bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2024–12–29
eightteen papers selected by
Dylan Ryan, University of Cambridge
  1. Epstein-Barr virus hijacks B cell metabolism to establish persistent infection and drive pathogenesis.
  2. Exogenous acetate attenuates inflammatory responses through HIF-1α-dependent glycolysis regulation in macrophage.
  3. Itaconate facilitates viral infection via alkylating GDI2 and retaining Rab GTPase on the membrane.
  4. Amelioration of signaling deficits underlying metabolic shortfall in TREM2R47H human iPSC-derived microglia.
  5. Immunometabolic reprogramming in macrophages infected with active and dormant Cryptococcus neoformans: differential modulation of respiration, glycolysis, and fatty acid utilization.
  6. Immunometabolism in the Aging Heart.
  7. Sinomenine modulates the metabolic reprogramming induced by sepsis via CHRNA7.
  8. Polyamines: Key Players in Immunometabolism and Immune Regulation.
  9. Trained Immunity Enhances Host Resistance to Infection in Aged Mice.
  10. Metabolic Reprogramming of Macrophages by Biomimetic Melatonin-Loaded Liposomes Effectively Attenuates Acute Gouty Arthritis in a Mouse Model.
  11. Targeting P4HA1 promotes CD8+ T cell progenitor expansion toward immune memory and systemic anti-tumor immunity.
  12. Heightened cholesterol 25-hydroxylase expression in aged lung during Streptococcus pneumoniae.
  13. The impact of glucose metabolism on inflammatory processes in sepsis-induced acute lung injury.
  14. A unique inflammaging profile generated by T cells from people with obesity is metformin resistant.
  15. Sodium butyrate prevents lipopolysaccharide induced inflammation and restores the expression of tight junction protein in human epithelial Caco-2 cells.
  16. Pyrimidine synthesis enzyme CTP synthetase 1 suppresses antiviral interferon induction by deamidating IRF3.
  17. Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus.
  18. Altered Purinergic Signaling and CD8+ T Cell Dysregulation in STAT3 GOF Syndrome.
  1. Trends Immunol. 2024 Dec 20. pii: S1471-4906(24)00296-5. [Epub ahead of print]
    Epstein-Barr virus hijacks B cell metabolism to establish persistent infection and drive pathogenesis.
    Bojana Müller-Durovic, Jessica Jäger, Glenn R Bantug, Christoph Hess.
      When B cells engage in an immune response, metabolic reprogramming is key to meeting cellular energetic and biosynthetic demands. Epstein-Barr virus (EBV) is a highly prevalent gamma-herpesvirus, latently infecting B cells for the human host's lifetime. By hijacking signaling pathways of T cell-dependent humoral immunity, EBV activates B cells in a T cell-independent manner, forcing lymphoblastoid transformation. Interlinked with this coercion of signaling pathways, EBV has also evolved strategies to manipulate B cell metabolism. In this opinion article we integrate recent findings from studies of B cell metabolic reprogramming after EBV infection and during antigen-specific activation, respectively. We hypothesize that defining EBV host-cell metabolic vulnerabilities that differ from pathways required for B cell immunity might uncover novel therapeutic targets against EBV-related diseases.
    Keywords:  B cells; Epstein–Barr virus; IDO1; NAD; cellular metabolism; glycolysis; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.it.2024.11.011
  2. Cell Mol Life Sci. 2024 Dec 27. 82(1): 21
    Exogenous acetate attenuates inflammatory responses through HIF-1α-dependent glycolysis regulation in macrophage.
    Na Li, Yi Gong, Yalin Zhu, Bo Li, Changli Wang, Zhefan Wang, Jun Wang, Jie Huang, Jinjun Bian, Yan Zhang.
      Cytokine storm is a hallmark for acute systemic inflammatory disease like sepsis. Intrinsic microbiome-derived short-chain fatty acid (SCFAs) like acetate modulates immune cell function and metabolism has been well studied. However, it remains poorly investigated about the effects and the underlying mechanism of exogenous acetate in acute inflammation like sepsis. Here, we observed that serum acetate accumulates in patients undergoing abdominal gastrointestinal surgery and in septic mice. Short exposure to high-dose exogenous acetate protects mice from sepsis by inhibiting glycolysis in macrophages, both in vivo and in vitro. Hypoxia-inducible factor 1 subunit alpha (HIF-1α) stabilization or overexpression reverses the decreased glycolysis and pro-inflammatory cytokine production in macrophages and abrogates acetate's protective effect in septic mice. Meanwhile, we also found acetyl-CoA synthetase-2, but not GPR41 or GPR43, plays a key role in acetate's immunosuppressive effect. Acetate transiently increases acetyl-coenzyme A production, promoting histone acetylation and decreasing acetyl-transfer to NF-κB p65. These findings suggest that short exposure to mM-level acetate inhibits macrophage immune response linked to HIF-1α-dependent glycolysis. Taken together, we demonstrate short-term exposure of exogenous acetate could regulate inflammatory responses through attenuating HIF-1α-dependent glycolysis.
