bims-imicid 2024-12-22 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–12–22
twenty-two papers selected by
Dylan Ryan, University of Cambridge

Time-of-day control of mitochondria regulates NLRP3 inflammasome activation in macrophages.
Pregnancy Entails a Metabolic Rewiring of Maternal Circulating Neutrophils.
Navigating the metabolic landscape of regulatory T cells: from autoimmune diseases to tumor microenvironments.
Unraveling Diabetic Kidney Disease: The Roles of Mitochondrial Dysfunction and Immunometabolism.
Salmonella-induced SIRT1 and SIRT3 are crucial for maintaining the metabolic switch in bacteria and host for successful pathogenesis.
Exploring tryptophan metabolism in cardiometabolic diseases.
Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
Fundamental Neurochemistry Review: Lipids across microglial states.
A Constant Filgotinib Delivery Adhesive Platform Based on Polyethylene Glycol (PEG) Hydrogel for Accelerating Wound Healing via Restoring Macrophage Mitochondrial Homeostasis.
Phase Partitioning of the Neutrophil Oxidative Burst is Coordinated by Accessory Pathways of Glucose Metabolism and Mitochondrial Activity.
Fructose-1,6-diphosphate inhibits viral replication by promoting the lysosomal degradation of HMGB1 and blocking the binding of HMGB1 to the viral genome.
Exercise-induced anxiety impairs local and systemic inflammatory response and glucose metabolism in C57BL/6J mice.
Immunometabolism in head and neck squamous cell carcinoma: Hope and challenge.
Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response.
Multiomic profiling of chronically activated CD4+ T cells identifies drivers of exhaustion and metabolic reprogramming.
An Optimized Ex Vivo n-3 PUFA Supplementation Strategy for Primary Human Macrophages Shows That DHA Suppresses Prostaglandin E2 Formation.
Hospitalised older adults with community-acquired pneumonia and sepsis have dysregulated neutrophil function but preserved glycolysis.
The microbiota metabolite, phloroglucinol, confers long-term protection against inflammation.
Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids.
5-Aminolevulinic Acid (5-ALA) Plays an Important Role in the Function of Innate Immune Cells.
Mitochondrial metabolism and epigenetic crosstalk drive the SASP.
STING exerts antiviral innate immune response by activating pentose phosphate pathway.

FASEB J. 2024 Dec 13. 38(24): e70235

Time-of-day control of mitochondria regulates NLRP3 inflammasome activation in macrophages.

James R O'Siorain, Shannon L Cox, Cloé Payet, Frances K Nally, Yan He, Tabea T Drewinksi, Oran D Kennedy, Jennifer K Dowling, Mark Mellett, James O Early, Annie M Curtis.

  Macrophages are innate immune cells that orchestrate the process of inflammation, which varies across time of day. This ensures appropriate biological timing of the immune response with the external environment. The NLRP3 inflammasome mediates IL-1-family cytokine release via pyroptosis. Mitochondria play a multifaceted role regulating NLRP3 inflammasome activity. Mitochondria exhibit distinct metabolic changes across time of day, which are influenced by clock genes. However, whether the macrophage clock regulates the NLRP3 inflammasome via mitochondrial control remains unclear. We find heightened mitochondrial membrane potential (Δψm) and enhanced NLRP3 inflammasome activation from peritoneal exudate cells (PECs) isolated at circadian time (CT) 12 compared to CT 0. In vitro time-of-day synchronization of bone-marrow derived macrophages (BMDMs) induced time-dependent differences in NLRP3 inflammasome activation. Myeloid-specific Bmal1-deletion enhanced NLRP3 inflammasome activity in PECs at CT0 and in unsynchronized BMDMs compared to controls. Pharmacologically disrupting Δψm in synchronized cells reduced NLRP3 inflammasome activation to comparable levels, and the same occurred with Bmal1-deletion. These results further demonstrate circadian clock timing of the NLRP3 inflammasome, which is dependent on mitochondrial function and driven through the circadian gene Bmal1.

Keywords:  NLRP3 inflammasome; circadian rhythms; macrophages; mitochondria; pyroptosis

DOI:  https://doi.org/10.1096/fj.202400508RR
J Cell Physiol. 2024 Dec 16. e31502

Pregnancy Entails a Metabolic Rewiring of Maternal Circulating Neutrophils.

Guillermina Calo, Fátima Merech, Florencia Sabbione, Vanesa Hauk, Brenda Lara, Luciana Doga, Luciana D'eramo, Aldo Squassi, Rosanna Ramhorst, Analía Trevani, Daiana Vota, Claudia Pérez Leirós.

