bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2024–12–15
25 papers selected by
Dylan Ryan, University of Cambridge



  1. Sci Immunol. 2024 Dec 13. 9(102): eadl4613
      The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of Asns in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.
    DOI:  https://doi.org/10.1126/sciimmunol.adl4613
  2. EMBO Rep. 2024 Dec 12.
      Cholesterol metabolism is associated with innate immune responses; however, the underlying mechanism remains unclear. Here, we perform chemical screening to isolate small molecules influencing RIG-I activity, a cytoplasmic viral RNA sensor. We find that statins, which inhibit cholesterol synthesis, dramatically enhance RIG-I-dependent antiviral responses in specific cell types. Since statins exhibit pleiotropic effects on type I interferon (IFN) responses, we further focus on their effects on RIG-I signaling. The restriction of cholesterol synthesis induces expression of noncanonical type I IFNs, such as IFN-ω, in an SREBP1 transcription factor-dependent manner. This pathway subsequently enhances RIG-I-mediated signaling following viral infection. Administration of statins augments RIG-I-dependent cytokine expression in the lungs of mice. Conversely, a mouse obesity model shows a diminished RIG-I response. Single-cell transcriptome analyses reveal a subset of alveolar macrophages that increase RIG-I expression in response to inhibited cholesterol synthesis in vivo. This study reveals SREBP1-mediated noncanonical type I IFN expression, linking cholesterol metabolism and RIG-I signaling.
    Keywords:  Cholesterol; Innate Immunity; RIG-I; Type I Interferon; Virus
    DOI:  https://doi.org/10.1038/s44319-024-00346-9
  3. Sci Adv. 2024 Dec 13. 10(50): eadq3073
      Down syndrome (DS), caused by trisomy 21 (T21), results in immune and metabolic dysregulation. People with DS experience co-occurring conditions at higher rates than the euploid population. However, the interplay between immune and metabolic alterations and the clinical manifestations of DS are poorly understood. Here, we report an integrated analysis of immunometabolic pathways in DS. Using multi-omics data, we infered cytokine-metabolite relationships mediated by specific transcriptional programs. We observed increased mediation of immunometabolic interactions in those with DS compared to euploid controls by genes in interferon response, heme metabolism, and oxidative phosphorylation. Unsupervised clustering of immunometabolic relationships in people with DS revealed subgroups with different frequencies of co-occurring conditions. Across the subgroups, we observed distinct mediation by DNA repair, Hedgehog signaling, and angiogenesis. The molecular stratification associates with the clinical heterogeneity observed in DS, suggesting that integrating multiple omic profiles reveals axes of coordinated dysregulation specific to DS co-occurring conditions.
    DOI:  https://doi.org/10.1126/sciadv.adq3073
  4. Science. 2024 Dec 12. eadj3020
      Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.
    DOI:  https://doi.org/10.1126/science.adj3020
  5. Discov Immunol. 2024 ;3(1): kyae016
       Background: Immunometabolism is a crucial determinant of immune cell function, influencing cellular activation and differentiation through metabolic pathways. The intricate interplay between metabolism and immune responses is highlighted by the distinct metabolic programs utilized by immune cells to support their functions. Of particular interest is the pentose phosphate pathway (PPP), a key metabolic pathway branching out of glycolysis that plays a pivotal role in generating NADPH and pentose sugars crucial for antioxidant defense and biosynthesis. The sedoheptulose kinase Carbohydrate Kinase-like protein (CARKL), an enzyme involved in the PPP, emerges as a critical regulator of cell metabolism and was previously shown to play a role in macrophage function.
    Methods: This study delves into the impact of CARKL expression on T-cell functionality, revealing dynamic alterations in response to cellular activation. Notably, CARKL overexpression leads to significant metabolic shifts in T cells, affecting mitochondrial respiration, ATP production, and inflammatory cytokine profiles. Furthermore, CARKL modulation influences T-cell motility by regulating chemokine receptor expression, particularly compromising CXCR3 expression and impairing T-cell migration in response to specific chemokine signals.
