bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2023‒01‒29
twenty-six papers selected by
Dylan Ryan
University of Cambridge

  1. Immunity. 2023 Jan 18. pii: S1074-7613(22)00675-6. [Epub ahead of print]
      Neuronal signals have emerged as pivotal regulators of group 2 innate lymphoid cells (ILC2s) that regulate tissue homeostasis and allergic inflammation. The molecular pathways underlying the neuronal regulation of ILC2 responses in lungs remain to be fully elucidated. Here, we found that the abundance of neurotransmitter dopamine was negatively correlated with circulating ILC2 numbers and positively associated with pulmonary function in humans. Dopamine potently suppressed lung ILC2 responses in a DRD1-receptor-dependent manner. Genetic deletion of Drd1 or local ablation of dopaminergic neurons augmented ILC2 responses and allergic lung inflammation. Transcriptome and metabolic analyses revealed that dopamine impaired the mitochondrial oxidative phosphorylation (OXPHOS) pathway in ILC2s. Augmentation of OXPHOS activity with oltipraz antagonized the inhibitory effect of dopamine. Local administration of dopamine alleviated allergen-induced ILC2 responses and airway inflammation. These findings demonstrate that dopamine represents an inhibitory regulator of ILC2 responses in allergic airway inflammation.
    Keywords:  DRD1; allergic airway inflammation; dopamine; group 2 innate lymphoid cells; neuroimmune interaction
  2. Cell Rep. 2023 Jan 27. pii: S2211-1247(23)00057-8. [Epub ahead of print]42(2): 112046
    ImmGen Consortium
      The diversity of mononuclear phagocyte (MNP) subpopulations across tissues is one of the key physiological characteristics of the immune system. Here, we focus on understanding the metabolic variability of MNPs through metabolic network analysis applied to three large-scale transcriptional datasets: we introduce (1) an ImmGen MNP open-source dataset of 337 samples across 26 tissues; (2) a myeloid subset of ImmGen Phase I dataset (202 MNP samples); and (3) a myeloid mouse single-cell RNA sequencing (scRNA-seq) dataset (51,364 cells) assembled based on Tabula Muris Senis. To analyze such large-scale datasets, we develop a network-based computational approach, genes and metabolites (GAM) clustering, for unbiased identification of the key metabolic subnetworks based on transcriptional profiles. We define 9 metabolic subnetworks that encapsulate the metabolic differences within MNP from 38 different tissues. Obtained modules reveal that cholesterol synthesis appears particularly active within the migratory dendritic cells, while glutathione synthesis is essential for cysteinyl leukotriene production by peritoneal and lung macrophages.
    Keywords:  CP: Immunology; CP: Metabolism; ImmGen; immunometabolism; mononuclear phagocytes; myeloid cells; network analysis; single-cell RNA-seq
  3. Biochim Biophys Acta Mol Basis Dis. 2023 Jan 24. pii: S0925-4439(23)00022-4. [Epub ahead of print] 166656
      Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide. Immune response gene 1 (IRG1) catalyzes the production of bio-active itaconate, which is actively involved in the regulation of signal transduction. A recent study has found that the expression of IRG1 was significantly down-regulated in obesity-associated fatty liver, but the potential roles of IRG1 in the development NAFLD remain unclear. The present study found that genetic deletion of IRG1 aggravated high fat diet (HFD)-induced metabolic disturbance, including obesity, dyslipidemia and insulin resistance. In addition, HFD induced more severe liver steatosis and higher serum ALT and AST level in IRG1 KO mice, which were accompanied with altered expression of genes involved in lipid uptake, synthesis and catabolism. RNA-seq and immunoblot analysis indicated that deficiency of IRG1 is associated with suppressed activation of AKT, a master metabolic regulator. Mechanistically, IRG1/itaconate enhanced the antioxidative NRF2 pathway and prevented redox-sensitive suppression of AKT. Interestingly, supplementation with 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, alleviated HFD-induced oxidative stress, AKT suppression and liver steatosis. Therefore, IRG1 probably functions as a protective regulator in the development of NAFLD and the cell-permeable 4-OI might have potential value for the pharmacological intervention of NAFLD.
    Keywords:  AKT; Immune responsive gene 1; Itaconate; NRF2; Nonalcoholic fatty liver disease
  4. Nat Commun. 2023 Jan 25. 14(1): 399
      Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid infection model revealed that HIV infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of caspase-1, IL-1β, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (TregDys)/T helper 17 (Th17) cell ratios. Blockade of caspase-1 and polyamine synthesis intermediates reversed the TregDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 infection. Lastly, oral mucosal TregDys/Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and Treg dysfunction.