    Keywords:  Acetate; Glycolysis; HIF-1alpha; Inflammation; Macrophage
    DOI:  https://doi.org/10.1007/s00018-024-05521-8
  3. Signal Transduct Target Ther. 2024 Dec 27. 9(1): 371
    Itaconate facilitates viral infection via alkylating GDI2 and retaining Rab GTPase on the membrane.
    Shulei Yin, Yijie Tao, Tianliang Li, Chunzhen Li, Yani Cui, Yunyan Zhang, Shenhui Yin, Liyuan Zhao, Panpan Hu, Likun Cui, Yunyang Wu, Yixian He, Shu Yu, Jie Chen, Shaoteng Lu, Guifang Qiu, Mengqi Song, Qianshan Hou, Cheng Qian, Zui Zou, Sheng Xu, Yizhi Yu.
      Metabolic reprogramming of host cells plays critical roles during viral infection. Itaconate, a metabolite produced from cis-aconitate in the tricarboxylic acid cycle (TCA) by immune responsive gene 1 (IRG1), is involved in regulating innate immune response and pathogen infection. However, its involvement in viral infection and underlying mechanisms remain incompletely understood. Here, we demonstrate that the IRG1-itaconate axis facilitates the infections of VSV and IAV in macrophages and epithelial cells via Rab GTPases redistribution. Mechanistically, itaconate promotes the retention of Rab GTPases on the membrane via directly alkylating Rab GDP dissociation inhibitor beta (GDI2), the latter of which extracts Rab GTPases from the membrane to the cytoplasm. Multiple alkylated residues by itaconate, including cysteines 203, 335, and 414 on GDI2, were found to be important during viral infection. Additionally, this effect of itaconate needs an adequate distribution of Rab GTPases on the membrane, which relies on Rab geranylgeranyl transferase (GGTase-II)-mediated geranylgeranylation of Rab GTPases. The single-cell RNA sequencing data revealed high expression of IRG1 primarily in neutrophils during viral infection. Co-cultured and in vivo animal experiments demonstrated that itaconate produced by neutrophils plays a dominant role in promoting viral infection. Overall, our study reveals that neutrophils-derived itaconate facilitates viral infection via redistribution of Rab GTPases, suggesting potential targets for antiviral therapy.
    DOI:  https://doi.org/10.1038/s41392-024-02077-8
  4. FEBS J. 2024 Dec 26.
    Amelioration of signaling deficits underlying metabolic shortfall in TREM2R47H human iPSC-derived microglia.
    Foteini Vasilopoulou, Thomas M Piers, Jingzhang Wei, John Hardy, Jennifer M Pocock.
      The microglial triggering receptor expressed on myeloid cells 2 (TREM2) is required for diverse microglia responses in neurodegeneration, including immunometabolic plasticity, phagocytosis, and survival. We previously identified that patient iPSC-derived microglia (iPS-Mg) harboring the Alzheimer's disease (AD) TREM2R47H hypomorph display several functional deficits linked to metabolism. To investigate whether these deficits are associated with disruptions in metabolite signaling, we generated common variant, TREM2R47H and TREM2-/- variant human iPS-Mg. We assessed the ability of supplementation with citrate or succinate, key metabolites and cell cycle breaking points upon microglia activation, to overcome these functional deficits with potential impact on neurons. Succinate supplementation was more effective than citrate at overcoming mitochondrial deficits in OXPHOS and did not promote a glycolytic switch. Citrate enhanced the lipid content of TREM2R47H iPS-Mg and was more effective at overcoming Αβ phagocytic deficits, whereas succinate increased lipid content and phagocytic capacity in TREM2-/- iPS-Mg. Microglia cytokine secretion upon pro-inflammatory activation was moderately affected by citrate or succinate showing a condition-dependent increasing trend. Neither metabolite altered basal levels of soluble TREM2 shedding. In addition, neither citrate nor succinate enhanced glycolysis; instead, drove their effects through oxidative phosphorylation. IPS-neurons exposed to conditioned medium from TREM2 variant iPS-Mg showed changes in oxidative phosphorylation, which could be ameliorated when iPS-Mg were first treated with citrate or succinate. Our data point to discrete pathway linkage between microglial metabolism and functional outcomes with implications for AD pathogenesis and treatments.