  Immunometabolism is an emerging growing field that focuses on the role of cellular metabolism in the regulation of immune cell function and fate. Thus, proliferation, differentiation, activation, and function of immune cell populations are modulated by reprogramming their fueling and metabolic pathways. Pregnancy entails a fine immune and metabolic regulation of the maternal-fetal interaction to assist the energetic demands of the fetus where trophoblast cells have a central role. Maternal neutrophil functional shaping by trophoblast cells has been proposed though their metabolic conditioning during pregnancy has not been studied yet. Here, we explored the effects of trophoblast-derived factors on the metabolic rewiring of neutrophils from nonpregnant women and its impact on central functions like reactive oxygen species (ROS) production, neutrophil extracellular trap (NET) release, and migration. In parallel, the immunometabolic status and function of neutrophils isolated from pregnant women (16-20 weeks) was compared with nonpregnant age-matched control samples. Trophoblast-derived factors induced glucose uptake and lipid droplet accumulation without activating ROS production or NET release. Conditioned media from trophoblast cells also inhibited PMA-induced NETosis partly by impairing glucose uptake in neutrophils. In turn, neutrophils from pregnant women had increased basal ROS production, lipid accumulation, and glucose uptake compared to neutrophils from nonpregnant women, accompanied by a higher release of PMA-induced NETs. Interestingly, PMA-induced NETs was blocked by a fatty acid oxidation inhibitor in neutrophils from pregnant women indicating the contribution of fatty acid metabolism to neutrophil activity during pregnancy. Results are consistent with immunometabolic mechanisms underlying the functional shaping of neutrophils during pregnancy and point out the contribution of trophoblast-derived factors to their metabolic profiling. These findings provide novel immunometabolic clues to understand immune homeostasis maintenance during pregnancy and raise the clinical potential of monitoring neutrophil metabolism during normal and complicated pregnancies.

Keywords:  NETs; human neutrophils; immunometabolism; pregnancy; trophoblast factors

DOI:  https://doi.org/10.1002/jcp.31502
Curr Opin Immunol. 2024 Dec 12. pii: S0952-7915(24)00101-8. [Epub ahead of print]92 102511

Navigating the metabolic landscape of regulatory T cells: from autoimmune diseases to tumor microenvironments.

Janika Härm, Yu-Tong Fan, Dirk Brenner.

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, playing crucial roles in modulating autoimmune conditions and contributing to the suppressive tumor microenvironment. Their cellular metabolism governs their generation, stability, proliferation, and suppressive function. Enhancing Treg metabolism to boost their suppressive function offers promising therapeutic potential for alleviating inflammatory symptoms in autoimmune diseases. Conversely, inhibiting Treg metabolism to reduce their suppressive function can enhance the efficacy of traditional immunotherapy in cancer patients. This review explores recent advances in targeting Treg metabolism in autoimmune diseases and the metabolic adaptations of Tregs within the tumor microenvironment that increase their immunosuppressive function.

DOI: https://doi.org/10.1016/j.coi.2024.102511
Kidney Int Rep. 2024 Dec;9(12): 3386-3402

Unraveling Diabetic Kidney Disease: The Roles of Mitochondrial Dysfunction and Immunometabolism.

Phoom Narongkiatikhun, Ye Ji Choi, Hailey Hampson, Jimmy Gotzamanis, Guanshi Zhang, Daniel H van Raalte, Ian H de Boer, Robert G Nelson, Kalie L Tommerdahl, Phillip J McCown, Jenny Kanter, Kumar Sharma, Petter Bjornstad, Pierre Jean Saulnier.

  Mitochondria are essential for cellular energy production and are implicated in numerous diseases, including diabetic kidney disease (DKD). Current evidence indicates that mitochondrial dysfunction results in alterations in several metabolic pathways within kidney cells, thereby contributing to the progression of DKD. Furthermore, mitochondrial dysfunction can engender an inflammatory milieu, leading to the activation and recruitment of immune cells to the kidney tissue, potentially perturbing intrarenal metabolism. In addition, this inflammatory microenvironment has the potential to modify immune cell metabolism, which may further accentuate the immune-mediated kidney injury. This understanding has led to the emerging field of immunometabolism, which views DKD as not just a metabolic disorder caused by hyperglycemia but also one with significant immune contributions. Targeting mitochondrial function and immunometabolism may offer protective effects for the kidneys, complementing current therapies and potentially mitigating the risk of DKD progression. This comprehensive review examines the impact of mitochondrial dysfunction and the potential role of immunometabolism in DKD. We also discuss tools for investigating these mechanisms and propose avenues for integrating this research with existing therapies. These insights underscore the modulation of mitochondrial function and immunometabolism as a critical strategy for decelerating DKD progression.