  5. Cell Signal. 2023 Jan 18. pii: S0898-6568(23)00020-7. [Epub ahead of print] 110606
      Metabolic reprogramming of macrophages initiates the polarization of pro-inflammatory macrophages that exacerbates adipocyte dysfunction and obesity. The imbalance of mitochondrial Ca2+ homeostasis impairs mitochondrial function and promotes inflammation. Connexin 43 (Cx43), a ubiquitous gap junction protein, has been demonstrated to regulate intracellular Ca2+ homeostasis. Here we explored whether macrophage Cx43 affects the obesity process by regulating the polarization of macrophage. HFD treatment induced obesity and exacerbated macrophages infiltration with upregulation of macrophages Cx43. Macrophage-specific knockout of Cx43 reduced HFD-induced obesity by alleviating inflammation in adipose tissue, with less pro-inflammatory M1 macrophage infiltration. Consistently, inhibition or knockdown of Cx43 improved palmitic acid (PA) induced mitochondrial dysfunction, as indicated by improved oxidative phosphorylation (OXPHOS), reduced formation of mitochondria-associated membranes (MAM) and mitochondrial Ca2+ overload. Mechanistically, Cx43 interacted with the mitochondrial Ca2+ uniporter (MCU) and knockdown of Cx43 alleviated PA-induced succinate dehydrogenase (SDH) oxidation by lowering MCU-mediated mitochondrial Ca2+ uptake, which then, promoting the polarization of pro-inflammatory M1 macrophages. Thus, this study identified Cx43 as a mitochondrial Ca2+ regulator that aggravates obesity via promoting macrophages polarized to M1 pro-inflammatory phenotype and suggests that Cx43 might be a promising therapeutic target antagonizing obesity.
    Keywords:  Cx43; Inflammation; Macrophage polarization; Mitochondrial Ca(2+) overload; Obesity
  6. Cytokine Growth Factor Rev. 2023 Jan 18. pii: S1359-6101(23)00001-1. [Epub ahead of print]
      Th17-polarized CD4+ effector T-cells together with their immunosuppressive regulatory T-cell (Treg) counterparts, with transcriptional profiles governed by the lineage transcription factors RORγt/RORC2 and FOXP3, respectively, are important gatekeepers at mucosal interfaces. Alterations in the Th17/Treg ratios, due to the rapid depletion of Th17 cells and increased Treg frequencies, are a hallmark of both HIV and SIV infections and a marker of disease progression. The shift in Th17/Treg balance, in favor of increased Treg frequencies, contributes to gut mucosal permeability, immune dysfunction, and microbial translocation, subsequently leading to chronic immune activation/inflammation and disease progression. Of particular interest, Th17 cells and Tregs share developmental routes, with changes in the Th17 versus Treg fate decision influencing the pro-inflammatory versus anti-inflammatory responses. The differentiation and function of Th17 cells and Tregs rely on independent yet complementary metabolic pathways. Several pathways have been described in the literature to be involved in Th17 versus Treg polarization, including 1) the activity of ectonucleotidases CD39/CD73; 2) the increase in TGF-β1 production; 3) a hypoxic environment, and subsequent upregulation in hypoxia-inducible factor-1α (HIF-1α); 4) the increased mTOR activity and glycolysis induction; 5) the lipid metabolism, including fatty acid synthesis, fatty acids oxidation, cholesterol synthesis, and lipid storage, which are regulated by the AMPK, mevalonate and PPARγ pathways; and 6) the tryptophan catabolism. These metabolic pathways are understudied in the context of HIV-1 infection. The purpose of this review is to summarize the current knowledge on metabolic pathways that are dysregulated during HIV-1 infection and their impact on Th17/Treg balance.
    Keywords:  AMPK; CD39; CD73; Ectonucleotidases; Glycolysis; HIF-1α; HIV; Hypoxia; IDO-1; Immunometabolism; MTOR; PPAR-γ; Regulatory T-cells (Tregs); TGF-β1; Th17 cells; Tryptophan
  7. J Virol. 2023 Jan 23. e0136322
      Viral infections alter host cell metabolism and homeostasis; however, the mechanisms that regulate these processes have only begun to be elucidated. We report here that Zika virus (ZIKV) infection activates the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2), which precedes oxidative stress. Downregulation of Nrf2 or inhibition of glutathione (GSH) synthesis resulted in significantly increased viral replication. Interestingly, 6-amino-nicotinamide (6-AN), a nicotinamide analog commonly used as an inhibitor of the pentose phosphate pathway (PPP), decreased viral replication by over 1,000-fold. This inhibition was neither recapitulated by the knockdown of PPP enzymes, glucose 6-phosphate dehydrogenase (G6PD), or 6-phosphogluconate dehydrogenase (6PGD), nor prevented by supplementation with ribose 5-phosphate. Instead, our metabolomics and metabolic phenotype studies support a mechanism in which 6-AN depletes cells of NAD(H) and impairs NAD(H)-dependent glycolytic steps resulting in inhibition of viral replication. The inhibitory effect of 6-AN was rescued with precursors of the salvage pathway but not with those of other NAD+ biosynthesis pathways. Inhibition of glycolysis reduced viral protein levels, which were recovered transiently. This transient recovery in viral protein synthesis was prevented when oxidative metabolism was inhibited by blockage of the mitochondrial pyruvate carrier, fatty acid oxidation, or glutaminolysis, demonstrating a compensatory role of mitochondrial metabolism in ZIKV replication. These results establish an antagonistic role for the host cell Nrf2/GSH/NADPH-dependent antioxidant response against ZIKV and demonstrate the dependency of ZIKV replication on NAD(H). Importantly, our work suggests the potential use of NAD(H) antimetabolite therapy against the viral infection. IMPORTANCE Zika virus (ZIKV) is a major public health concern of international proportions. While the incidence of ZIKV infections has declined substantially in recent years, the potential for the reemergence or reintroduction remains high. Although viral infection alters host cell metabolism and homeostasis to promote its replication, deciphering the mechanism(s) involved in these processes is important for identifying therapeutic targets. The present work reveals the complexities of host cell redox regulation and metabolic dependency of ZIKV replication. An antagonistic effect of the Nrf2/GSH/NADP(H)-dependent antioxidant response against ZIKV infection and an essential role of NAD(H) metabolism and glycolysis for viral replication are established for the first time. These findings highlight the potential use of NAD(H) antimetabolites to counter ZIKV infection and pathogenesis.