    Keywords:  Alzheimer's disease; R47H TREM2 variant; TCA‐metabolites; human microglia; metabolism; neurodegeneration
    DOI:  https://doi.org/10.1111/febs.17353
  5. Infect Immun. 2024 Dec 23. e0048724
    Immunometabolic reprogramming in macrophages infected with active and dormant Cryptococcus neoformans: differential modulation of respiration, glycolysis, and fatty acid utilization.
    Clara Luna Marina, Raffael J Araújo de Castro, Paula Bellozi, Ana M Cruz, Pedro Henrique Bürgel, Paul G Weightman Potter, Craig Beall, Aldo Henrique Tavares, Andreza De Bem, Alexandre Alanio, Carolina Coelho, Anamélia Lorenzetti Bocca.
      Dormancy is an adaptation in which cells reduce their metabolism, transcription, and translation to stay alive under stressful conditions, preserving the capacity to reactivate once the environment reverts to favorable conditions. Dormancy and reactivation of Cryptococcus neoformans (Cn) are closely linked to intracellular residency within macrophages. Our previous work showed that in vitro murine macrophages rely on the viable but not cultivable (VBNC-a dormancy phenotype) fungus from active Cn, with striking differences in immunometabolic gene expression. Here, we analyzed the influence of VBNC and active Cn on the immunometabolism of infected macrophages, combining metabolic gene expression, mitochondrial membrane potential (ΔΨm), oxygen consumption analysis, and uptake of glucose and fatty acids. The active fungus induced mitochondrial depolarization, and increased glycolysis and mitochondrial oxygen consumption. VBNC infection in bone marrow-derived macrophage (BMDM) caused an attenuated modification in mitochondrial metabolism. However, we found differences in BMDM infected with VBNC vs those infected with active fungus, where VBNC induced an increment in fatty acid uptake in M0 and M1 BMDM, measured by incorporation of BODIPY-palmitate, accompanied by an increase in expression of fatty acid transporters Fabp1 and Fabp4. Overall, distinct fatty acid-related responses induced by VBNC and active Cn suggest different immunomodulatory reactions, depending on the microbial growth stage. We posit that, for VBNC, some of these macrophage metabolic responses reflect the establishment of prolonged microbial intracellular residency and possibly initial stages of granuloma formation.
    Keywords:  Acod1; Cryptococcus neoformans; Fabp1; Fabp4; VBNC; dormancy; immunometabolism; macrophage
    DOI:  https://doi.org/10.1128/iai.00487-24
  6. J Am Heart Assoc. 2024 Dec 24. e039216
    Immunometabolism in the Aging Heart.
    Kranti A Mapuskar, Barry London, Zeb R Zacharias, Jon C D Houtman, Bryan G Allen.
      Structural, functional, and molecular-level changes in the aging heart are influenced by a dynamic interplay between immune signaling and cellular metabolism that is referred to as immunometabolism. This review explores the crosstalk between cellular metabolic pathways including glycolysis, oxidative phosphorylation, fatty acid metabolism, and the immune processes that govern cardiac aging. With a rapidly aging population that coincides with increased cardiovascular risk and cancer incidence rates, understanding the immunometabolic underpinnings of cardiac aging provides a foundation for identifying therapeutic targets to mitigate cardiac dysfunction. Aging alters the immune environment of the heart by concomitantly driving the changes in immune cell metabolism, mitochondrial dysfunction, and redox signaling. Shifts in these metabolic pathways exacerbate inflammation and impair tissue repair, creating a vicious cycle that accelerates cardiac functional decline. Treatment with cancer therapy further complicates this landscape, as aging-associated immunometabolic disruptions augment the susceptibility to cardiotoxicity. The current review highlights therapeutic strategies that target the immunometabolic axis to alleviate cardiac aging pathologies. Interventions include modulating metabolic intermediates, improving mitochondrial function, and leveraging immune signaling pathways to restore cardiac health. Advances in immunometabolism thus hold significant potential for translating preclinical findings into therapies that improve the quality of life for the aging population and underscore the need for approaches that address the immunometabolic mechanisms of cardiac aging, providing a framework for future research.
