by adenosine, which is only modestly impacted by inhibiting adenosine generation or signaling. In contrast, metabolism of adenosine to inosine augmented T cell function and culture of T cells with inosine induced multi-level reprogramming leading to stemness and improved anti-tumor potency. We demonstrate the feasibility of introducing inosine during GMP cell manufacturing as a novel strategy to generate enhanced CAR-T cells.
  3. JCI Insight. 2023 May 11. pii: e160345. [Epub ahead of print]
      T cells play an important role in acute kidney injury (AKI). Metabolic programming of T cells regulates their function, is a rapidly emerging field, and is unknown in AKI. We induced ischemic AKI in C57B6 mice and collected kidneys and spleens at multiple time points. T cells were isolated and analyzed by an immune-metabolic assay. Unbiased machine learning analyses identified a distinct T cell subset with reduced VDAC1 and mTOR expression in post-AKI kidneys. Ischemic kidneys showed higher expression of trimethylation of histone H3 lysine 27 (H3K27Me3) and glutaminase. Splenic T cells from post-AKI mice had higher expression of GLUT1, hexokinase II, and CPT1a. Human nonischemic and ischemic kidney tissue displayed similar findings to mouse kidneys. Given a convergent role for glutamine in T cell metabolic pathways and the availability of a relatively safe glutamine antagonist JHU083, effects on AKI were evaluated. JHU083 attenuated renal injury and reduced T cell activation and proliferation in ischemic and nephrotoxic AKI, whereas T cell-deficient mice were not protected by glutamine blockade. In vitro hypoxia demonstrated upregulation of glycolysis-related enzymes. T cells undergo metabolic reprogramming during AKI, and reconstitution of metabolism by targeting T cell glutamine pathway could be a promising novel therapeutic approach.
    Keywords:  Immunology; Nephrology; T cells
  4. Front Immunol. 2023 ;14 1172467
      The naked mole-rat (NMR) is a unique long-lived rodent which is highly resistant to age-associated disorders and cancer. The immune system of NMR possesses a distinct cellular composition with the prevalence of myeloid cells. Thus, the detailed phenotypical and functional assessment of NMR myeloid cell compartment may uncover novel mechanisms of immunoregulation and healthy aging. In this study gene expression signatures, reactive nitrogen species and cytokine production, as well as metabolic activity of classically (M1) and alternatively (M2) activated NMR bone marrow-derived macrophages (BMDM) were examined. Polarization of NMR macrophages under pro-inflammatory conditions led to expected M1 phenotype characterized by increased pro-inflammatory gene expression, cytokine production and aerobic glycolysis, but paralleled by reduced production of nitric oxide (NO). Under systemic LPS-induced inflammatory conditions NO production also was not detected in NMR blood monocytes. Altogether, our results indicate that NMR macrophages are capable of transcriptional and metabolic reprogramming under polarizing stimuli, however, NMR M1 possesses species-specific signatures as compared to murine M1, implicating distinct adaptations in NMR immune system.
    Keywords:  immunometabolism; inducible NO-synthase; macrophage; naked mole-rat; polarization
  5. Cell Rep. 2023 May 05. pii: S2211-1247(23)00492-8. [Epub ahead of print]42(5): 112481
      The one-carbon metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is involved in the regulation of tumor oncogenesis and immune cell functions, but whether it can contribute to macrophage polarization remains elusive. Here, we show that MTHFD2 suppresses polarization of interferon-γ-activated macrophages (M(IFN-γ)) but enhances that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, MTHFD2 interacts with phosphatase and tensin homolog (PTEN) to suppress PTEN's phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase activity and enhance downstream Akt activation, independent of the N-terminal mitochondria-targeting signal of MTHFD2. MTHFD2-PTEN interaction is promoted by IL-4 but not IFN-γ. Furthermore, amino acid residues (aa 215-225) of MTHFD2 directly target PTEN catalytic center (aa 118-141). Residue D168 of MTHFD2 is also critical for regulating PTEN's PIP3 phosphatase activity by affecting MTHFD2-PTEN interaction. Our study suggests a non-metabolic function of MTHFD2 by which MTHFD2 inhibits PTEN activity, orchestrates macrophage polarization, and alters macrophage-mediated immune responses.