Keywords:  diabetic kidney disease; immunometabolism; metabolic reprogramming; mitochondrial dysfunction; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.ekir.2024.09.019
Elife. 2024 Dec 18. pii: RP93125. [Epub ahead of print]13

Salmonella-induced SIRT1 and SIRT3 are crucial for maintaining the metabolic switch in bacteria and host for successful pathogenesis.

Dipasree Hajra, Raju S Rajmani, Ayushi Devendrasingh Chaudhary, Shashi Kumar Gupta, Dipshikha Chakravortty.

  Sirtuins are the major players in host immunometabolic regulation. However, the role of sirtuins in the modulation of the immune metabolism pertaining to salmonellosis is largely unknown. Here, our investigation focussed on the role of two important sirtuins, SIRT1 and SIRT3, shedding light on their impact on intracellular Salmonella's metabolic switch and pathogenesis establishment. Our study indicated the ability of the live Salmonella Typhimurium to differentially regulate the levels of SIRT1 and SIRT3 for maintaining the high glycolytic metabolism and low fatty acid metabolism in Salmonella. Perturbing SIRT1 or SIRT3 through knockdown or inhibition resulted in a remarkable shift in the host metabolism to low fatty acid oxidation and high glycolysis. This switch led to decreased proliferation of Salmonella in the macrophages. Further, Salmonella-induced higher levels of SIRT1 and SIRT3 led to a skewed polarization state of the macrophages from a pro-inflammatory M1 state toward an immunosuppressive M2, making it more conducive for the intracellular life of Salmonella. Alongside, governing immunological functions by modulating p65 NF-κB acetylation, SIRT1, and SIRT3 also skew Salmonella-induced host metabolic switch by regulating the acetylation status of HIF-1α and PDHA1. Interestingly, though knockdown of SIRT1/3 attenuated Salmonella proliferation in macrophages, in in vivo mice model of infection, inhibition or knockdown of SIRT1/3 led to more dissemination and higher organ burden, which can be attributed to enhanced ROS and IL-6 production. Our study hence reports for the first time that Salmonella modulates SIRT1/3 levels to maintain its own metabolism for successful pathogenesis.

Keywords:  SIRT1; SIRT3; Salmonella enterica serovar Typhimurium; Salmonella metabolism; bacterial dissemination; immune regulation; infectious disease; metabolic shift; microbiology

DOI:  https://doi.org/10.7554/eLife.93125
Trends Endocrinol Metab. 2024 Dec 17. pii: S1043-2760(24)00317-5. [Epub ahead of print]

Exploring tryptophan metabolism in cardiometabolic diseases.

Nirmala Mouttoulingam, Soraya Taleb.

  Tryptophan (Trp) metabolism is linked to health and disease, with indoleamine 2,3-dioxygenase 1 (IDO) being a key enzyme in its breakdown outside the liver. This process produces metabolites that influence metabolic and inflammatory responses. A distinctive feature of the gut is its involvement in three major Trp catabolic pathways: the IDO-driven kynurenine pathway, bacteria-produced indoles, and serotonin. Dysregulation of these pathways is associated with gastrointestinal and chronic inflammatory diseases. Understanding these mechanisms could reveal how gut function affects overall systemic health and disease susceptibility. Here, we review current insights into Trp metabolism, its impact on host physiology and cardiometabolic diseases, and its role in the gut-periphery connection, highlighting its relevance for therapeutic innovation.

Keywords:  atherosclerosis; gut; indoleamine 2,3-dioxygenase 1; metabolic diseases; tryptophan

DOI:  https://doi.org/10.1016/j.tem.2024.11.009
Cell Syst. 2024 Dec 18. pii: S2405-4712(24)00346-6. [Epub ahead of print]15(12): 1225-1244

Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.

Bing Feng, Rongrong Li, Weilin Li, Li Tang.

  Many cancer immunotherapies rely on robust CD8+ T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8+ tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation. Targeting metabolism holds promise for enhancing CD8+ T cell-mediated antitumor immunity. Here, we overview the metabolic features of CD8+ TILs and their impact on T cell effector function and differentiation. We also highlight immunoengineering strategies by leveraging the Yin-Yang of metabolic modulation for improving cancer immunotherapy.

Keywords:  CD8(+) T cell; cancer immunotherapy; metabolic immunoengineering

DOI:  https://doi.org/10.1016/j.cels.2024.11.010
J Neurochem. 2025 Jan;169(1): e16259

Fundamental Neurochemistry Review: Lipids across microglial states.