    Keywords:  6-AN; GSH; Nrf2; Zika virus; oxidative stress; pentose phosphate pathway
  8. J Mycol Med. 2023 Jan 16. pii: S1156-5233(23)00003-3. [Epub ahead of print]33(2): 101359
      The overuse of antifungal and immunosuppressant drugs and the higher frequency of organ transplantation has resulted in mycosis being increasingly intractable, and there is a great need for the development of new therapies. Melanin is an important virulence factor that can inhibit the inflammatory response in the host and facilitate fungal survival by several methods. However, a recent study showed that the Akt/mTOR/HIF1α axis in macrophages was activated after melanin-binding proteins recognised the DHN melanin of Aspergillus fumigatus, with a resulting metabolic shift towards glycolysis (i.e., metabolic reprogramming). As a result, antimicrobial compounds (e.g., inflammatory mediators and reactive oxygen species) were increased to fight the fungal invasion. Actually, DHN melanin from other fungi and DOPA melanin can induce inflammation and stimulate the production of melanin-binding antibodies. In addition, DOPA melanin contains conserved repeating units that are similar to those of DHN melanin. Therefore, we evaluated the associated evidence to propose an interesting and reasonable hypothesis that melanin promotes inflammation by metabolic reprogramming, which could provide a research direction for antifungal therapy. It suggests that regulating the metabolism of immune cells can guide the inflammatory response against fungi, despite the presence of immunosuppressant melanin. Since the biochemical molecules of glycolysis are clearly described, regulating glycolysis in macrophages may be easier than inventing new antifungal drugs. Further clarification of our hypothesis may strengthen the candidacy of melanin for future antifungal vaccines.
    Keywords:  DHNmelanin; DOPA melanin; Glycolysis; Immunometabolism; Inflammation; Metabolic reprogramming
  9. Mol Ther. 2023 Jan 24. pii: S1525-0016(23)00018-7. [Epub ahead of print]
      Sepsis, a critical condition resulting from the systemic inflammatory response to severe microbial infection, represents a global public health challenge. However, effective treatment or intervention to prevent and combat sepsis is still lacking. Here, we reported that hyodeoxycholic acid (HDCA) has excellent anti-inflammatory properties in sepsis. We discovered that the plasma concentration of HDCA was remarkably lower in patients with sepsis and negatively correlated with the severity of the disease. Similar changes in HDCA levels in plasma and cecal contents samples were observed in a mouse model of sepsis, and these changes were associated with a reduced abundance of HDCA-producing strains. Interestingly, HDCA administration significantly decreased systemic inflammatory responses, prevented organ injury, and prolonged the survival of septic mice. We demonstrated that HDCA suppressed excessive activation of inflammatory macrophages via competitively blocking lipopolysaccharide (LPS) binding to toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 (MD2) receptor complex, a unique mechanism that characterizes HDCA as an endogenous inhibitor of inflammatory signaling. Additionally, we verified these findings in TLR4 knockout mice. Our study highlights the potential value of HDCA as a therapeutic molecule for sepsis.
  10. J Immunol. 2023 Jan 25. pii: ji2200746. [Epub ahead of print]
      Besides antiviral functions, type I IFN expresses potent anti-inflammatory properties and is being widely used to treat certain autoimmune conditions, such as multiple sclerosis. In a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis, administration of IFN-β effectively attenuates the disease development. However, the precise mechanisms underlying IFN-β-mediated treatment remain elusive. In this study, we report that IFN-induced protein with tetratricopeptide repeats 2 (Ifit2), a type I and type III IFN-stimulated gene, plays a previously unrecognized immune-regulatory role during autoimmune neuroinflammation. Mice deficient in Ifit2 displayed greater susceptibility to experimental autoimmune encephalomyelitis and escalated immune cell infiltration in the CNS. Ifit2 deficiency was also associated with microglial activation and increased myeloid cell infiltration. We also observed that myelin debris clearance and the subsequent remyelination were substantially impaired in Ifit2-/- CNS tissues. Clearing myelin debris is an important function of the reparative-type myeloid cell subset to promote remyelination. Indeed, we observed that bone marrow-derived macrophages, CNS-infiltrating myeloid cells, and microglia from Ifit2-/- mice express cytokine and metabolic genes associated with proinflammatory-type myeloid cell subsets. Taken together, our findings uncover a novel regulatory function of Ifit2 in autoimmune inflammation in part by modulating myeloid cell function and metabolic activity.