    Conclusions: These findings underscore the multifaceted role of CARKL as a metabolic regulator shaping T-cell responses. Overall, our data reveal the complex regulatory mechanisms orchestrated by CARKL in T-cell function, with implications for immune regulation. Further exploration of the molecular interactions between CARKL and metabolic reprogramming in T cells could provide valuable insights into immune regulation and potential therapeutic strategies.
    Keywords:  CARKL; T cells; immunometabolism; inflammation; pentose phosphate pathway; reprogramming
    DOI:  https://doi.org/10.1093/discim/kyae016
  6. Cancer Res. 2024 Dec 09.
      Immunosuppression by adenosine is an important cancer immune checkpoint. Extracellular adenosine signals through specific receptors and can be transported across the cell membrane through nucleoside transporters. While adenosine receptors are well-known to regulate tumor immunity, the impact of adenosine transporters remains unexplored. In this study, we investigated the effect on tumor immunity of equilibrative nucleoside transporter-1 (ENT1), the major regulator of extracellular adenosine concentrations. Blocking or deleting host ENT1 significantly enhanced CD8+ T cell-dependent antitumor responses. Tumors inoculated into ENT1-deficient mice showed increased infiltration of effector CD8+ T cells with an enhanced cytotoxic transcriptomic profile and significant upregulation of granzyme B, IFN-γ, IL-2, TNF-α, and CXCL10. ENT1-deficiency was further associated with decreased tumor-infiltrating T regulatory cells and CD206high macrophages and suppressed CCL17 production. ENT1-deficiency notably potentiated the therapeutic activity of PD-1 blockade. T cells upregulated ENT1 upon activation, and blocking ENT1 enhanced their function when co-cultured with cognate antigen/HLA-matched melanoma cells. Mechanistically, ENT1-mediated adenosine uptake inhibited the activity of phosphoribosyl pyrophosphate synthetase (PRPS) in activated T cells, thereby suppressing production of uridine 5'-monophosphate (UMP) and its derivatives required for DNA and RNA synthesis. In summary, this study identified ENT1-mediated adenosine uptake as an important mechanism of adenosine-mediated immunosuppression and pyrimidine starvation that can be targeted to enhance antitumor T cell responses.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1875
  7. bioRxiv. 2024 Nov 25. pii: 2024.11.25.625088. [Epub ahead of print]
      Glutamine metabolism is essential for T cell activation and functions. The inhibition of glutaminolysis impairs Th17 cell differentiation and alters Th1 cell functions. There is evidence for an active glutaminolysis in the immune cells of lupus patients. Treatment of lupus-prone mice with glutaminolysis inhibitors ameliorated disease in association with a reduced frequency of Th17 cells. This study was performed to determine the role of glutaminolysis in murine Tfh cells, a critical subset of helper CD4 + T cells in lupus that provide help to autoreactive B cells to produce autoantibodies. We showed that lupus Tfh present a high level of glutamine metabolism. The pharmacological inhibition of glutaminolysis with DON had little effect on the Tfh cells of healthy mice, but it reduced the expression of the critical costimulatory molecule ICOS on lupus Tfh cells, in association with a reduction of autoantibody production, germinal center B cell dynamics, as well as a reduction of the frequency of atypical age-related B cells and plasma cells. Accordingly, profound transcriptomic and metabolic changes, including an inhibition of glycolysis, were induced in lupus Tfh cells by DON, while healthy Tfh cells showed little changes. The T cell-specific inhibition of glutaminolysis by deletion of the gene encoding for the glutaminase enzyme GLS1 largely phenocopied the effects of DON on Tfh cells and B cells in an autoimmune genetic background with little effect in a congenic control background. These results were confirmed in an induced model of lupus. Finally, we showed that T cell-specific Gls1 deletion impaired T- dependent humoral responses in autoimmune mice as well as their Tfh response to a viral infection. Overall, these results demonstrated a greater intrinsic requirement of lupus Tfh cells for their helper functions, and they suggest that targeting glutaminolysis may be beneficial to treat lupus.