    Keywords:  CP: Immunology; MTHFD2; PTEN; macrophage polarization
  6. Elife. 2023 May 11. pii: e84280. [Epub ahead of print]12
      Oxygenation levels are a determinative factor in T cell function. Here we describe that the oxygen tensions sensed by mouse and human T cells at the moment of activation act to persistently modulate both differentiation and function. We found that in a protocol of CAR-T cell generation, 24 hours of low oxygen levels during initial CD8+ T cell priming is sufficient to enhance antitumour cytotoxicity in a preclinical model. This is the case even when CAR-T cells are subsequently cultured under high oxygen tensions prior to adoptive transfer. Increased hypoxia inducible transcription factor (HIF) expression was able to alter T cell fate in a similar manner to exposure to low oxygen tensions; however, only a controlled or temporary increase in HIF signalling was able to consistently improve cytotoxic function of T cells. These data show that oxygenation levels during and immediately after T cell activation play an essential role in regulating T cell function.
    Keywords:  human; immunology; inflammation; mouse
  7. Mol Biol Cell. 2023 May 10. mbcE23010032
      As an important substrate for cell metabolism, the short-chain fatty acid acetate emerges as a regulator of cell fate and function. However, its role in T cell survival and its underlying mechanisms remain largely unknown. Here, we demonstrate that acetate modulates T cell apoptosis via potentiation of α-tubulin acetylation. We further show that acetate treatment effectively increases the expression of the tumor necrosis factor receptor (TNFR) family member CD30 by enhancing its gene transcription. Moreover, CD30 physically associates with and stabilizes the deacetylase HDAC6, which deacetylates α-tubulin to decrease microtubule stability. Proteomic profiling of Cd30 knockout (Cd30-/-) T cells reveals elevated expression of anti-apoptotic BCL2 family proteins and thus promotes T cell survival via a microtubule-Bcl-2 axis. Taken together, our results demonstrate that acetate is a regulator of T cell survival by controlling levels of acetylated α-tubulin. This suggests that therapeutic manipulation of acetate metabolism may facilitate optimal T cell responses in pathological conditions.
  8. Metabolism. 2023 May 06. pii: S0026-0495(23)00190-7. [Epub ahead of print] 155587
      BACKGROUND: Systemic sclerosis (SSc) is a chronic and systemic autoimmune disease marked by the skin and visceral fibrosis. Metabolic alterations have been found in SSc patients; however, serum metabolomic profiling has not been thoroughly conducted. Our study aimed to identify alterations in the metabolic profile in both SSc patients before and during treatment, as well as in mouse models of fibrosis. Furthermore, the associations between metabolites and clinical parameters and disease progression were explored.METHODS: High-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS)/MS was performed in the serum of 326 human samples and 33 mouse samples. Human samples were collected from 142 healthy controls (HC), 127 newly diagnosed SSc patients without treatment (SSc baseline), and 57 treated SSc patients (SSc treatment). Mouse serum samples were collected from 11 control mice (NaCl), 11 mice with bleomycin (BLM)-induced fibrosis and 11 mice with hypochlorous acid (HOCl)-induced fibrosis. Both univariate analysis and multivariate analysis (orthogonal partial least-squares discriminate analysis (OPLS-DA)) were conducted to unravel differently expressed metabolites. KEGG pathway enrichment analysis was performed to characterize the dysregulated metabolic pathways in SSc. Associations between metabolites and clinical parameters of SSc patients were identified by Pearson's or Spearman's correlation analysis. Machine learning (ML) algorithms were applied to identify the important metabolites that have the potential to predict the progression of skin fibrosis.
    RESULTS: The newly diagnosed SSc patients without treatment showed a unique serum metabolic profile compared to HC. Treatment partially corrected the metabolic changes in SSc. Some metabolites (phloretin 2'-O-glucuronide, retinoyl b-glucuronide, all-trans-retinoic acid, and betaine) and metabolic pathways (starch and sucrose metabolism, proline metabolism, androgen and estrogen metabolism, and tryptophan metabolism) were dysregulated in new-onset SSc, but restored upon treatment. Some metabolic changes were associated with treatment response in SSc patients. Metabolic changes observed in SSc patients were mimicked in murine models of SSc, indicating that they may reflect general metabolic changes associated with fibrotic tissue remodeling. Several metabolic changes were associated with SSc clinical parameters. The levels of allysine and all-trans-retinoic acid were negatively correlated, while D-glucuronic acid and hexanoyl carnitine were positively correlated with modified Rodnan skin score (mRSS). In addition, a panel of metabolites including proline betaine, phloretin 2'-O-glucuronide, gamma-linolenic acid and L-cystathionine were associated with the presence of interstitial lung disease (ILD) in SSc. Specific metabolites identified by ML algorithms, such as medicagenic acid 3-O-b-D-glucuronide, 4'-O-methyl-(-)-epicatechin-3'-O-beta-glucuronide, valproic acid glucuronide, have the potential to predict the progression of skin fibrosis.