  11. Curr Opin Plant Biol. 2023 Jan 24. pii: S1369-5266(22)00163-7. [Epub ahead of print]73 102334
      Toll and interleukin-1 receptor (TIR) domain is a conserved immune module in prokaryotes and eukaryotes. Signaling regulated by TIR-only proteins or TIR domain-containing intracellular immune receptors is critical for plant immunity. Recent studies demonstrated that TIR domains function as enzymes encoding a variety of activities, which manifest different mechanisms for regulation of plant immunity. These enzymatic activities catalyze metabolism of NAD+, ATP and other nucleic acids, generating structurally diversified nucleotide metabolites. Signaling roles have been revealed for some TIR enzymatic products that can act as second messengers to induce plant immunity. Herein, we summarize our current knowledge about catalytic production of these nucleotide metabolites and their roles in plant immune signaling. We also highlight outstanding questions that are likely to be the focus of future investigations about TIR-produced signaling molecules.
    Keywords:  2’,3’-cAMP/cGMP synthetases; ADP-ribose transferase; Nucleotide metabolites; Plant immunity; Second messengers; TIR NADases
  12. Arthritis Rheumatol. 2023 Jan 27.
      OBJECTIVES: Rheumatoid arthritis (RA) CD8+ T-cells (CD8) maintain their effector pro-inflammatory phenotype by changing their metabolism towards aerobic glycolysis. However, their massive energetic and biosynthetic needs may require additional substrates other than glucose. Since systemic alterations in lipid metabolism have been reported in RA patients, we explored the role of fatty acid (FA) metabolism in CD8 to identify potential targets to curb their pro-inflammatory potential.METHODS: The expression of FA metabolism-related genes was analyzed for total and CD8-subsets in the data of RA patients and healthy controls retrieved from the gene expression omnibus database. Functional assays were performed on peripheral-blood CD8 isolated from RA (n=31), PsA (n=26), and SpA (n=21) patients under different therapies (DMARD, biologicals, and JAK inhibitors) and controls (n=13). We quantified the expression of FA transporters, lipid uptake, intracellular FA content, cytokine production, activation, proliferation, and capacity to inhibit tumor cell growth, either with or without FA metabolism inhibitors.
    RESULTS: The CD8 gene expression profile of FA metabolism-related genes was significantly different between untreated RA patients and controls. RA patients with a good clinical response after 6 months MTX therapy significantly increased the expression of FA metabolism-related genes. Cell-surface expression of FA transporters FABP4 and GPR84 and FA uptake was higher in effector and memory CD8 of RA patients than for controls. In vitro blockade of FA metabolism significantly impaired CD8 effector functions.
    CONCLUSIONS: RA CD8 present an altered FA metabolism which can provide potential therapeutic targets to control the pro-inflammatory profile. Particularly, therapies directed against the transport and oxidation of free FA.
  13. Immunology. 2023 Jan 28.
      The NLRP3 inflammasome plays a crucial role in innate immunity and is involved in the pathogenesis of autoinflammatory diseases. Glycolysis regulates NLRP3 inflammasome activation in macrophages. However, how lactic acid fermentation and pyruvate oxidation controlled by the mitochondrial pyruvate carrier (MPC) affect NLRP3 inflammasome activation and autoinflammatory disease remains elusive. We found that inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC-0160 or pioglitazone, increased NLRP3 inflammasome activation and IL-1β secretion in macrophages. Glycolytic reprogramming induced by MPC inhibition skewed mitochondrial ATP-associated oxygen consumption into cytosolic lactate production, which enhanced NLRP3 inflammasome activation in response to monosodium urate (MSU) crystals. As pioglitazone is an insulin sensitizer used for diabetes, its MPC inhibitory effect in diabetic individuals was investigated. The results showed that MPC inhibition exacerbated MSU-induced peritonitis in diabetic mice and increased the risk of gout in patients with diabetes. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3-related autoinflammatory diseases. This article is protected by copyright. All rights reserved.
    Keywords:  Gout; Mitochondrial pyruvate carrier; NLRP3 inflammasome; Pioglitazone
  14. Cell Mol Gastroenterol Hepatol. 2023 Jan 24. pii: S2352-345X(23)00004-8. [Epub ahead of print]
      OBJECTIVE & AIMS: Many studies have revealed crucial roles of the gut microbiota and its metabolites in liver disease progression. However, the mechanism underlying their effects on liver ischemia/reperfusion (I/R) injury remain largely unknown. Here, we investigate the function of gut microbiota and its metabolites in liver I/R injury.METHODS: C57BL/6 mice was pretreated with an antibiotic cocktail. Then, we used multi-omics detection methods including 16s rRNA sequencing, ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) to explore the changes of gut microbiota and metabolites both in feces and portal blood in order to reveal the mechanism of their protective effect in liver I/R injury.