    Keywords:  cardiac aging; immunometabolism; inflammaging; oxidative phosphorylation
    DOI:  https://doi.org/10.1161/JAHA.124.039216
  7. Life Sci. 2024 Dec 23. pii: S0024-3205(24)00922-6. [Epub ahead of print] 123332
    Sinomenine modulates the metabolic reprogramming induced by sepsis via CHRNA7.
    Jie Zhao, Zi Wang, Xinxin Zou, Jinlong Lao, Yan Zhang, Wenjie Zhang, Jingrong Yu, Fengjie Huang.
       BACKGROUND AND PURPOSE: Sepsis is a condition capable of causing systemic inflammation and metabolic reprogramming. Previous studies have shown that sinomenine (SIN) can mitigate sepsis by reducing inflammation, while the effect on metabolic reprogramming is unclear. The aim of this study is to investigate the function of SIN in metabolic reprogramming in sepsis.
    EXPERIMENTAL APPROACH: Differential metabolites in lung tissue and serum were analyzed by 1H Nuclear Magnetic Resonance (1H NMR) and metabolomics were used to compare metabolic changes in septic mice. Nicotinic acetylcholine receptors alpha7 subunit (CHRNA7)-Knockdown (KD) mice and other techniques, were used to detect the expression of markers of several metabolic pathways.
    KEY RESULTS: Metabolomics studies showed that SIN could affect energy metabolism, particularly glucose metabolism, and this effect may be related to the activation of CHRNA7. Further studies showed that SIN could inhibit aerobic glycolysis, promote glutamine anaplerosis, reduce pentose phosphate pathway flux and ultimately mediate metabolic reprogramming.
    CONCLUSION AND IMPLICATIONS: SIN restores glycolysis and glutamine anaplerosis by interacting with CHRNA7, thereby mediating metabolic reprogramming and mitigating sepsis. These findings shed light on the mechanism of SIN in attenuating sepsis from a metabolic perspective.
    Keywords:  CHRNA7; Metabolic reprogramming; Sepsis; Sinomenine
    DOI:  https://doi.org/10.1016/j.lfs.2024.123332
  8. J Cell Immunol. 2024 ;6(5): 196-208
    Polyamines: Key Players in Immunometabolism and Immune Regulation.
    Shanmuga S Mahalingam, Pushpa Pandiyan.
      Polyamines are small organic molecules ubiquitously present in all living organisms and function as crucial regulators of biological processes ranging from fundamental cellular metabolism to immune regulation. Dysregulation of polyamine metabolism has been implicated in numerous diseases, including neurodegenerative disorders, inflammatory conditions, autoimmune diseases, and cancer. This review provides an overview of pathophysiology of these conditions, highlighting polyamines' role in immunometabolic alterations in the context of immune regulation. Exploring the intricate mechanisms of polyamine metabolism holds promise for advancing our understanding of disease processes and developing potential innovative therapeutic interventions.
    Keywords:  Cancer; HIV; Immune regulation; Immunometabolism; Polyamines; Tumorigenesis
    DOI:  https://doi.org/10.33696/immunology.6.206
  9. J Leukoc Biol. 2024 Dec 26. pii: qiae259. [Epub ahead of print]
    Trained Immunity Enhances Host Resistance to Infection in Aged Mice.
    Dan Hao, Katherine R Caja, Margaret A McBride, Allison M Owen, Julia K Bohannon, Antonio Hernandez, Sabah Ali, Sujata Dalal, David L Williams, Edward R Sherwood.
      Aging significantly increases the incidence and severity of infections, with individuals aged 65 and above accounting for 65% of sepsis cases. Innate immune training, known as "trained immunity" or "innate immune memory", has emerged as a potential strategy to enhance infection resistance by modulating the aging immune system. We investigated the impact of β-glucan-induced trained immunity on aged mice (18-20 months old) compared to young adult mice (10-12 weeks old). Our findings showed that β-glucan equally augmented the host resistance to infection in both young and aged mice. This enhancement was characterized by augmented bacterial clearance, enhanced leukocyte recruitment and decreased cytokine production in response to Pseudomonas aeruginosa infection. Furthermore, young and aged trained macrophages displayed heightened metabolic capacity and improved antimicrobial functions, including enhanced phagocytosis and respiratory burst. RNA-seq analysis showed a distinctive gene expression pattern induced by trained immunity in macrophages characterized by activation of pathways regulating inflammation and the host response to infection and suppression of pathways regulating cell division, which was consistently observed in both young and aged groups. As compared to macrophages from young mice, aged macrophages showed increased activation of gene ontology pathways regulating angiogenesis, connective tissue deposition and wound healing. Our results indicate that immune training can be effectively induced in aging mice, providing valuable insights into potential strategies for enhancing infection resistance in the elderly.