    CONCLUSIONS: Serum of SSc patients demonstrates profound metabolic changes. Treatment partially restored the metabolic changes in SSc. Moreover, certain metabolic changes were associated with clinical manifestations such as skin fibrosis and ILD, and could predict the progression of skin fibrosis.
    Keywords:  Biomarkers; Machine learning algorithm; Metabolic reprogramming; Metabolomics; Systemic sclerosis
  9. Mult Scler Relat Disord. 2023 Apr 16. pii: S2211-0348(23)00223-7. [Epub ahead of print]75 104719
      BACKGROUND: Teriflunomide (TER) (Aubagio™) is an FDA-approved disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). The mechanism of action of TER is thought to be related to the inhibition of dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway required by rapidly dividing lymphocytes. Several large pivotal studies have established the efficacy and safety of TER in patients with RRMS. Despite this, little is known about how the adaptive and innate immune cell subsets are affected by the treatment in patients with MS.METHODS: We recruited 20 patients with RRMS who were newly started on TER and performed multicolor flow cytometry and functional assays on peripheral blood samples. A paired t-test was used for the statistical analysis and comparison.
    RESULTS: Our data showed that TER promoted a tolerogenic environment by shifting the balance between activated pathogenic and naïve or immunosuppressive immune cell subsets. In our cohort, TER increased the expression of the immunosuppressive marker CD39 on regulatory T cells (Tregs) while it decreased the expression of the activation marker CXCR3 on CD4+ T helper cells. TER treatment also reduced switched memory (sm) B cells while it increased naïve B cells and downregulated the expression of co-stimulatory molecules CD80 and CD86. Additionally, TER reduced the percentage and absolute numbers of natural killer T (NKT) cells, as well as the percentage of natural killer (NK) cells and showed a trend toward reducing the CD56dim NK pathogenic subset.
    CONCLUSION: TER promotes the tolerogenic immune response and suppresses the pathogenic immune response in patients with RRMS.
    Keywords:  Adaptive immunity; Aubagio; Innate immunity; Multiple sclerosis; Teriflunomide
  10. Cancer Lett. 2023 May 05. pii: S0304-3835(23)00159-3. [Epub ahead of print] 216208
      Cancer immunotherapy targeting myeloid-derived suppressor cells (MDSCs) is one of the most promising anticancer strategies. Metabolic reprogramming is vital for MDSC activation, however, the regulatory mechanisms of cholesterol metabolic reprogramming in MDSCs remains largely unexplored. Using the receptor-interacting protein kinase 3 (RIPK3)-deficient MDSC model, a previously established tumor-infiltrating MDSC-like model, we found that the cholesterol accumulation was significantly decreased in these cells. Moreover, the phosphorylated AKT-mTORC1 signaling was reduced, and downstream SREBP2-HMGCR-mediated cholesterol synthesis was blunted. Interestingly, cholesterol deficiency profoundly elevated the immunosuppressive activity of MDSCs. Mechanistically, cholesterol elimination induced nuclear accumulation of LXRβ, thereby promoting LXRβ-RXRα heterodimer binding of a novel composite element in the promoter of Arg1. Furthermore, itraconazole enhanced the immunosuppressive activity of MDSCs to boost tumor growth by suppressing the RIPK3-AKT-mTORC1 pathway and impeding cholesterol synthesis. Our findings demonstrate that RIPK3 deficiency leads to cholesterol abrogation in MDSCs, which facilitates tumor-infiltrating MDSC activation, and highlight the therapeutic potential of targeting cholesterol synthesis to overcome tumor immune evasion.