    RESULTS: We found that antibiotic pretreatment (ABX) could significantly reduce the severity of I/R-induced hepatic injury, and this effect could be transferred to germ-free (GF) mice by fecal microbiota transplantation (FMT), suggesting a protective role of the gut microbiota depletion. During I/R, the rates of serum α-ketoglutarate (aKG) production and glutamate reduction, downstream products of gut microbiota-derived glutamine were more significant in the ABX mice. Then, we showed that aKG could promote alternative (M2) macrophage activation through oxidative phosphorylation (OXPHOS) and Oligomycin A could inhibit M2 macrophage polarization and reversed this protective effect.
    CONCLUSIONS: These findings show that the gut microbiota and its metabolites play critical roles in hepatic I/R injury by modulating macrophage metabolic reprogramming. Potential therapies that target macrophage metabolism, including antibiotic therapies and novel immunometabolism modulators can be exploited for the treatment of liver I/R injury.
    Keywords:  Liver ischemia/reperfusion injury; a-ketoglutarate; glutamine; immunometabolism; macrophage reprogramming; microbiota
  15. Mitochondrion. 2023 Jan 20. pii: S1567-7249(23)00005-3. [Epub ahead of print]
      Mitochondria play a central role in oxidative phosphorylation (OXPHOS), bioenergetics linked with ATP production, fatty acids biosynthesis, calcium signaling, cell cycle regulation, apoptosis, and innate immune response. Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infection manipulates the host cellular machinery for its survival and replication in the host cell. The infectiaon causes perturbed the cellular metabolism that favours viral replication leading to mitochondrial dysfunction and chronic inflammation. By localizing to the mitochondria, SARS CoV proteins increase reactive oxygen species (ROS) levels, perturbation of Ca2+ signaling, changes in mtDNA copy number, mitochondrial membrane potential (MMP), mitochondrial mass, and induction of mitophagy. These proteins also influence the fusion and fission kinetics, size, structure, and distribution of mitochondria in the infected host cells. This results in compromised bioenergetics, altered metabolism, and innate immune signaling, and hence can be a key player in determining the outcome of SARS-CoV infection. SARS-CoV infection contributes to stress and activates apoptotic pathways. This review summarizes how mitochondrial function and dynamics are affected by SARS-CoV and how the mitochondria-SARS-CoV interaction benefits viral survival and growth by evading innate host immunity. We also highlight how the SARS-CoV-mediated mitochondrial dysfunction contributes to post-COVID complications. Besides, a discussion on targeting virus-mitochondria interactions as a therapeutic strategy is presented.
    Keywords:  CoV; Mitochondria; Mitochondrial localization signal; ROS; SARS; Virus
  16. Clin Biochem. 2023 Jan 18. pii: S0009-9120(23)00007-3. [Epub ahead of print]114 1-10
      OBJECTIVES: Primary Sjögren's syndrome (pSS) is an autoinflammatory disease characterized by inflammation of the exocrine glands. Elevated inflammation causes an increase in kynurenine pathway (KP) metabolite levels by activating indoleamine 2,3-dioxygenase (IDO). The aim of this study was to measure serum KP metabolite concentrations in patients with pSS and to evaluate the relationship between these metabolites with disease activity score and clinical manifestations.DESIGN & METHODS: A total of 80 patients with pSS and 80 healthy controls were enrolled in this study. Serum tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA), 3-hydroxykynurenine (3HK), quinolinic acid (QUIN) concentrations were quantified with liquid chromatography with tandem mass spectrometry (LC-MS/MS). Demographic characteristics, clinical manifestations and disease activity score (ESSDAI) of the participants were recorded.
    RESULTS: The serum level of KYN and QUIN were significantly higher in patients with pSS with low and moderate activity compared those healthy controls, while the serum level of TRP, KYNA/KYN and 3HK/KYN were lower. In addition, the significant difference for the serum level of KYNA was only in patients with moderate activity from healthy controls, and the difference was higher in favor of pSS patients. Moreover, the KYN/TRP levels were significantly increased with disease activity. The ESSDAI score was positively correlated with KYN/TRP ratio, but negatively correlated with KYNA/KYN ratio.
    CONCLUSIONS: These findings indicated that KP metabolites may play a role in the etiopathogenesis, activation and progression of pSS.