    DOI:  https://doi.org/10.1101/2024.11.25.625088
  8. Microb Pathog. 2024 Dec 09. pii: S0882-4010(24)00683-1. [Epub ahead of print] 107216
      Increasing evidence suggests that immune cell clearance is closely linked to cellular metabolism. Neurosyphilis, a severe neurological disorder caused by Treponema pallidum (T. pallidum) infection, significantly impacts the brain. Microglia, the innate immune cells of the central nervous system, play a critical role in neuroinflammation and immune surveillance. However, the inability of the nervous system to fully eliminate T. pallidum points to a compromised clearance function of microglia. This study investigates how T. pallidum alters the immune clearance ability of microglia and explores the underlying metabolic mechanisms. RNA sequencing (RNA seq), LC-MS metabolomics, and XFe96 Seahorse assays were employed to assess metabolic activity in microglial cells. Western blotting, qPCR, and immunofluorescence imaging were utilized to evaluate autophagy flux and extent of T. pallidum infections. Transcriptomic analysis revealed that T. pallidum alters the transcription expression of key glycolytic enzymes, including hexokinase 1 (HK1), hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), leading to significant metabolic dysregulation. Specifically, metabolomic analysis showed reduced levels of phosphoenolpyruvate and citrate, while lactate production was notably increased. Functional assays confirmed that T. pallidum impairs glycolytic activity in microglial, as evidenced by decreased glycolytic flux, glycolytic reserve capacity, and maximum glycolytic capacity. Moreover, our results indicate that HK2, a crucial glycolytic enzyme, is closely associated with the autophagy. T. pallidum infection inhibits HK2 expression, which in turn suppresses autophagic flux by reducing the formation of lysosome-associated membrane protein 2 (LAMP2) and disrupting autophagosome- lysosome fusion. These findings suggest that T. pallidum hijacks microglial metabolic pathways, specifically glycolysis, to evade immune clearance. By inhibiting the glycolytic enzyme HK2, T. pallidum modulates autophagy and enhances immune evasion, providing a novel insight into the pathogenesis of neurosyphilis. This study paves the way for further investigations into the role of metabolic reprogramming in the immune escape mechanisms of T. pallidum.
    Keywords:  Autophagy; Glycolysis; Hexokinase 2; Microglia; Treponema pallidum
    DOI:  https://doi.org/10.1016/j.micpath.2024.107216
  9. Acta Pharm Sin B. 2024 Nov;14(11): 5026-5036
      Periodontitis is a chronic inflammatory disease marked by a dysregulated immune microenvironment, posing formidable challenges for effective treatment. The disease is characterized by an altered glucose metabolism in macrophages, specifically an increase in aerobic glycolysis, which is linked to heightened inflammatory responses. This suggests that targeting macrophage metabolism could offer a new therapeutic avenue. In this study, we developed an immunometabolic intervention using quercetin (Q) encapsulated in bioadhesive mesoporous polydopamine (Q@MPDA) to treat periodontitis. Our results demonstrated that Q@MPDA could reprogram inflammatory macrophages to an anti-inflammatory phenotype (i.e., from-M1-to-M2 repolarization). In a murine periodontitis model, locally administered Q@MPDA reduced the presence of inflammatory macrophages, and decreased the levels of inflammatory cytokines (IL-1β and TNF-α) and reactive oxygen species (ROS) in the periodontium. Consequently, it alleviated periodontitis symptoms, reduced alveolar bone loss, and promoted tissue repair. Furthermore, our study revealed that Q@MPDA could inhibit the glycolysis of inflammatory macrophages while enhancing oxidative phosphorylation (OXPHOS), facilitating the shift from M1 to M2 macrophage subtype. Our findings suggest that Q@MPDA is a promising treatment for periodontitis via immunometabolic rewiring.