    Keywords:  Cholesterol; Metabolism; Myeloid-derived suppressor cells; Tumor immunity; Tumor microenvironment
  11. Immunol Rev. 2023 May 12.
      Dendritic cells (DCs) are innate immune cells that detect and process environmental signals and communicate them with T cells to bridge innate and adaptive immunity. Immune signals and microenvironmental cues shape the function of DC subsets in different contexts, which is associated with reprogramming of cellular metabolic pathways. In addition to integrating these extracellular cues to meet bioenergetic and biosynthetic demands, cellular metabolism interplays with immune signaling to shape DC-dependent immune responses. Emerging evidence indicates that lipid metabolism serves as a key regulator of DC responses. Here, we summarize the roles of fatty acid and cholesterol metabolism, as well as selective metabolites, in orchestrating the functions of DCs. Specifically, we highlight how different lipid metabolic programs, including de novo fatty acid synthesis, fatty acid β oxidation, lipid storage, and cholesterol efflux, influence DC function in different contexts. Further, we discuss how dysregulation of lipid metabolism shapes DC intracellular signaling and contributes to the impaired DC function in the tumor microenvironment. Finally, we conclude with a discussion on key future directions for the regulation of DC biology by lipid metabolism. Insights into the connections between lipid metabolism and DC functional specialization may facilitate the development of new therapeutic strategies for human diseases.
    Keywords:  cholesterol; dendritic cells; fatty acid; innate immunity; lipid metabolism; lipid metabolites
  12. Int Immunopharmacol. 2023 May 04. pii: S1567-5769(23)00567-2. [Epub ahead of print]119 110246
      Evidence demonstrates that T cells are implicated in developing SLE, and each of them dominantly uses distinct metabolic pathways. Indeed, intracellular enzymes and availability of specific nutrients orchestrate fate of T cells and lead to differentiation of regulatory T cells (Treg), memory T cells, helper T cells, and effector T cells. The function of T cells in inflammatory and autoimmune responses is determined by metabolic processes and activity of their enzymes. Several studies were conducted to determine metabolic abnormalities in SLE patients and clarify how these modifications could control the functions of the involved T cells. Metabolic pathways such as glycolysis, mitochondrial pathways, oxidative stress, mTOR pathway, fatty acid and amino acid metabolisms are dysregulated in SLE T cells. Moreover, immunosuppressive drugs used in treating autoimmune diseases, including SLE, could affect immunometabolism. Developing drugs to regulate autoreactive T cell metabolism could be a promising therapeutic approach for SLE treatment. Accordingly, increased knowledge about metabolic processes paves the way to understanding SLE pathogenesis better and introduces novel therapeutic options for SLE treatment. Although monotherapy with metabolic pathways modulators might not be sufficient to prevent autoimmune disease, they may be an ideal adjuvant to reduce administration doses of immunosuppressive drugs, thus reducing drug-associated adverse effects. This review summarized emerging data about T cells that are involved in SLE pathogenesis, focusing on immunometabolism dysregulation and how these modifications could affect the disease development.
    Keywords:  Autoimmunity; Immunometabolism; SLE T cell; Systemic lupus erythematous
  13. Curr Med Chem. 2023 May 09.
      Identifying metabolic signatures induced by the immune response to vaccines allows to discriminate vaccinated from non-vaccinated subjects and decipher the molecular mechanisms associated with the host immune response. This review illustrates and discusses the results of metabolomics-based studies on the innate and adaptive immune response to vaccines, long-term functional reprogramming (immune memory), and adverse reactions. Glycolysis is not overexpressed by vaccines, suggesting that the immune cell response to vaccinations does not require rapid energy availability as that is necessary during an infection. Vaccines strongly impact lipids metabolism, including saturated or unsaturated fatty acids, inositol phosphate, and cholesterol. Cholesterol is strategic for synthesizing 25-hydroxycholesterol in activated macrophages and dendritic cells and stimulates the conversion of macrophages and T cells in M2 macrophage and Treg, respectively. In conclusion, the large-scale application of metabolomics enables the identification of candidate predictive biomarkers of vaccine efficacy/tolerability.
    Keywords:  immune cells; metabolic reprogramming; metabolomics; system vaccinology; trained immunity; vaccines
  14. Front Immunol. 2023 ;14 1180488
      Innate immune responses to pathogens, mediated by activation of pattern recognition receptors and downstream signal transduction cascades, trigger rapid transcriptional and epigenetic changes to support increased expression of pro-inflammatory cytokines and other effector molecules. Innate immune cells also rapidly rewire their metabolism. The most prominent metabolic alteration following innate immune activation is rapid up-regulation of glycolysis. In this mini-review, we summarize recent advances regarding the mechanisms of rapid glycolytic activation in innate immune cells, highlighting the relevant signaling components. We also discuss the impact of glycolytic activation on inflammatory responses, including the recently elucidated links of metabolism and epigenetics. Finally, we highlight unresolved mechanistic details of glycolytic activation and possible avenues of future research in this area.