    Keywords:   β-glucan; immunometabolism; infection; trained immunity
    DOI:  https://doi.org/10.1093/jleuko/qiae259
  10. Adv Sci (Weinh). 2024 Dec 24. e2410107
    Metabolic Reprogramming of Macrophages by Biomimetic Melatonin-Loaded Liposomes Effectively Attenuates Acute Gouty Arthritis in a Mouse Model.
    Chuchu Ma, Yuyu Jiang, Yan Xiang, Chang Li, Xiaoying Xie, Yunkai Zhang, Yang You, Laozhi Xie, Jianing Gong, Yinzhe Sun, Shiqiang Tong, Qingxiang Song, Jun Chen, Wenze Xiao.
      Gouty arthritis is characterized by an acute inflammatory response triggered by monosodium urate (MSU) crystals deposited in the joints and periarticular tissues. Current treatments bring little effects owing to serious side effects, necessitating the exploration of new and safer therapeutic options. Macrophages play a critical role in the initiation, progression, and resolution of acute gout, with the cellular profiles closely linked to their activation and polarization. This suggests that metabolic regulation can be of significance in managing gouty inflammation. In this study, it is demonstrated that melatonin, a natural hormone, modulates the metabolic remodeling of inflammatory macrophages by shifting their metabolism from glycolysis to oxidative phosphorylation, further altering functions of the pathogenic macrophage. To improve melatonin delivery to the inflamed sites, macrophage membrane-coated melatonin-loaded liposomes (MLT-MLP) are developed. Benefiting from the inflammation-homing characteristic of macrophage membrane, such engineered liposomes effectively target the inflamed site and demonstrate potent anti-inflammatory effects, achieving an enhanced amelioration of acute gouty arthritis. In conclusion, this study proposes a novel strategy aimed at metabolic reprogramming of macrophages to attenuate the pathological injuries in acute gout, providing a potential therapeutic strategy of gout-associated diseases, especially gouty arthritis.
    Keywords:  acute gout; biomimetic; macrophage; melatonin; metabolic reprogramming
    DOI:  https://doi.org/10.1002/advs.202410107
  11. Cancer Cell. 2024 Dec 23. pii: S1535-6108(24)00476-8. [Epub ahead of print]
    Targeting P4HA1 promotes CD8+ T cell progenitor expansion toward immune memory and systemic anti-tumor immunity.
    Shijun Ma, Li-Teng Ong, Zemin Jiang, Wee Chyan Lee, Puay Leng Lee, Mubaraka Yusuf, Henrik J Ditzel, Yulan Wang, Qingfeng Chen, Wenyu Wang, Xiaojian Wu, Ern Yu Tan, Qiang Yu.
      Successful immunotherapy relies on both intratumoral and systemic immunity, which is yet to be achieved for most patients with cancer. Here, we identify P4HA1, encoding prolyl 4-hydroxylase 1, as a crucial regulator of CD8+ T cell differentiation strongly upregulated in tumor-draining lymph nodes (TDLNs) and hypoxic tumor microenvironment. P4HA1 accumulates in mitochondria, disrupting the tricarboxylic acid (TCA) cycle through aberrant α-ketoglutarate and succinate metabolism, promoting mitochondria unfitness and exhaustion while suppressing progenitor expansion. Targeting P4HA1 enhances both adoptive and endogenous TCF1+ CD8+ T progenitor expansion while mitigating the development of exhaustion in the tumor, TDLN, and blood, enabling a notable and durable systemic anti-cancer immunity. We propose that P4HA1 induction in CD8+ T cells in cancer orchestrates an immune-escape program, offering a T cell-directed target for system immunotherapy in solid tumors.
    Keywords:  CAR T cells; P4HA1; PD-1; T cell exhaustion; T cell memory; cancer immunotherapy; hypoxia; mitochondria; solid tumors; systemic immunity
    DOI:  https://doi.org/10.1016/j.ccell.2024.12.001
  12. Front Aging. 2024 ;5 1480886
    Heightened cholesterol 25-hydroxylase expression in aged lung during Streptococcus pneumoniae.
    David G Thomas, Jianjun Yang, Soo Jung Cho, Heather Stout-Delgado.