    Keywords:  Glycolysis; Immunometabolic rewiring; Macrophage; Mesoporous polydopamine; Mitochondrial reactive oxygen species; Oxidative phosphorylation (OXPHOS); Periodontitis; Quercetin
    DOI:  https://doi.org/10.1016/j.apsb.2024.07.008
  10. Cell Mol Immunol. 2024 Dec 13.
      Proper cellular metabolism in T cells is critical for a productive immune response. However, when dysregulated by intrinsic or extrinsic metabolic factors, T cells may contribute to a wide spectrum of diseases, such as cancers and autoimmune diseases. However, the metabolic regulation of T cells remains incompletely understood. Here, we show that MYO1F is required for human and mouse T-cell activation after TCR stimulation and that T-cell-specific Myo1f knockout mice exhibit an increased tumor burden and attenuated EAE severity due to impaired T-cell activation in vivo. Mechanistically, after TCR stimulation, MYO1F is phosphorylated by LCK at tyrosines 607 and 634, which is critical for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) acetylation at Lys84, 86 and 227 mediated by α-TAT1, which is an acetyltransferase, and these processes are important for its activation, cellular glycolysis and thus the effector function of T cells. Importantly, we show that a fusion protein of VAV1-MYO1F, a recurrent peripheral T-cell lymphoma (PTCL)-associated oncogenic protein, promotes hyperacetylation of GAPDH and its activation, which leads to aberrant glycolysis and T-cell proliferation, and that inhibition of the activity of GAPDH significantly limits T-cell activation and proliferation and extends the survival of hVAV1-MYO1F knock-in mice. Moreover, hyperacetylation of GAPDH was confirmed in human PTCL patient samples containing the VAV1-MYO1F gene fusion. Overall, this study revealed not only the mechanisms by which MYO1F regulates T-cell metabolism and VAV1-MYO1F fusion-induced PTCL but also promising therapeutic targets for the treatment of PTCL.
    Keywords:  GAPDH; MYO1F; Peripheral T-cell lymphoma (PTCL); T cell activation; VAV1-MYO1F fusion
    DOI:  https://doi.org/10.1038/s41423-024-01247-6
  11. Cancer Cell. 2024 Dec 03. pii: S1535-6108(24)00438-0. [Epub ahead of print]
      Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8+ T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2024.11.003
  12. Sci Transl Med. 2024 Dec 11. 16(777): eadi6682
      The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between ABCG1 expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.
    DOI:  https://doi.org/10.1126/scitranslmed.adi6682
  13. Redox Biol. 2024 Nov 29. pii: S2213-2317(24)00427-0. [Epub ahead of print]79 103449
      Macrophages play an important role in the development of vascular diseases, with their homeostasis closely linked to metabolic reprogramming. This study aims to explore the role of circular RNA-mediated epigenetic remodeling in maintaining macrophage homeostasis during diabetes-induced microvascular dysfunction. We identified a circular RNA, circRNA-sperm antigen with calponin homology and coiled-coil domains 1 (cSPECC1), which is significantly up-regulated in diabetic retinas and in macrophages under diabetic stress. cSPECC1 knockdown in macrophages attenuates M1 macrophage polarization and disrupts macrophage-endothelial crosstalk in vitro. cSPECC1 knockdown in macrophages mitigates diabetes-induced retinal inflammation and ameliorates retinal vascular dysfunction. Mechanistically, cSPECC1 regulates GPX2 expression by recruiting eIF4A3, enhancing GPX2 mRNA stability and altering arachidonic acid metabolism. The metabolic intermediate 12-HETE has emerged as a key mediator, regulating both macrophage homeostasis and the crosstalk between macrophages and endothelial cells. Exogenous 12-HETE supplementation interrupts the anti-angiogenic effects of cSPECC1 knockdown. Collectively, circSPECC1 emerges as a novel regulator of macrophage-mediated vascular integrity and inflammation. Targeting the metabolic reprogramming of macrophages presents a promising therapeutic strategy for mitigating diabetes-induced vascular dysfunction.