    Keywords:  dendritic cell; glycolysis; inflammation; macrophage; metabolism; pattern recognition receptors
  15. Immunol Rev. 2023 May 09.
      The phagocytosis of dying cells by macrophages, termed efferocytosis, is a tightly regulated process that involves the sensing, binding, engulfment, and digestion of apoptotic cells. Efferocytosis not only prevents tissue necrosis and inflammation caused by secondary necrosis of dying cells, but it also promotes pro-resolving signaling in macrophages, which is essential for tissue resolution and repair following injury or inflammation. An important factor that contributes to this pro-resolving reprogramming is the cargo that is released from apoptotic cells after their engulfment and phagolysosomal digestion by macrophages. The apoptotic cell cargo contains amino acids, nucleotides, fatty acids, and cholesterol that function as metabolites and signaling molecules to bring about this re-programming. Here, we review efferocytosis-induced changes in macrophage metabolism that mediate the pro-resolving functions of macrophages. We also discuss various strategies, challenges, and future perspectives related to drugging efferocytosis-fueled macrophage metabolism as strategy to dampen inflammation and promote resolution in chronic inflammatory diseases.
    Keywords:  cell metabolism; efferocytosis; inflammation resolution; macrophages
  16. Dev Comp Immunol. 2023 May 08. pii: S0145-305X(23)00098-8. [Epub ahead of print] 104728
      d-lactate is a metabolite originating from bacterial metabolism that accumulates as a result of dietary disturbances in cattle, leading to ruminal acidosis. d-lactate exerts functions as a metabolic signal inducing metabolic reprogramming and extracellular trap (ET) release in polymorphonuclear leucocytes (PMNs). We previously demonstrated that d-lactate induces metabolic reprogramming via hypoxia-induced factor 1 alpha (HIF-1α) stabilization in bovine fibroblast-like synoviocytes (FLSs). In the present study, the role of HIF-1 in ET formation induced by d-lactate was assessed. HIF-1α stabilization in PMNs was controlled by mitochondrial reactive oxygen species (mtROS) release. Furthermore, inhibition of mitochondrial complex I and scavenging of mtROS decreased d-lactate-triggered ETosis. d-lactate-enhanced HIF-1α accumulation was dependent on the PI3K/Akt pathway but independent of GSK-3β activity. Pharmacological blockade of the PI3K/Akt/HIF-1 and GSK-3β axes inhibited d-lactate-triggered ETosis and downregulated PDK1 and LDHA expression. However, only GSK-3β inhibition decreased the expression of glycogen metabolism enzymes and prevented the decline in glycogen stores induced by d-lactate exposure. The results of this study suggest that mtROS, PI3K/Akt/HIF-1 and GSK-3β axes regulate carbohydrate metabolism adaptations that support d-lactate-induced ET formation in cattle.
    Keywords:  (mt)ROS; Bovine PMN; ETosis; HIF-1; Metabolism; d-lactate
  17. Clin Transl Med. 2023 05;13(5): e1257
      Macrophages are the central immune cells in atherosclerosis (AS) and play a critical role in the initiation, progression and invasion of atherosclerotic plaques. Metabolic reprogramming is a crucial feature that determines macrophage function and is driven by a combination of intrinsic alterations in macrophages and extrinsic factors such as cytokines acting in the plaque microenvironment. Intrinsic macrophage mechanisms activate signal transduction pathways that change metabolic enzyme activity, and the expression of metabolic regulators. Extrinsic signalling mechanisms involve lipids and cytokines in the microenvironment, promoting and amplifying macrophage metabolic reprogramming. This review describes the intrinsic and extrinsic mechanisms driving macrophage metabolic reprogramming in the AS microenvironment and the interplay of these metabolic rewires in the microenvironment. Moreover, we discuss whether targeting these different pathways to treat macrophage microenvironmental changes can alter the fate of the vulnerable plaques.
    Keywords:  atherosclerosis; macrophage; metabolic reprogramming; plaque microenvironment
  18. Oncologist. 2023 May 09. pii: oyad113. [Epub ahead of print]
      AIM: Tumor metabolism plays an important role in tumorigenesis and tumor progression. This study evaluated the potential association of tumor cell metabolism and immune cell tumor infiltration with the clinical course of hepatocellular carcinoma (HCC).METHODS: Gene-wise normalization and principal component analysis were performed to evaluate the metabolic system. A tumor microenvironment score system of tumor immune cell infiltration was constructed to evaluate its association with metabolic subtypes. Finally, we analyzed the impact of metabolism and immune cell infiltration on the clinical course of HCC.