       Introduction: Alveolar macrophages (AM) are critical effectors of the immune response and are essential for host responses to Streptococcus pneumoniae. Changes in lipid metabolism in AM can alter cellular function and biology. Impaired metabolism can contribute to excessive lipid accumulation and pro-inflammatory signaling. Our current study was designed to examine the role of cholesterol 25-hydroxylase (Ch25h), a redox enzyme that catalyzes the oxidation of cholesterol to 25-hydroxycholesterol (25-HC), in modulating AM responses in the aged lung during S. pneumoniae infection.
    Methods: To observe the impact of aging on Ch25h expression in AM during infection, in vitro and in vivo murine models of S. pneumoniae were used.
    Results: At baseline and in response to infection, cholesterol metabolism significantly altered in aged AM, which corresponded with increased lipid droplet formation. In vitro, treatment of aged macrophages with Ch25 h-specific siRNA improved S. pneumoniae clearance and enhanced phagocytic receptor expression. In vivo siRNA targeting significantly reduced Ch25h expression in aged lungs and improved clinical parameters during S. pneumoniae infection. Reduction of Ch25h was associated with changes in phagocytosis and antibacterial signaling, correlated with changes in cholesterol metabolism, and increased S. pneumoniae clearance.
    Discussion: The results of our current study demonstrate that Ch25h plays an essential role in modulating aged AM responses to S. pneumoniae.
    Keywords:  CH25H; Streptococcus pneumoniae; aging; cholesterol; lipid metabolism; macrophage
    DOI:  https://doi.org/10.3389/fragi.2024.1480886
  13. Front Immunol. 2024 ;15 1508985
    The impact of glucose metabolism on inflammatory processes in sepsis-induced acute lung injury.
    Shilei Cheng, Yufei Li, Xiaoliang Sun, Zhirui Liu, Liang Guo, Jueheng Wu, Xiaohan Yang, Sisi Wei, Guanghan Wu, Shilong Xu, Fan Yang, Jianbo Wu.
      Acute lung injury (ALI) is a prevalent and critical complication of sepsis, marked by high incidence and mortality rates, with its pathogenesis still not being fully elucidated. Recent research has revealed a significant correlation between the metabolic reprogramming of glucose and sepsis-associated ALI (S-ALI). Throughout the course of S-ALI, immune cells, including macrophages and dendritic cells, undergo metabolic shifts to accommodate the intricate demands of immune function that emerge as sepsis advances. Indeed, glucose metabolic reprogramming in S-ALI serves as a double-edged sword, fueling inflammatory immune responses in the initial stages and subsequently initiating anti-inflammatory responses as the disease evolves. In this review, we delineate the current research progress concerning the pathogenic mechanisms linked to glucose metabolic reprogramming in S-ALI, with a focus on the pertinent immune cells implicated. We encapsulate the impact of glucose metabolic reprogramming on the onset, progression, and prognosis of S-ALI. Ultimately, by examining key regulatory factors within metabolic intermediates and enzymes, We have identified potential therapeutic targets linked to metabolic reprogramming, striving to tackle the inherent challenges in diagnosing and treating Severe Acute Lung Injury (S-ALI) with greater efficacy.
    Keywords:  ALI; glycolysis; immune response; metabolic reprogramming; oxidative phosphorylation (OXPHOS); sepsis
    DOI:  https://doi.org/10.3389/fimmu.2024.1508985
  14. Geroscience. 2024 Dec 21.
    A unique inflammaging profile generated by T cells from people with obesity is metformin resistant.
    S SantaCruz-Calvo, S Saraswat, G H Kalantar, E Zukowski, H Marszalkowski, A Javidan, F Gholamrezaeinejad, L P Bharath, P A Kern, X D Zhang, B S Nikolajczyk.
      The alarmingly high prevalence of obesity in older adults coupled with the negative health effects of chronic inflammation in both obesity and aging highlight the importance of studies investigating the impacts of obesity on age-related inflammation. Since shifts in peripheral T-cell metabolism and function drive systemic inflammation in both obesity and aging, we hypothesize that obesity impacts the Th17-dominated inflammaging profile we identified in lean subjects and thus modifies the anti-inflammatory effects of geroprotective drugs like metformin. New cytokine profiling data showed that CD4+ T cells from older people with obesity generate a profile that specifically excludes Th17 cytokines. Metformin failed to change the age-associated T-cell profile in obesity, despite lowering both mitochondrial respiration and reactive oxygen species (ROS) production. Metformin did not improve macroautophagy in T cells from older people with obesity, in sharp contrast to the ability of metformin to promote autophagy in T cells from older lean subjects. These data indicate that body mass index modifies the mechanisms supporting inflammaging in T cells from older subjects, and that metformin-mediated restoration of redox balance is insufficient to stem obesity-associated inflammaging. We conclude that obesity fundamentally changes the mechanisms that promote inflammaging, and thus obesity becomes a critical consideration for clinical trials of geroprotective agents such as metformin.