    Keywords:  Circular RNAs; Diabetic retinopathy; Macrophage homeostasis; Metabolic reprogramming; Vascular dysfunction
    DOI:  https://doi.org/10.1016/j.redox.2024.103449
  14. J Biol Chem. 2024 Dec 09. pii: S0021-9258(24)02565-1. [Epub ahead of print] 108063
      Understanding the fundamental biochemical and metabolic requirements for the replication of coronaviruses within infected cells is of notable interest for the development of broad-based therapeutic strategies, given the likelihood of emergence of new pandemic-potential virus species, as well as future variants of SARS-CoV-2. Here we demonstrate members of the glutaminase family of enzymes (GLS and GLS2), which catalyze the hydrolysis of glutamine to glutamate (i.e., the first step in glutamine metabolism), play key roles in coronavirus replication in host cells. Using a range of human seasonal and zoonotic coronaviruses, we show three examples where GLS expression increases during coronavirus infection of host cells, and another where GLS2 is upregulated. The viruses hijack the metabolic machinery responsible for glutamine metabolism to generate the building blocks for biosynthetic processes and satisfy the bioenergetic requirements demanded by the 'glutamine addiction' of virus-infected cells. We demonstrate that genetic silencing of glutaminase enzymes reduces coronavirus infection and that newer members of two classes of allosteric inhibitors targeting these enzymes, designated as SU1, a pan-GLS/GLS2 inhibitor, and UP4, a specific GLS inhibitor, block viral replication in epithelial cells. Moreover, treatment of SARS-CoV-2 infected K18-human ACE2 transgenic mice with SU1 resulted in their complete survival compared to untreated control animals, which succumbed within 10 days post-infection. Overall, these findings highlight the importance of glutamine metabolism for coronavirus replication in human cells and mice and show that glutaminase inhibitors can block coronavirus infection and thereby may represent a novel class of broad-based anti-viral drug candidates.
    Keywords:  GLS; GLS inhibitor UP4; GLS2; HCoV-229E; HCoV-OC43; SARS-CoV-2; glutamine metabolism; pan-glutaminase inhibitor SU1
    DOI:  https://doi.org/10.1016/j.jbc.2024.108063
  15. Front Aging Neurosci. 2024 ;16 1503336
       Introduction: During aging, many cellular processes, such as autophagic clearance, DNA repair, mitochondrial health, metabolism, nicotinamide adenine dinucleotide (NAD+) levels, and immunological responses, become compromised. Urolithin A (UA) and Nicotinamide Riboside (NR) are two naturally occurring compounds known for their anti-inflammatory and mitochondrial protective properties, yet the effects of these natural substances on microglia cells have not been thoroughly investigated. As both UA and NR are considered safe dietary supplements, it is equally important to understand their function in normal cells and in disease states.
    Methods: This study investigates the effects of UA and NR on immune signaling, mitochondrial function, and microglial activity in a human microglial cell line (HMC3).
    Results: Both UA and NR were shown to reduce DNA damage-induced cellular senescence. However, they differentially regulated gene expression related to neuroinflammation, with UA enhancing cGAS-STING pathway activation and NR displaying broader anti-inflammatory effects. Furthermore, UA and NR differently influenced mitochondrial dynamics, with both compounds improving mitochondrial respiration but exhibiting distinct effects on production of reactive oxygen species and glycolytic function.
    Discussion: These findings underscore the potential of UA and NR as therapeutic agents in managing neuroinflammation and mitochondrial dysfunction in neurodegenerative diseases.
    Keywords:  aging; innate immune signaling; microglia; mitochondrial health; nicotinamide riboside; urolithin A
    DOI:  https://doi.org/10.3389/fnagi.2024.1503336
  16. Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01415-3. [Epub ahead of print]43(12): 115064
      The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.
    Keywords:  CP: Metabolism; immunometabolism; metabolic reprogramming; metabolite sensing; tumor metabolism; tumor therapy
    DOI:  https://doi.org/10.1016/j.celrep.2024.115064
  17. Cell Death Differ. 2024 Dec 10.
      Disturbances in tumor cell metabolism reshape the tumor microenvironment (TME) and impair antitumor immunity, but the implicit mechanisms remain elusive. Here, we found that spermine synthase (SMS) was significantly upregulated in tumor cells, which correlated positively with the immunosuppressive microenvironment and predicted poor survival in hepatocellular carcinoma (HCC) patients. Via "subcutaneous" and "orthotopic" HCC syngeneic mouse models and a series of in vitro coculture experiments, we identified elevated SMS levels in HCC cells played a role in immune escape mainly through its metabolic product spermine, which induced M2 polarization of tumor-associated macrophages (TAMs) and subsequently corresponded with a decreased antitumor functionality of CD8+ T cells. Mechanistically, we discovered that spermine reprogrammed TAMs mainly by activating the PI3K-Akt-mTOR-S6K signaling pathway. Spermine inhibition in combination with immune checkpoint blockade effectively diminished tumor burden in vivo. Our results expand the understanding of the critical role of metabolites in regulating cancer progression and antitumor immunity and open new avenues for developing novel therapeutic strategies against HCC.