    RESULTS: A total of 673 HCC patients were categorized into cholesterogenic (25.3%), glycolytic (14.6%), mixed (10.4%), and quiescent (49.8%) types based on glycolysis and cholesterol biosynthesis gene expression. The subgroups including the glycolytic genotyping expression (glycolytic and mixed types) showed a higher mortality rate. The glycolytic, cholesterogenic, and mixed types were positively correlated with M0 macrophage, resting mast cell, and naïve B-cell infiltration (P = .013, P = .019, and P = .006, respectively). In TCGA database, high CD8+ T cell and low M0 macrophage infiltration were associated with prolonged overall survival (OS, P = .0017 and P < .0001, respectively). Furthermore, in glycolytic and mixed types, patients with high M0 macrophage infiltration had a shorter OS (P = .03 and P = .013, respectively), and in quiescent type, patients with low naïve B-cell infiltration had a longer OS (P = .007).
    CONCLUSIONS: Tumor metabolism plays a prognostic role and correlates with immune cell infiltration in HCC. M0 macrophage and CD8+ T cell appear to be promising prognostic biomarker for HCC. Finally, M0 macrophages may represent a useful immunotherapeutic target in patients with HCC.
    Keywords:  hepatocellular carcinoma; immune microenvironment; macrophage; metabolic reprogramming; programmed cell death-Ligand 1(PD-L1)
  19. Front Immunol. 2023 ;14 1153915
      Macrophage infiltration into adipose tissue is a key pathological factor inducing adipose tissue dysfunction and contributing to obesity-induced inflammation and metabolic disorders. In this review, we aim to present the most recent research on macrophage heterogeneity in adipose tissue, with a focus on the molecular targets applied to macrophages as potential therapeutics for metabolic diseases. We begin by discussing the recruitment of macrophages and their roles in adipose tissue. While resident adipose tissue macrophages display an anti-inflammatory phenotype and promote the development of metabolically favorable beige adipose tissue, an increase in pro-inflammatory macrophages in adipose tissue has negative effects on adipose tissue function, including inhibition of adipogenesis, promotion of inflammation, insulin resistance, and fibrosis. Then, we presented the identities of the newly discovered adipose tissue macrophage subtypes (e.g. metabolically activated macrophages, CD9+ macrophages, lipid-associated macrophages, DARC+ macrophages, and MFehi macrophages), the majority of which are located in crown-like structures within adipose tissue during obesity. Finally, we discussed macrophage-targeting strategies to ameliorate obesity-related inflammation and metabolic abnormalities, with a focus on transcriptional factors such as PPARγ, KLF4, NFATc3, and HoxA5, which promote macrophage anti-inflammatory M2 polarization, as well as TLR4/NF-κB-mediated inflammatory pathways that activate pro-inflammatory M1 macrophages. In addition, a number of intracellular metabolic pathways closely associated with glucose metabolism, oxidative stress, nutrient sensing, and circadian clock regulation were examined. Understanding the complexities of macrophage plasticity and functionality may open up new avenues for the development of macrophage-based treatments for obesity and other metabolic diseases.
    Keywords:  adipose tissue; macrophages; metabolic diseases; obesity; plasticity
  20. Obesity (Silver Spring). 2023 May 09.
      OBJECTIVE: People with obesity (PWO) have functionally defective natural killer (NK) cells, with a decreased capacity to produce cytokines and kill target cells, underpinned by defective cellular metabolism. It is plausible that the changes in peripheral NK cell activity are contributing to the multimorbidity in PWO, which includes an increased risk of cancer. This study investigated whether therapy with long-acting glucagon-like peptide-1 (GLP-1) analogues, which are an effective treatment for obesity, could restore NK cell functionality in PWO.METHODS: In a cohort of 20 PWO, this study investigated whether 6 months of once weekly GLP-1 therapy (semaglutide) could restore human NK cell function and metabolism using multicolor flow cytometry, enzyme-linked immunosorbent assays, and cytotoxicity assays.
    RESULTS: These data demonstrate that PWO who received GLP-1 therapy have improved NK cell function, as measured by cytotoxicity and interferon-γ/granzyme B production. In addition, the study demonstrates increases in a CD98-mTOR-glycolysis metabolic axis, which is critical for NK cell cytokine production. Finally, it shows that the reported improvements in NK cell function appear to be independent of weight loss.