    Keywords:  Immunomudulatory; Inflammation; Kynurenine pathway; Primary Sjögren’s syndrome
  17. Biochem Biophys Res Commun. 2023 Jan 13. pii: S0006-291X(23)00069-4. [Epub ahead of print]645 47-54
      Interleukin (IL)-31 is a recently-identified cytokine with a well-defined role in the pathogenesis of pruritus. Previously, we reported that adenosine upregulates IL-17A secretion by T-helper (Th)17 cells; however, the effect of adenosine on T cell subsets other than Th17 remains unclear. In this report, we show that adenosine upregulated production of IL-31 by cluster of differentiation (CD)4+ T cells. IL-31 was also upregulated by administration of an adenosine A2a receptor (A2aR) agonist (PSB0777), and adenosine-mediated IL-31 production was inhibited by an A2aR antagonist (istradefylline). Production of Th2-related cytokines (IL-4, IL-10, and IL-13) by CD4+ T cells showed the same tendency. Immune subset analyses revealed that adenosine upregulated IL-31 secretion by CD4+ chemokine receptor 3high T cells, and that Th2 cells differentiated from naïve CD4+ T cells. Administration of istradefylline to mice with atopic dermatitis suppressed the symptoms, suggesting that A2aR antagonists are an effective treatment for inflammatory dermatitis. Taken together, the results indicate that adenosine upregulates secretion of Th2-related cytokines by effector T cells in the skin, thereby triggering atopic dermatitis and associated pruritus.
    Keywords:  A2a receptor; Adenosine; Allergy; Atopic dermatitis; CD4(+) T cells; IL-31
  18. Int Immunopharmacol. 2023 Jan 25. pii: S1567-5769(23)00062-0. [Epub ahead of print]116 109739
      Dendritic cells (DCs) play pivotal roles in immune responses. The differentiation and function of DCs are regulated by environmental metabolites. Putrescine is ubiquitous in various metabolic microenvironments and its immunoregulation has been of increasing interest. However, the mechanisms associated with its DC-induced immunoregulation remain unclear. In this study, we found putrescine promoted induction of immature bone marrow derived DCs (BMDCs), along with the increased phagocytosis and migration, and altered cytokine secretion in immature BMDCs. Transcriptomic profiles indicated significantly impaired inflammatory-related pathways, elevated oxidative phosphorylation, and decreased p-STAT3 (Tyr705) expression. Additionally, putrescine performed minor influence on the lipopolysaccharide (LPS)-induced maturation of BMDCs but significantly impaired LPS-induced DC-elicited allogeneic T-cell proliferation as well as the cytokine secretion. Furthermore, molecular docking and dynamics on the conjugation between putrescine and STAT3 revealed that putrescine could be stably bound to the hydrophilic cavity in STAT3 and performed significant influence on the Tyr705 phosphorylation. CUT&Tag analysis uncovered altered motifs, downregulated IFN-γ response, and upregulated p53 pathway in Putrescine group compared with Control group. In summary, our results demonstrated for the first time that putrescine might accelerate the differentiation of BMDCs by inhibiting the phosphorylation of STAT3 at Tyr705. Given that both DCs and putrescine have ubiquitous and distinct roles in various immune responses and pathogeneses, our findings may provide more insights into polyamine immunoregulation on DCs, as well as distinct strategies in the clinical utilization of DCs by targeting polyamines.
    Keywords:  DC; Mitochondrial respiratory activity; Putrescine; STAT3; Th2 response
  19. Nat Commun. 2023 Jan 26. 14(1): 422
      The ubiquitous pathogen Toxoplasma gondii has a complex lifestyle with different metabolic activities at different stages that are intimately linked to the parasitic environments. Here we identified the eukaryotic regulator of cellular homeostasis AMP-activated protein kinase (AMPK) in Toxoplasma and discovered its role in metabolic programming during parasite's lytic cycle. The catalytic subunit AMPKα is quickly phosphorylated after the release of intracellular parasites to extracellular environments, driving energy-producing catabolism to power parasite motility and invasion into host cells. Once inside host cells, AMPKα phosphorylation is reduced to basal level to promote a balance between energy production and biomass synthesis, allowing robust parasite replication. AMPKγ depletion abolishes AMPKα phosphorylation and suppresses parasite growth, which can be partially rescued by overexpressing wildtype AMPKα but not the phosphorylation mutants. Thus, through the cyclic reprogramming by AMPK, the parasites' metabolic needs at each stage are satisfied and the lytic cycle progresses robustly.
  20. BMC Infect Dis. 2023 Jan 23. 23(1): 42
      BACKGROUND: Coronavirus disease 2019 is a type of acute infectious pneumonia and frequently confused with influenza since the initial symptoms. When the virus colonized the patient's mouth, it will cause changes of the oral microenvironment. However, few studies on the alterations of metabolism of the oral microenvironment affected by SARS-CoV-2 infection have been reported. In this study, we explored metabolic alterations of oral microenvironment after SARS-CoV-2 infection.METHODS: Untargeted metabolomics (UPLC-MS) was used to investigate the metabolic changes between oral secretion samples of 25 COVID-19 and 30 control participants. To obtain the specific metabolic changes of COVID-19, we selected 25 influenza patients to exclude the metabolic changes caused by the stress response of the immune system to the virus. Multivariate analysis (PCA and PLS-DA plots) and univariate analysis (students' t-test) were used to compare the differences between COVID-19 patients and the controls. Online hiplot tool was used to perform heatmap analysis. Metabolic pathway analysis was conducted by using the MetaboAnalyst 5.0 web application.