    Keywords:  Age-related inflammation; Autophagy; Partial least squares discriminant analysis; Redox balance; Systemic inflammation
    DOI:  https://doi.org/10.1007/s11357-024-01441-4
  15. Cell Immunol. 2024 Dec 21. pii: S0008-8749(24)00115-1. [Epub ahead of print]408 104912
    Sodium butyrate prevents lipopolysaccharide induced inflammation and restores the expression of tight junction protein in human epithelial Caco-2 cells.
    Jyotsana Bakshi, K P Mishra.
      The gastrointestinal (GI) tract is susceptible to damage under high altitude hypoxic conditions, leading to gastrointestinal discomfort and intestinal barrier injury. Sodium butyrate, a short-chain fatty acid present as a metabolite in the gut, has emerged as a promising therapeutic agent due to its ability to act as an immunomodulatory agent and restore intestinal barrier integrity. This study aimed to explore the mechanism by which sodium butyrate exhibits anti inflammatory effect on intestinal epithelial cells. In vitro, Caco-2 epithelial cells and RAW 264.7 macrophages were used to investigate the protective role of sodium butyrate on Lipopolysaccharide (LPS) induced inflammation. Cell viability assays demonstrated that 1 mM (110.86 μg/mL) of sodium butyrate did not exhibit cytotoxicity on cells in vitro. Treatment with sodium butyrate suppressed reactive oxygen species levels and TNF-α production in LPS-stimulated macrophages, indicating its efficacy in mitigating inflammatory responses. Western blot analysis revealed that sodium butyrate attenuated the expression of iNOS in RAW 264.7 macrophage cells. Moreover, sodium butyrate also reversed the LPS induced over expression of HIF-1α, NLRP3, IL-1β as well as NF-kB in Caco-2 epithelial cells and also had a suppressive effect on IL-8 secretion after LPS stimulation. Immunocytochemistry demonstrated that sodium butyrate enhanced tight junction protein occludin expression in Caco-2 cells while also restoring the decreased permeability of the Caco-2 monolayer due to LPS. These results indicate that sodium butyrate may influence immune responses by suppressing inflammatory mediators and improving the integrity of the epithelial barrier. Understanding the intricate interactions between gut metabolites and host immune responses may help in the development of innovative therapeutic strategies to alleviate intestinal inflammation in high altitude environments.
    Keywords:  Cytokines; Gut immunity; Inflammasome; Inflammation; Sodium butyrate
    DOI:  https://doi.org/10.1016/j.cellimm.2024.104912
  16. Immunity. 2024 Dec 13. pii: S1074-7613(24)00535-1. [Epub ahead of print]
    Pyrimidine synthesis enzyme CTP synthetase 1 suppresses antiviral interferon induction by deamidating IRF3.
    Youliang Rao, Chao Qin, Ali Can Savas, Qizhi Liu, Shu Feng, Guoli Hou, Taolin Xie, Pinghui Feng.
      Metabolism is typically contextualized in conjunction with proliferation and growth. The roles of metabolic enzymes beyond metabolism-such as in innate immune responses-are underexplored. Using a focused short hairpin RNA (shRNA)-mediated screen, we identified CTP synthetase 1 (CTPS1), a rate-limiting enzyme of pyrimidine synthesis, as a negative regulator of interferon induction. Mechanistically, CTPS1 interacts with and deamidates interferon regulatory factor 3 (IRF3). Deamidation at N85 impairs IRF3 binding to promoters containing IRF3-responsive elements, thus muting interferon (IFN) induction. Employing CTPS1 conditional deletion and IRF3 deamidated or deamidation-resistant knockin mice, we demonstrated that CTPS1-driven IRF3 deamidation restricts IFN induction in response to viral infection in vivo. However, during immune activation, IRF3 deamidation by CTPS1 is inhibited by glycogen synthase kinase 3 beta (GSK3β) to promote IFN induction. This work demonstrates how CTPS1 tames innate immunity independent of its role in pyrimidine synthesis, thus expanding the functional repertoire of metabolic enzymes into immune regulation.
    Keywords:  CTP synthetase; RNA and DNA viruses; interferon production; interferon regulatory factor; protein deamidation; pyrimidine synthesis enzyme
    DOI:  https://doi.org/10.1016/j.immuni.2024.11.020
  17. Clin Exp Immunol. 2024 Dec 25. pii: uxae127. [Epub ahead of print]
    Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus.