Marianela E Traetta, Haley A Vecchiarelli, Marie-Ève Tremblay.

  The capacity of immune cells to alter their function based on their metabolism is the basis of the emerging field of immunometabolism. Microglia are the resident innate immune cells of the central nervous system, and it is a current focus of the field to investigate how alterations in their metabolism impact these cells. Microglia have the ability to utilize lipids, such as fatty acids, as energy sources, but also alterations in lipids can impact microglial form and function. Recent studies highlighting different microglial states and transcriptional signatures have highlighted modifications in lipid processing as defining these states. This review highlights these recent studies and uses these altered pathways to discuss the current understanding of lipid biology in microglia. The studies highlighted here review how lipids may alter microglial phagocytic functioning or alter their pro- and anti-inflammatory balance. These studies provide a foundation by which lipid supplementation or diet alterations could influence microglial states and function. Furthermore, targets modulating microglial lipid metabolism may provide new treatment avenues.

Keywords:  immunometabolism; lipid; microglia; microglial states

DOI:  https://doi.org/10.1111/jnc.16259
Small. 2024 Dec 16. e2408791

A Constant Filgotinib Delivery Adhesive Platform Based on Polyethylene Glycol (PEG) Hydrogel for Accelerating Wound Healing via Restoring Macrophage Mitochondrial Homeostasis.

Jian Xie, Yiqian Huang, Xiaofeng Hu, Xiaowei Wu, Xi Luo, Pengfei Wei, Wei Jing, Bo Zhao, Jiansheng Su.

  Skin wound healing is often hindered by disrupted mitochondrial homeostasis and imbalanced macrophage glucose metabolism, posing a critical challenge to improve patient outcomes. Developing new wound healing dressings capable of effectively regulating macrophage immune-metabolic functions remains a pressing issue. Herein, a highly adhesive polyethylene glycol (PEG) hydrogel loaded with the Janus kinase 1 (JAK1) inhibitor Filgotinib (Fil@GEL) is prepared to modulate macrophage metabolic reprogramming and restore normal mitochondrial function. Fil@GEL exhibits superior shear adhesion strength compared to commercially available tissue binder products, providing adequate adhesion for skin wound closure. Additionally, Fil@GEL exhibits the capacity to inhibit M1-type macrophage polarization by suppressing the JAK-STAT signaling pathway, and induces a metabolic shift in macrophages from aerobic glycolysis to oxidative phosphorylation, which results in decreased lactate production, reduced reactive oxygen species (ROS) levels, and the restoration of mitochondrial homeostasis. The Fil@GEL hydrogel significantly accelerates skin wound healing compared to the control group, reduces intra-wound inflammation, and promotes collagen regeneration. In summary, this highly adhesive hydrogel demonstrates exceptional performance as a drug carrier, exerting immunometabolic modulation through firm wound adhesion and sustained filgotinib release, underscoring its substantial potential as an effective wound dressing.

Keywords:  adhesive hydrogel dressing; macrophages; metabolic reprogramming; mitochondrial homeostasis; wound healing

DOI:  https://doi.org/10.1002/smll.202408791
J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02593-6. [Epub ahead of print] 108091

Phase Partitioning of the Neutrophil Oxidative Burst is Coordinated by Accessory Pathways of Glucose Metabolism and Mitochondrial Activity.

Tyler Jobe, Jonah Stephan, Collin K Wells, Maleesha De Silva, Pawel K Lorkiewicz, Bradford G Hill, Marcin Wysoczynski.

  Neutrophils are a part of the innate immune system and produce reactive oxygen species (ROS) to extinguish pathogens. The major source of ROS in neutrophils is NADPH oxidase, which is fueled by NADPH generated via the pentose phosphate pathway; however, it is unclear how other accessory glucose metabolism pathways and mitochondrial activity influence the respiratory burst. We examined the temporal dynamics of the respiratory burst and delineated how metabolism changes over time after neutrophil activation. Bone marrow-derived neutrophils were stimulated with phorbol 12-myristate 13-acetate (PMA), and the respiratory burst was measured via extracellular flux analysis. Metabolomics experiments utilizing 13C6-glucose highlighted the activation of glycolysis as well as ancillary pathways of glucose metabolism in activated neutrophils. PMA stimulation acutely increased 13C enrichment into glycerol 3-phosphate (G3P) and citrate, whereas increases in 13C enrichment in the glycogen intermediate, UDP-hexose, and end products of the hexosamine and serine biosynthetic pathways occurred only during the late phase of the oxidative burst. Targeted inhibition of the G3P shuttle, glycogenolysis, serine biosynthesis, and mitochondrial respiration demonstrated that the G3P shuttle contributes to the general magnitude of ROS production; that glycogen contributes solely to the early respiratory burst; and that the serine biosynthetic pathway activity and Complex III-driven mitochondrial activity influence respiratory burst duration. Collectively, these results show that the neutrophil oxidative burst is highly dynamic, with coordinated changes in metabolism that control the initiation, magnitude, and duration of ROS production.