    CONCLUSIONS: The restoration, by GLP-1 therapy, of NK cell functionality in PWO may be contributing to the overall benefits being seen with this class of medication.
  21. Cell Biosci. 2023 May 10. 13(1): 81
      Nicotinamide adenine dinucleotide (NAD+) is a critical metabolite that acts as a cofactor in energy metabolism, and serves as a cosubstrate for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ metabolism can regulate functionality attributes of innate and adaptive immune cells and contribute to inflammatory responses. Thus, the manipulation of NAD+ bioavailability can reshape the courses of immunological diseases. Here, we review the basics of NAD+ biochemistry and its roles in the immune response, and discuss current challenges and the future translational potential of NAD+ research in the development of therapeutics for inflammatory diseases, such as COVID-19.
    Keywords:  Disease therapy; Immunoregulation; Metabolic homeostasis; Nicotinamide adenine dinucleotide (NAD+); Plasticity
  22. PLoS Pathog. 2023 May 08. 19(5): e1011381
      Inflammasome activation is an essential innate immune defense mechanism against Salmonella infections. Salmonella has developed multiple strategies to avoid or delay inflammasome activation, which may be required for long-term bacterial persistence. However, the mechanisms by which Salmonella evades host immune defenses are still not well understood. In this study, Salmonella Enteritidis (SE) random insertion transposon library was screened to identify the key factors that affect the inflammasome activation. The type I secretion system (T1SS) protein SiiD was demonstrated to repress the NLRP3 inflammasome activation during SE infection and was the first to reveal the antagonistic role of T1SS in the inflammasome pathway. SiiD was translocated into host cells and localized in the membrane fraction in a T1SS-dependent and partially T3SS-1-dependent way during SE infection. Subsequently, SiiD was demonstrated to significantly suppress the generation of mitochondrial reactive oxygen species (mtROS), thus repressing ASC oligomerization to form pyroptosomes, and impairing the NLRP3 dependent Caspase-1 activation and IL-1β secretion. Importantly, SiiD-deficient SE induced stronger gut inflammation in mice and displayed NLRP3-dependent attenuation of the virulence. SiiD-mediated inhibition of NLRP3 inflammasome activation significantly contributed to SE colonization in the infected mice. This study links bacterial T1SS regulation of mtROS-ASC signaling to NLRP3 inflammasome activation and reveals the essential role of T1SS in evading host immune responses.
  23. bioRxiv. 2023 Apr 27. pii: 2023.04.27.538596. [Epub ahead of print]
      Short chain fatty acids (SCFAs) are products of bacterial fermentation that help maintain important gut functions such as the intestinal barrier, signaling, and immune homeostasis. The main SCFAs acetate, propionate, and butyrate have demonstrated beneficial effects for the host, including importance in combatting infections caused by pathogens such as Clostridioides difficile . Despite the potential role of SCFAs in mitigating C. difficile infection, their direct effect on C. difficile remains unclear. Through a set of in vitro experiments, we investigated how SCFAs influence C. difficile growth, sporulation, and toxin production. Similar to previous studies, we observed that butyrate decreased growth of C. difficile strain 630 in a dose-dependent manner. The presence of butyrate also increased C. difficile sporulation, with minimal increases in toxin production. RNA-Seq analysis validated our experimental results, demonstrating increased expression of sporulation-related genes in conjunction with alternative metabolic and related C. difficile regulatory pathways, such as the carbon catabolite repressor, CcpA. Collectively, these data suggest that butyrate may signal alternative C. difficile metabolic pathways, thus modifying its growth and virulence to persist in the gut environment.IMPORTANCE: Several studies suggest that butyrate may be important in alleviating gut infections, such as reducing inflammation caused by the healthcare-associated Clostridioides difficile . While studies in both animal models and human studies correlate high levels of butyrate with reduced C. difficile burden, the direct impact of butyrate on C. difficile remains unclear. Our study demonstrates that butyrate directly influences C. difficile by increasing its sporulation and modifying its metabolism, potentially using butyrate as a biomarker to shift survival strategies in a changing gut environment. These data point to additional therapeutic approaches to combat C. difficile in a butyrate-directed manner.