    Anna Radziszewska, Hannah Peckham, Restuadi Restuadi, Melissa Kartawinata, Dale Moulding, Nina M de Gruijter, George A Robinson, Maryam Butt, Claire T Deakin, Meredyth G Ll Wilkinson, Lucy R Wedderburn, Elizabeth C Jury, Elizabeth C Rosser, Coziana Ciurtin.
      Juvenile systemic lupus erythematosus (JSLE) is an autoimmune condition which causes significant morbidity in children and young adults and is more severe in its presentation than adult-onset SLE. While many aspects of immune dysfunction have been studied extensively in adult-onset SLE, there is limited and contradictory evidence of how cytotoxic CD8+ T cells contribute to disease pathogenesis and studies exploring cytotoxicity in JSLE are virtually non-existent. Here, we report that CD8+ T cell cytotoxic capacity is reduced in JSLE versus healthy controls, irrespective of treatment or disease activity. Transcriptomic and serum metabolomic analysis identified that this reduction in cytotoxic CD8+ T cells in JSLE was associated with upregulated type I interferon (IFN) signalling, mitochondrial dysfunction, and metabolic disturbances when compared to controls. Greater interrogation of the influence of these pathways on altered cytotoxic CD8+ T cell function demonstrated that JSLE CD8+ T cells had enlarged mitochondria and enhanced sensitivity to IFN-α leading to selective apoptosis of effector memory (EM) CD8+ T cells, which are enriched for cytotoxic mediator-expressing cells. This process ultimately contributes to the observed reduction in CD8+ T cell cytotoxicity in JSLE, reinforcing the growing evidence that mitochondrial dysfunction is a key pathogenic factor affecting multiple immune cell populations in type I IFN-driven rheumatic diseases.
    Keywords:  CD8+ T cells; cytotoxicity; interferon; juvenile systemic lupus erythematosus
    DOI:  https://doi.org/10.1093/cei/uxae127
  18. bioRxiv. 2024 Dec 13. pii: 2024.12.12.626682. [Epub ahead of print]
    Altered Purinergic Signaling and CD8+ T Cell Dysregulation in STAT3 GOF Syndrome.
    Jose S Campos Duran, Samir Sayed, Megan C Dalalo, Andrea A Mauracher, Montana S Knight, Peyton E Conrey, Aaron B Schultz, Ceire A Hay, Robert B Lindell, Christian A Howard, Eric D Abrams, Erica G Schmitt, Martin A Thelin, Sarah Bluestein, Christine M Seroogy, Tamara C Pozos, Akaluck Thatayatikom, Ingrid Lundgren, Amelie Gauthier, Scott W Canna, Helen C Su, Michael D Keller, Ottavia M Delmonte, Lisa R Forbes Satter, Steven M Holland, Jenna R E Bergerson, Jennifer W Leiding, Neil Romberg, Alexandra F Freeman, Alejandro V Villarino, Mark S Anderson, Megan A Cooper, Tiphanie P Vogel, Sarah E Henrickson.
      Signal transduction downstream of activating stimuli controls CD8+ T cell biology, however these external inputs can become uncoupled from transcriptional regulation in Primary Immune Regulatory Disorders (PIRDs). Gain-of-function (GOF) variants in STAT3 amplify cytokine signaling and cause a severe PIRD characterized by early onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity. The molecular mechanisms by which STAT3 GOF variants drive this pathology remain unclear. We found that naive CD8+ T cells have an increased capacity for IFN-g and TNF-a secretion. Given this dysregulation of CD8+ T cell function, we evaluated changes in immunoregulatory pathways and found evidence of dysregulated purinergic signaling via high dimensional immune profiling, single-cell RNA sequencing, and functional assessment. Specifically, while expression of CD39, which transforms ATP to AMP, was increased on CD8+ T cells from patients with STAT3 GOF, downstream purinergic family members, CD73 and the adenosine receptor, A2AR, were downregulated, impairing the potential to produce or sense inhibitory adenosine. Patients with STAT3 GOF can be clinically treated with JAK inhibitors, and this partially normalized naive CD8+ T cell dysregulation, including aberrant cytokine production. The extent of normalization scaled with normalization of CD73 and A2AR. This suggests that a dysregulated purinergic signaling axis plays an important role in CD8+ T cell dysregulation in STAT3 GOF, which may have implications for other inflammatory disorders with amplified STAT signaling.
    DOI:  https://doi.org/10.1101/2024.12.12.626682
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