Keywords:  glycolysis; innate immunity; mitochondria; pathogen; reactive oxygen species

DOI:  https://doi.org/10.1016/j.jbc.2024.108091
PLoS Pathog. 2024 Dec;20(12): e1012782

Fructose-1,6-diphosphate inhibits viral replication by promoting the lysosomal degradation of HMGB1 and blocking the binding of HMGB1 to the viral genome.

Penghui Hu, Huiyi Li, Zemin Ji, Weijia Jing, Zihan Li, Sujun Yu, Xiao Shan, Yan Cui, Baochen Wang, Hongyuan Dong, Yanzhao Zhou, Zhe Wang, Hui Xiong, Xiaomei Zhang, Hui-Chieh Li, Jinrong Wang, Jiuzhou Tang, Ting Wang, Keliang Xie, Yuping Liu, Haizhen Zhu, Qiujing Yu.

Fructose-1,6-diphosphate (FBP), a key glycolytic metabolite, is recognized for its cytoprotective effects during stress. However, the role of FBP in viral infections is unknown. Here, we demonstrate that virus-infected cells exhibit elevated FBP levels. Exogenous FBP inhibits both RNA and DNA virus infections in vitro and in vivo. Modulating intracellular FBP levels by regulating the expression of the metabolic enzymes FBP1 and PFK1 significantly impacts viral infections. Mechanistically, the inhibitory effects of FBP are not a result of altered viral adhesion or entry and are largely independent of type I interferon-mediated immune responses; rather, they occur through modulation of HMGB1. During viral infections, FBP predominantly reduces the protein levels of HMGB1 by facilitating its lysosomal degradation. Furthermore, FBP interacts with HMGB1 and disrupts the binding of HMGB1 to viral genomes, thereby further inhibiting viral replication. Our findings underscore the potential of FBP as a therapeutic target for controlling viral infections.

DOI: https://doi.org/10.1371/journal.ppat.1012782
Brain Behav Immun Health. 2025 Feb;43 100910

Exercise-induced anxiety impairs local and systemic inflammatory response and glucose metabolism in C57BL/6J mice.

I Gálvez, M C Navarro, S Torres-Piles, L Martín-Cordero, M D Hinchado, E Ortega.

   Introduction: The complex physiological and psychological responses to regular exercise are yet to be fully elucidated. Exercise strongly modulates the immune system, inducing a plethora of dynamic responses involving the innate immune cell function and inflammatory processes that contribute to both potential health benefits and harmful side effects. Indeed, the relationship between physical exercise, stress, immunity, and metabolism serves as a paramount model of neuroimmunoendocrine interaction. Thus, the objective of this study was to conduct a comprehensive analysis of both systemic and local immunophysiological responses together with behavioral responses to a protocol of anxiety-inducing exercise.
Material and methods: C57BL/6J mice were randomly allocated into sedentary or exercised groups, where the anxiety-inducing exercise protocol was based on a 14-day consecutive program of swimming in water at 38 °C. Anxiety-like behavior was corroborated through the elevated plus maze test. Systemic biomarkers of the stress response were assessed using ELISA technique and the expression of systemic inflammatory cytokines with Bio-Plex system. Phagocytic/microbicide activity, the expression of M1/M2 phenotype markers (CD11c, iNOS, CD206, ARG-1) and cytokines of the inflammatory response (MCP-1, IL-8, IL-6, TNF-α, TGF-β, IL-10) of peritoneal macrophages were determined via flow cytometry. Adipose tissue macrophage infiltration was studied through fluorescence immunohistochemistry.
Results: Anxiety-like behavior, elevated circulating glucose concentrations, systemic stress and inflammatory responses, together with increased oxidative stress and inflammatory profile of peritoneal macrophages, and macrophage infiltration in white adipose tissue were observed in exercised animals.
Conclusions: A protocol of exercise that induces anxiety is associated with a neuroimmunoendocrine dysregulation affecting the feedback between the inflammatory and the stress responses, together with detrimental metabolic effects in glucose modulation. Systemic inflammatory alterations are accompanied by detrimental inflammatory responses in tissue macrophage populations. Altogether, these results show that exercise associated with anxiety, stress, pro-inflammatory responses, and hyperglycaemia represents a model of 'dangerous exercise'.