    DOI:  https://doi.org/10.1038/s41418-024-01409-z
  18. Eur J Immunol. 2024 Dec 09. e202451440
      Potassium ions (K+) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K+ concentration to 50 mM (high-[K+]e). Here, we demonstrate that high-[K+]e decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory receptor CD28 and thereby dysregulates intracellular signal transduction cascades. High-[K+]e also alters the metabolic profiles of T-cells, limiting the metabolism of glucose and glutamine, consistent with functional exhaustion. These changes skew T-cell differentiation, favouring Th2 and iTreg subsets that promote tumour growth while restricting antitumour Th1 and Th17 subsets. Similar phenotypes were noted in T-cells present within the necrosis-prone core versus the outer zones of hepatocellular carcinoma (HCC)/colorectal carcinoma (CRC) tumours as analysed by GeoMx digital spatial profiling and flow-cytometry. Our results thus expand the understanding of the contribution of high-[K+]e to the immunosuppressive milieu in the TME.
    Keywords:  T‐cell exhaustion; T‐lymphocytes; immune suppression; metabolomics
    DOI:  https://doi.org/10.1002/eji.202451440
  19. JDS Commun. 2024 Nov;5(6): 740-744
      Dairy cows are susceptible to several health disorders throughout their lactation. Objectives were to characterize an in vitro model to study bioenergetic measures in CD4+ T lymphocytes in dairy cows. Twenty-four healthy mid-lactation multiparous Holstein dairy cows were enrolled at a mean (±SD) of 234 ± 22 DIM. Cows were blocked according to DIM and blood was collected to isolate peripheral blood mononuclear cells followed by magnetic separation of CD4+ T lymphocytes using bovine-specific monoclonal antibodies. The isolated CD4+ T lymphocytes from each cow were split into 2 tubes and randomly assigned to incubate in an assay medium as control (CON) or with a combination of phorbol myristate acetate and ionomycin (PMA+IMY) to evaluate metabolic function under a resting and activated state. Mitochondrial and glycolytic functional kinetics were recorded in CD4+ T lymphocytes based on real-time measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) under basal conditions and in response to complex V inhibitor (oligomycin), a protonophore uncoupler (BAM 15), and complex I and complex III inhibitors (rotenone and antimycin A). The mean (±SD) viability and purity of CD4+ T lymphocytes was 92.5 ± 2.9% and 95.2 ± 2.9%, respectively. The basal OCR in CD4+ T lymphocytes treated with PMA+IMY was greater than CON; nevertheless, the maximal respiration rate (CON = 58.0 vs. PMA+IMY = 47.3 ± 5.7 pmol/min) and sparing respiratory capacity rate (CON = 42.0 vs. PMA+IMY = 28.7 ± 4.2 pmol/min) were decreased in activated CD4+ T lymphocytes. The ECAR in CD4+ T lymphocytes increased progressively over time in PMA+IMY compared with CON, which indicated an increase in aerobic glycolysis in PMA+IMY compared with CON (CON = 46.9 vs. PMA+IMY = 86.4 ± 7.0 pmol/min). Activated CD4+ T lymphocytes exhibit a metabolic switch from oxidative phosphorylation to aerobic glycolysis, which may support rapid cell proliferation. The results observed in this experiment demonstrate the sensitivity of the technique to detect changes in metabolic function under different cellular conditions, providing a robust framework to study immuno-metabolism in dairy cattle.