    RESULTS: PLS-DA plots showed significant separation of COVID-19 patients and the controls. A total of 45 differential metabolites between COVID-19 and control group were identified. Among them, 35 metabolites were defined as SARS-CoV-2 specific differential metabolites. Especially, the levels of cis-5,8,11,14,17-eicosapentaenoic acid and hexanoic acid changed dramatically based on the FC values. Pathway enrichment found the most significant pathways were tyrosine-related metabolism. Further, we found 10 differential metabolites caused by the virus indicating the body's metabolism changes after viral stimulation. Moreover, adenine and adenosine were defined as influenza virus-specific differential metabolites.
    CONCLUSIONS: This study revealed that 35 metabolites and tyrosine-related metabolism pathways were significantly changed after SARS-CoV-2 infection. The metabolic alterations of oral microenvironment in COVID-19 provided new insights into its molecular mechanisms for research and prognostic treatment.
    Keywords:  COVID-19; Influenza; Metabolic pathways; Metabolomics; Oral microenvironment
  21. Biochem Biophys Res Commun. 2022 Dec 29. pii: S0006-291X(22)01748-X. [Epub ahead of print]646 19-29
      There is a trend of increasing young cases with gastric cancer globally. Sensitive early diagnosis methods and new therapeutic approaches are still the focus of clinical diagnosis and therapy of gastric cancer. USP14 plays an extensive role in tumor malignancy and fat metabolism regulation. However, researchers still have gaps in their knowledge of its substrates, which makes it difficult for deubiquitinases to become clinical targets. TAMs were isolated from tumor or polarized from primary THP1 cells by tumors cell lines under the control of IU1 and FAO inhibitor therapy. Cytokines controlled macrophages were compared to evaluate the capability to induce USP14 expression. Fatty acid uptake assay and OCR measurement were used to analyze macrophage metabolism. USP14 is found the correlation with tumor poor prognosis and poor immunophenotype in gastric cancer patients and mouse tumor models. Activation of USP14 determines elevated protein stability of SIRT1 and is required for activation of macrophage fatty acid oxidation and immunosuppressive phenotype. Although overexpression of USP14 is not sufficient to polarize macrophages to the M2 phenotype, inhibition of USP14 by IU1 in tumor-bearing mice disrupts the suppressive activity of cancer-promoting macrophages and effectively reshapes immune microenvironment characteristics. Our study provides evidence that a novel therapeutic strategy that targets to lipid metabolism of macrophages in tumors could be a potential option for emerging treatments for gastric cancer.
    Keywords:  Fatty acid oxidation; Gastric cancer (GC); Immunotherapy; Macrophage polarization; USP14
  22. Front Immunol. 2022 ;13 1113924
      Unique patterns of response to immune checkpoint inhibitor therapy, discernable in the earliest clinical trials, demanded a reconsideration of the standard methods of radiological treatment assessment. Immunomonitoring, that characterizes immune responses, offers several significant advantages over the tumor-centric approach currently used in the clinical practice: 1) better understanding of the drugs' mechanism of action and treatment resistance, 2) earlier assessment of response to therapy, 3) patient/therapy selection, 4) evaluation of toxicity and 5) more accurate end-point in clinical trials. PET imaging in combination with the right agent offers non-invasive tracking of immune processes on a whole-body level and thus represents a method uniquely well-suited for immunomonitoring. Small molecule metabolic tracers, largely neglected in the immuno-PET discourse, offer a way to monitor immune responses by assessing cellular metabolism known to be intricately linked with immune cell function. In this review, we highlight the use of small molecule metabolic tracers in imaging immune responses, provide a view of their value in the clinic and discuss the importance of image analysis in the context of tracking a moving target.
    Keywords:  Immunotherapy; Metabolism; PET; T cells; Treatment response
  23. Respir Res. 2023 Jan 27. 24(1): 33
      Pulmonary inflammation involves complex changes of the immune cells, in which macrophages play important roles and their function might be influenced by metabolism. Slc38a6 acts as a carrier of nutrient for macrophages (Mφ) to exert the function. In this study, pneumonia patient blood was found up-regulated SLC38A6 expression, which correlated with monocytes number and white blood cell number. The similar result was also shown in LPS induced sepsis mice. To reveal the key role of Slc38a6, we used systemic and conditional knock-out mice. Either systemic or LyzCRE specific knock-out could alleviate the severity of sepsis mice, reduce the proinflammatory cytokine TNF-α and IL-1β expression in serum and decrease the monocytes number in bronchial alveolar lavage and peritoneal lavage via flow cytometry. In order to reveal the signal of up-regulated Slc38a6, the Tlr4 signal inhibitor TAK242 and TLR4 knock-out mice were used. By blocking Tlr4 signal in macrophages via TAK242, the expression of Slc38a6 was down-regulated synchronously, and the same results were also found in Tlr4 knock-out macrophages. However, in the overexpressed Slc38a6 macrophages, blocking Tlr4 signal via TAK242, 20% of the mRNA expression of IL-1β still could be expressed, indicating that up-regulated Slc38a6 participates in IL-1β expression process. Collectively, it is the first time showed that an amino acid transporter SLC38A6 up-regulated in monocytes/macrophages promotes activation in pulmonary inflammation. SLC38A6 might be a promising target molecule for pulmonary inflammation treatment.