Keywords:  Adipose tissue; Behavior; Corticosterone; Cytokines; Inflammation; M2; Macrophages; Oxidative burst; Regular exercise; Swimming

DOI:  https://doi.org/10.1016/j.bbih.2024.100910
Biochim Biophys Acta Mol Basis Dis. 2024 Dec 15. pii: S0925-4439(24)00623-9. [Epub ahead of print]1871(3): 167629

Immunometabolism in head and neck squamous cell carcinoma: Hope and challenge.

Yi-Jia-Ning Zhang, Yao Xiao, Zi-Zhan Li, Lin-Lin Bu.

  Immunotherapy has improved the survival rate of patients with head and neck squamous cell carcinoma (HNSCC), but less than 20 % of them have a durable response to these treatments. Excessive local recurrence and lymph node metastasis ultimately lead to death, making the 5-year survival rate of HNSCC still not optimistic. Cell metabolism has become a key determinant of the viability and function of cancer cells and immune cells. In order to maintain the enormous anabolic demand, tumor cells choose a specialized metabolism different from non-transformed somatic cells, leading to changes in the tumor microenvironment (TME). In recent years, our understanding of immune cell metabolism and cancer cell metabolism has gradually increased, and we have begun to explore the interaction between cancer cell metabolism and immune cell metabolism in a way which is meaningful for treatment. Understanding the different metabolic requirements of different cells that constitute the immune response to HNSCC is beneficial for revealing metabolic heterogeneity and plasticity, thereby enhancing the effect of immunotherapy. In this review, we have concluded that the relevant metabolic processes that affect the function of immune cells in HNSCC TME and proposed our own opinions and prospects on how to use metabolic intervention to enhance anti-tumor immune responses.

Keywords:  Head and neck squamous cell carcinoma; Immunometabolism; Immunotherapy; Prognosis

DOI:  https://doi.org/10.1016/j.bbadis.2024.167629
Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2412070121

Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response.

Heng Wang, Fang Xu, Chenlu Yao, Huaxing Dai, Jialu Xu, Bingbing Wu, Bo Tian, Xiaolin Shi, Chao Wang.

  Inhibiting indoleamine 2,3 dioxygenase (IDO) for anticancer therapy has garnered significant attention in recent years. However, current IDO inhibitors face significant challenges which limit their clinical application. Here, we genetically engineered a high tryptophan-expressing Clostridium butyricum (L-Trp CB) strain that can colonize tumors strictly following systemic administration. We revealed that butyrate produced by L-Trp CB can inhibit IDO activity, preventing tryptophan catabolism and kynurenine accumulation in tumors. In addition, the large released tryptophan by L-Trp CB can provide discrete signals that support CD8+ T cell activation and energy metabolism within the tumor microenvironment. We observed that L-Trp CB significantly restored the proportion and function of CD8+ T cells, leading to significantly delayed tumor growth in both mouse and rabbit multiple tumor models with limited side effects. We here provide a synthetic biology treatment strategy for enhanced tumor immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response in tumors.

Keywords:  IDO; T cell response; engineering bacteria; synthetic biology; tryptophan

DOI:  https://doi.org/10.1073/pnas.2412070121
PLoS Biol. 2024 Dec 17. 22(12): e3002943

Multiomic profiling of chronically activated CD4+ T cells identifies drivers of exhaustion and metabolic reprogramming.

Matthew L Lawton, Melissa M Inge, Benjamin C Blum, Erika L Smith-Mahoney, Dante Bolzan, Weiwei Lin, Christina McConney, Jacob Porter, Jarrod Moore, Ahmed Youssef, Yashasvi Tharani, Xaralabos Varelas, Gerald V Denis, Wilson W Wong, Dzmitry Padhorny, Dima Kozakov, Trevor Siggers, Stefan Wuchty, Jennifer Snyder-Cappione, Andrew Emili.