  24. bioRxiv. 2023 Apr 28. pii: 2023.04.26.538456. [Epub ahead of print]
      Dendritic cells (cDCs) are essential mediators of anti-tumor immunity. Cancers have developed mechanisms to render DCs dysfunctional within the tumor microenvironment. Utilizing CD63 as a unique surface marker, we demonstrate that mature regulatory DCs (mregDCs) suppress DC antigen cross-presentation while driving T H 2 and regulatory T cell differentiation within tumor-draining lymph node tissues. Transcriptional and metabolic studies show that mregDC functionality is dependent upon the mevalonate biosynthetic pathway and the master transcription factor, SREBP2. Melanoma-derived lactate activates DC SREBP2 in the tumor microenvironment (TME) and drives mregDC development from conventional DCs. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promotes anti-tumor CD8 + T cell activation and suppresses melanoma progression. CD63 + mregDCs reside within the sentinel lymph nodes of melanoma patients. Collectively, this work describes a tumor-driven SREBP2-dependent program that promotes CD63 + mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.One Sentence Summary: The metabolic transcription factor, SREBF2, regulates the development and tolerogenic function of the mregDC population within the tumor microenvironment.
  25. Elife. 2023 May 09. pii: e85307. [Epub ahead of print]12
      Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism.Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography-mass spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins.
    Results: CSF tryptophan was associated with 60-day mortality from TBM (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and -positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95% CI = 1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis.
    Conclusions: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy.
    Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).
    Keywords:  central nervous system; cerebrospinal fluid; human; immunology; inflammation; metabolomics; plasma; survival; tuberculous meningitis
  26. bioRxiv. 2023 Apr 26. pii: 2023.04.24.538020. [Epub ahead of print]
      Persistent systemic inflammation in persons with HIV (PWH) is accompanied by an increased risk of metabolic disease. Yet, changes in the innate and adaptive immune system in PWH who develop metabolic disease remain poorly defined. Using unbiased approaches, we show that PWH with prediabetes/diabetes have a significantly higher proportion of circulating CD14 + monocytes complexed to T cells. The complexed CD3 + T cells and CD14 + monocytes demonstrate functional immune synapses, increased expression of proinflammatory cytokines, and greater glucose utilization. Furthermore, these complexes harbor more latent HIV DNA compared to CD14 + monocytes or CD4 + T cells. Our results demonstrate that circulating CD3 + CD14 + T cell-monocyte pairs represent functional dynamic cellular interactions that likely contribute to inflammation and, in light of their increased proportion, may have a role in metabolic disease pathogenesis. These findings provide an incentive for future studies to investigate T cell-monocyte immune complexes as mechanistic in HIV cure and diseases of aging.Highlights: Persons with HIV and diabetes have increased circulating CD3 + CD14 + T cell-monocyte complexes. CD3 + CD14 + T cell-monocytes are a heterogenous group of functional and dynamic complexes. We can detect HIV in T cell-monocyte complexes. The proportion of CD3 + CD14 + T cell-monocyte complexes is positively associated with blood glucose levels and negatively with plasma IL-10 and CD4 + T regulatory cells.
  27. J Agric Food Chem. 2023 May 11.
      Urolithin A (UroA) is a microbial metabolite derived from ellagitannins and ellagic acid with good bioavailability. In this study, we explored the anticolitis activity of UroA and clarified the mechanism by 16S rDNA sequencing and metabonomics. UroA alleviated dextran sulfate sodium (DSS)-induced colitis in mice, characterized by a decreased disease activity index, increased colon length, and improved colonic histopathological lesions, along with inhibited phosphorylation of the mitogen-activated protein kinase signaling pathway. In addition, UroA improved gut microbiota dysbiosis and modulated the microbiota metabolome. Furthermore, targeted metabolomics focused on tryptophan catabolites showed that UroA significantly increased the production of indole-3-aldehyde (IAld) and subsequently led to increased colonic expression of aryl hydrocarbon receptor (AhR) and promoted the serum content of IL-22 in mice with colitis. Collectively, our data identified a novel anticolitis mechanism of UroA by improving gut microbiota dysbiosis, modulating microbial tryptophan metabolism, promoting IAld production, and triggering AhR/IL-22 axis activation. However, a limitation noted in this study is that these beneficial effects of UroA were found at 50 μM in vitro and 20 mg/kg in vivo, which were nonphysiological concentrations.
    Keywords:  aromatic hydrocarbon receptor; colitis; gut microbiota; metabolome; microbial tryptophan catabolites; urolithin A