    Keywords:  IL-1β; Macrophage activation; Pulmonary inflammation; SLC38A6
  24. Mucosal Immunol. 2023 Jan 20. pii: S1933-0219(23)00004-1. [Epub ahead of print]
      Gastrointestinal nematode infections cause morbidity and socio-economic loss in the most deprived communities. The shift in context of obesity has led to spatial overlap with endemic gastrointestinal nematode regions resulting in the emergence of a novel comorbidity. Despite this, the impact of high fat diet (HFD) on immune-regulated protection against gastrointestinal infections remains largely unknown. We employed the murine model of nematode infection, Trichuris muris, to investigate the effect of a HFD on the immune response against chronic infection. Surprisingly, diet induced obesity drove parasite expulsion in both single and repeated trickle low doses of T. muris eggs. Mechanistically, a HFD increased expression of the ST2 receptor on CD4+ T-cells priming an enhanced Th2 cytokine production following IL-33 stimulation ex vivo. Despite IL-33-/- mice demonstrating that IL-33 is not critical for host protective immunity to T. muris under a conventional diet, HFD fed T-cell deplete mice adoptively transferred with ST2-/- CD4 T-cells were unable to expel a T. muris infection unlike those transferred with ST2 sufficient cells. Collectively, this study demonstrates a HFD primes CD4+ T-cells to utilise the IL-33-ST2 axis in a novel induction of Type 2 immunity, providing insights into the emerging comorbidities of obesity and nematode infection.
    Keywords:  Diet; Helminth; IL-33; Intestine; T-cell
  25. Int Immunopharmacol. 2023 Jan 25. pii: S1567-5769(23)00081-4. [Epub ahead of print]116 109758
      Atherosclerosis is a chronic inflammatory disease, in which immune disorders constitute an essential part of vascular pathogenesis. Accumulating evidence indicates that dendritic cells (DCs) and their tryptophan metabolisms regulate host immune responses. However, the mechanistic involvement of metabolic products from DCs in dysregulating vascular immunity during the development of atherosclerosis is far from clear. Flow cytometry examination showed immune cells were accumulated and gradually increased in the atherosclerotic lesions during the atherosclerosis progression, in which IDO+DCs were enriched. To study the role of DC-expressed IDO in the development of atherosclerosis, we made a stable IDO-overexpressing DC line (IDOoeDCs) by lentiviral infection for adoptive transfer into pro-atherosclerotic mice. Compared with DCs containing empty vector (VectorCtrlDC)-treated group, treatment of IDOoeDCs led to a significant reduction of atherosclerotic lesions in the aorta, with decreased aortic infiltration of Th1 immune cells and reduced vascular inflammation. Importantly, IDOoeDCs increased aortic kynurenine (Kyn) concentration and aryl hydrocarbon receptor (AHR) expression, concomitant with CD4+CD25+Foxp3+Treg expansion in the aortic tissues, which were abrogated by AHR antagonist treatment. These results indicate that DC-expressed IDO reduces atherosclerotic lesions by inducing aortic CD4+CD25+Foxp3+Treg expansion through IDO-Kyn-AHR axis, which may represent a novel possibility for treatment or prevention of atherosclerosis.
    Keywords:  Aryl hydrocarbon receptor; Atherosclerosis; Dendritic cells; Indoleamine 2, 3-dioxygenase; Kynurenine; Regulatory T cells
  26. Microb Pathog. 2023 Jan 21. pii: S0882-4010(23)00035-9. [Epub ahead of print]175 106002
      Influenza A virus (IAV) exploits host metabolic pathways to support its replication. To improve the understanding of lipid metabolic changes that could occur upon IAV infection, a comprehensive analysis of lipid metabolites in A549 cells infected with the avian H9N2 virus at the different time points was performed. It was found that H9N2 infection could largely promote the level of lipid metabolites. Further, these metabolites were mainly included in glycerophospholipids (GPs), sphingolipids (SPs), glycerolipids (GLs), fatty acids (FAs), sterollipids (STs), triglycerides (TGs), and prenol lipids (PRs). Specifically, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these metabolites were mainly associated with the glycerphospholipid metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and autophagy. Furthermore, it is interesting to note that these metabolites, including FFA(19:1), PE(P-17:0_20:3), PE(P-18:1_20:2), LPC(14:0/0:0), PE(O-18:0_20:3), and MGDG(16:0_18:1), are upregulated and shared in the top 10 at 12 h, 24 h, 36 h, and 48 h after H9N2 infection, indicative of the possibility of acting as biomarkers for the diagnosis in the lung infected with influenza virus. These pathways and altered metabolites could provide new understandings about biological characteristics and pathogenicity of influenza virus and have the potential to serve as biomarkers for influenza.
    Keywords:  Influenza virus; Lipid metabolites; Metabolic pathways