Repeated antigen exposure leads to T-cell exhaustion, a transcriptionally and epigenetically distinct cellular state marked by loss of effector functions (e.g., cytotoxicity, cytokine production/release), up-regulation of inhibitory receptors (e.g., PD-1), and reduced proliferative capacity. Molecular pathways underlying T-cell exhaustion have been defined for CD8+ cytotoxic T cells, but which factors drive exhaustion in CD4+ T cells, that are also required for an effective immune response against a tumor or infection, remains unclear. Here, we utilize quantitative proteomic, phosphoproteomic, and metabolomic analyses to characterize the molecular basis of the dysfunctional cell state induced by chronic stimulation of CD4+ memory T cells. We identified a dynamic response encompassing both known and novel up-regulated cell surface receptors, as well as dozens of unexpected transcriptional regulators. Integrated causal network analysis of our combined data predicts the histone acetyltransferase p300 as a driver of aspects of this phenotype following chronic stimulation, which we confirmed via targeted small molecule inhibition. While our integrative analysis also revealed large-scale metabolic reprogramming, our independent investigation confirmed a global remodeling away from glycolysis to a dysfunctional fatty acid oxidation-based metabolism coincident with oxidative stress. Overall, these data provide both insights into the mechanistic basis of CD4+ T-cell exhaustion and serve as a valuable resource for future interventional studies aimed at modulating T-cell dysfunction.

DOI: https://doi.org/10.1371/journal.pbio.3002943
Mol Nutr Food Res. 2024 Dec 15. e202400716

An Optimized Ex Vivo n-3 PUFA Supplementation Strategy for Primary Human Macrophages Shows That DHA Suppresses Prostaglandin E2 Formation.

Rebecca Kirchhoff, Nadja Kampschulte, Carina Rothweiler, Nadine Rohwer, Karsten-Henrich Weylandt, Nils Helge Schebb.

  Evidence suggests beneficial effects of long-chain n-3 polyunsaturated fatty acids (PUFAs) in inflammatory diseases. However, the underlying mechanisms are still subject of research. For this purpose, we developed an ex vivo n-3 PUFA supplementation strategy. M2-like macrophages were supplemented for 2-3 days with 20-40 µM docosahexaenoic acid (DHA) during differentiation. Quality parameters include <3% oxylipins for PUFA-preparation, total fatty acids (FAs) <10 mM, and low oxylipins in plasma, n-3 PUFA <0.25 mM for the selection of donors of plasma as well as %n-6 in highly unsaturated fatty acids (HUFAs) ≥70% for donors of cells. Following supplementation, PUFA pattern of cells was shifted toward one described for blood and tissue from subjects with higher n-3 and lower n-6 PUFAs. This was accompanied by a decrease of arachidonic acid-derived oxylipins in a dose- and time-dependent manner in favor of n-3 PUFA ones. Stimulation with LPS resulted in decreased levels of pro-inflammatory prostaglandins in the DHA-supplemented cells, but no changes in cytokines. In vitro supplementation studies with n-3 PUFA need rigorous controls to exclude the background formation of oxylipins. By accounting for these possible confounders the described approach allows the mechanistic investigation of n-3 PUFAs in primary human immune cells, offering an alternative for intervention studies.

Keywords:  arachidonic acid cascade; fatty acids; inflammation; lipid mediators; oxylipins

DOI:  https://doi.org/10.1002/mnfr.202400716
Thorax. 2024 Dec 16. pii: thorax-2024-222215. [Epub ahead of print]

Hospitalised older adults with community-acquired pneumonia and sepsis have dysregulated neutrophil function but preserved glycolysis.

Frances Grudzinska, Aduragbemi A Faniyi, Kylie B R Belchamber, Celine Chen, Robert Stockley, Alice Jasper, Dhruv Parekh, Elizabeth Sapey, Aaron Scott, David R Thickett.

   OBJECTIVE: Community-acquired pneumonia (CAP) is a leading cause of hospitalisation in older adults and is associated with a high likelihood of adverse outcomes. Given the ageing population and lack of therapeutic advances in CAP, new strategies to manage the burden of this disease are needed. Neutrophil dysfunction has been widely demonstrated in CAP and is associated with poor outcomes. We hypothesised that impaired glycolytic metabolism was driving neutrophil dysfunction in older adults with CAP.
METHODS: To investigate the mechanism underlying neutrophil dysfunction in CAP, we recruited older adults with CAP and sepsis, age-matched controls and healthy young adults to assess neutrophil function and glycolytic metabolism in peripheral blood neutrophils.
RESULTS: We demonstrate that neutrophils from older donors with CAP display a broad range of functional defects, including inaccurate migration to interleukin 8, impaired respiratory burst in response to phorbol 12-myristate 13-acetate and increased spontaneous degranulation compared with age-matched controls. Glycolysis (assessed by extracellular flux and RNA-sequencing) was not significantly altered between age-matched groups; however, basal rates of neutrophil glycolysis were significantly higher in patients with CAP and older adult controls compared with healthy young adults, and stimulated glycolysis was significantly higher in young adults compared with older adults with and without CAP.
CONCLUSIONS: Our findings suggest that neutrophil dysfunction in older adults with CAP may be implicated in poor outcomes, irrespective of glycolytic metabolism.