    DOI:  https://doi.org/10.3168/jdsc.2024-0565
  20. Front Immunol. 2024 ;15 1496390
      Lactate has been traditionally regarded as a mere byproduct of glycolysis or metabolic waste. However, an increasing body of literature suggests its critical role in regulating various physiological and pathological processes. Lactate is generally associated with hypoxia, inflammation, viral infections, and tumors. It performs complex physiological roles by activating monocarboxylate transporter (MCT) or the G protein-coupled receptor GPR81 across the cell membrane. Lactate exerts immunosuppressive effects by regulating the functions of various immune cells (such as natural killer cells, T cells, dendritic cells, and monocytes) and its role in macrophage polarization and myeloid-derived suppressor cell (MDSC) differentiation in the tumor microenvironment. Lactic acid has also recently been found to increase the density of CD8+ T cells, thereby enhancing the antitumor immune response. Acute or chronic inflammatory diseases have opposite immune states in the inflammatory disease microenvironment. Factors such as cell types, transcriptional regulators, ionic mediators, and the microenvironment all contribute to the diverse functions lactate exhibits. Herein, we reviewed the pleiotropic effects of lactate on the regulation of various functions of immune cells in the tumor microenvironment and under inflammatory conditions, which may help to provide new insights and potential targets for the diagnosis and treatment of inflammatory diseases and malignancies.
    Keywords:  diseases; inflammatory; lactate; therapy; tumor
    DOI:  https://doi.org/10.3389/fimmu.2024.1496390
  21. Microb Pathog. 2024 Dec 09. pii: S0882-4010(24)00665-X. [Epub ahead of print]199 107198
      Lactate is a glycolytic end product that is further metabolized as an energy source. This end product has been associated with certain diseases, including sepsis and tumors, and it can regulate the transition of macrophages to an anti-inflammatory state. This study aimed to explore the effects of lactate on the inflammatory responses of mammary gland epithelial cells, which constitute the first line of defense against pathogens in mammary glands. Bovine mammary epithelial cells (BMECs) were challenged with lipopolysaccharide (LPS) in the presence or absence of D-sodium lactate (D-nala). LPS exposure increased the concentration of lactate both inside and outside the cells. Further, inhibiting glycolysis diminished the LPS-induced production of proinflammatory cytokines. Treatment with LPS, exogenous D-nala, and their combination upregulated the expression levels of MCT1, increased the intracellular levels of lactate and histone H3 lysine 18 lactylation (H3K18la), and activated the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway. The lactylation of H3K18 was mediated by p300/CBP. The p300/CBP inhibitor C646 decreased the level of H3K18la, reversing the activation of the NF-κB signaling pathway and release of proinflammatory cytokines. Therefore, LPS increased the intracellular level of lactate by upregulating MCT1 and glycolysis. D-nala exacerbated the LPS-induced inflammatory responses in BMECs. Moreover, intracellular lactate enhanced the activation of the NF-κB signaling pathway through the p300/CBP-mediated lactylation of H3K18. Thus, the findings of this study expand our understanding of lactate function in immune regulation.
    Keywords:  Bovine mammary epithelial cells; D-sodium lactate; Histone lactylation; NF-Kappa B; p300/CBP
    DOI:  https://doi.org/10.1016/j.micpath.2024.107198
  22. Int J Biol Sci. 2024 ;20(15): 5831-5849
      Lipopolysaccharide (LPS) mediated caspases-4 (humans) and caspase-11 (rodent) (caspase-4/11) signaling can cause maturation of inflammatory cytokine IL-1β and cellular pyroptosis in the macrophages through guanylate-binding proteins (GBPs). However, how caspase-4/11s bind with GBPs together to activate caspase-4/11 by LPS remains elusive. We here found that BA derivatives from gut microbiota can regulate sensitivity of macrophages to LPS and Gram-negative bacteria through lncRNA57RIK. BA derivatives such as deoxycholic acid (DCA) could induce lncRNA57RIK expression through sphingosine-1-phosphate receptor 2 (S1PR2) in the macrophages of mice and humans. Both murine and human lncRNA57RIK knockout (KO) macrophages did not produce immune response(s) to LPS or gram negative bacteria. LncRNA57RIK KO mice had also reduced inflammatory responses to LPS or Salmonella typhimurium (S. T) infection. Mechanistically, lncRNA57RIK could bind intracellular proteases caspase-4/11 with GBP1 together in the macrophages of human and mice to cause LPS-mediated activation of caspase-4/11. Thus, BA derivatives from gut microbiota promote GBPs-mediated activation of caspase-4/11 by LPS through lncRNA57RIK.
    Keywords:   lncRNA57RIK; caspase-4/11; guanylate-binding protein 1; macrophages; sphingosine-1-phosphate receptor 2
    DOI:  https://doi.org/10.7150/ijbs.97059
  23. Nat Rev Drug Discov. 2024 Dec 12.
      The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells. However, the anticancer activity of CD8 T cells and NK cells is rapidly diminished in the tumour microenvironment, closely linked to a decline in their metabolic capacities. Various strategies have been developed to restore cancer immunosurveillance, including targeting bioenergetic metabolism or genetic engineering. This Review provides an overview of metabolic dysfunction in CD8 T cells and NK cells within the tumour microenvironment, highlighting current therapies aiming to overcome these issues.
    DOI:  https://doi.org/10.1038/s41573-024-01098-w
  24. Invest Ophthalmol Vis Sci. 2024 Dec 02. 65(14): 23
       Purpose: The aim of this study was to elucidate the effect of itaconate (ITA) on experimental autoimmune uveitis (EAU), to explore its potential mechanism, and to identify potential therapeutic targets.
    Methods: We established an animal model of EAU by constructing an immune map of mice treated with ITA and exploring the therapeutic mechanism of ITA by single-cell RNA sequencing and flow cytometry.
    Results: ITA mitigated ocular inflammation associated with EAU and reversed the pathogenic differentiation linked to Th17 induction by EAU, along with the reactive oxygen species (ROS) and oxidative stress pathways. Subsequent to ITA intervention, the downregulated differentially expressed genes in the T-cell subset primarily centered around the heat shock protein (HSP) family. Activation of HSPs reversed the anti-inflammatory effects of ITA in EAU mice. ITA decreased ROS levels and HSP expression in CD4+ T cells, with DnaJ heat shock protein family (HSP40) member A1 (DNAJA1) exhibiting the most notable alterations among the HSPs. ITA suppressed the expression of DNAJA1/cell division cycle protein 45 (CDC45), thereby disrupting the pathogenic division cycle of CD4+ T cells and reducing their proliferation. Inhibiting DNAJA1 also held promise for modulating the Th17/Treg imbalance. Notably, ITA curtailed the expansion of CD4+ T cells in uveitis patients.
    Conclusions: Our research delved into the potential therapeutic mechanisms underlying ITA therapy in EAU, offering fresh perspectives on its utility in the treatment of autoimmune conditions. DNAJA1 emerges as a promising candidate for targeted therapeutic interventions in uveitis.
    DOI:  https://doi.org/10.1167/iovs.65.14.23
  25. Cell Rep Med. 2024 Dec 04. pii: S2666-3791(24)00640-2. [Epub ahead of print] 101869
      T cell exhaustion presents a major challenge for the efficacy of both immune checkpoint inhibitors (ICBs) and chimeric antigen receptor T (CAR-T) cell immunotherapies. To address this issue, we generate hypofunctional CAR-T cells that imitate the exhaustion state. By screening a Food and Drug Administration (FDA)-approved small molecule library using this model, we identify miltefosine as a potent molecule that restores the impaired function of CAR-T cells in a PD-1/PD-L1-independent manner. Impressively, in the terminally exhausted state where PD-1 antibody treatment is ineffective, miltefosine still enhances CAR-T cell activity. Single-cell sequencing analysis reveals that miltefosine treatment significantly increases the population of effector cells. Mechanistically, miltefosine improves impaired glycolysis and oxidative phosphorylation in hypofunctional CAR-T cells. In both allogeneic and syngeneic tumor models, miltefosine effectively enhances the solid tumor clearance ability of CAR-T cells and T cells, demonstrating its potential as an effective immunotherapeutic drug.
    Keywords:  T cell exhaustion; glycolytic metabolism; high-throughput drug screening; immunotherapy for solid tumors; miltefosine
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101869