Keywords:  Innate Immunity; Neutrophil Biology; Pneumonia; Respiratory Infection

DOI:  https://doi.org/10.1136/thorax-2024-222215
Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2438829

The microbiota metabolite, phloroglucinol, confers long-term protection against inflammation.

Janire Castelo, Sarai Araujo-Aris, Diego Barriales, Samuel Tanner Pasco, Iratxe Seoane, Ainize Peña-Cearra, Ainhoa Palacios, Carolina Simó, Virginia Garcia-Cañas, Muthita Khamwong, Itziar Martín-Ruiz, Monika Gonzalez-Lopez, Laura Barcena, José Ezequiel Martín Rodríguez, José Luís Lavín, Naiara Gutiez, Raquel Marcos, Estibaliz Atondo, Arantza Cobela, Laura Plaza-Vinuesa, Adrián Plata, Eneko Santos-Fernandez, Alberto Fernandez-Tejada, Mari Carmen Villarán, José Miguel Mancheño, Juana Maria Flores, Ana María Aransay, Aize Pellón, Blanca de Las Rivas, Rosario Muñoz, Abelardo Margolles, Patricia Ruas-Madiedo, Maria Victoria Selma, Mercedes Gomez de Agüero, Leticia Abecia, Juan Anguita, Héctor Rodríguez.

  Phloroglucinol is a key byproduct of gut microbial metabolism that has been widely used as a treatment for irritable bowel syndrome. Here, we demonstrate that phloroglucinol tempers macrophage responses to pro-inflammatory pathogens and stimuli. In vivo, phloroglucinol administration decreases gut and extraintestinal inflammation in murine models of inflammatory bowel disease and systemic infection. The metabolite induces modest modifications in the microbiota. However, the presence of an active microbiota is required to preserve its anti-inflammatory activity. Remarkably, the protective effect of phloroglucinol lasts partially at least 6 months. Single-cell transcriptomic analysis of bone marrow progenitors demonstrates the capacity of the metabolite to induce long-lasting innate immune training in hematopoietic lineages, at least partially through the participation of the receptor and transcription factor, aryl hydrocarbon receptor (AhR). Phloroglucinol induces alterations in metabolic and epigenetic pathways that are most prevalent in upstream progenitors as hallmarks of central trained immunity. These data identify phloroglucinol as a dietary-derived compound capable of inducing central trained immunity and modulating the response of the host to inflammatory insults.

Keywords:  Microbiota byproducts; central trained immunity; inflammation; phenolic derivatives

DOI:  https://doi.org/10.1080/19490976.2024.2438829
J Lipid Res. 2024 Dec 13. pii: S0022-2275(24)00235-9. [Epub ahead of print] 100730

Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids.

Shelley Barnhart, Masami Shimizu-Albergine, Eyal Kedar, Vishal Kothari, Baohai Shao, Melissa Krueger, Cheng-Chieh Hsu, Jingjing Tang, Jenny E Kanter, Farah Kramer, Danijel Djukovic, Vadim Pascua, Yueh-Ming Loo, Lucrezia Colonna, Sadie J Van den Bogaerde, Jie An, Michael Gale, Karen Reue, Edward A Fisher, Sina A Gharib, Keith B Elkon, Karin E Bornfeldt.

  Long-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive and unbiased approach to investigate the role of ACSL1 induction by interferon type I (IFN-I) in myeloid cells in vitro and in a mouse model of IFN-I overproduction. Our results show that IFN-I induces ACSL1 in macrophages via its interferon-α/β receptor, and consequently that expression of ACSL1 is increased in myeloid cells from individuals with systemic lupus erythematosus (SLE), an autoimmune condition characterized by increased IFN production. Taking advantage of a myeloid cell-targeted ACSL1-deficient mouse model and a series of lipidomics, proteomics, metabolomics and functional analyses, we show that IFN-I leverages induction of ACSL1 to increase accumulation of fully saturated phosphatidic acid species in macrophages. Conversely, ACSL1 induction is not needed for IFN-I's ability to induce the prototypical IFN-stimulated protein signature or to suppress proliferation or macrophage metabolism. Loss of ACSL1 in IFN-I stimulated myeloid cells enhances apoptosis and secondary necrosis in vitro, especially in the presence of increased saturated fatty acid load, and in a mouse model of atherosclerosis associated with IFN overproduction, resulting in larger lesion necrotic cores. We propose that ACSL1 induction is a mechanism used by IFN-I to increase phosphatidic acid saturation while protecting the cells from saturated fatty acid-induced cell death.

Keywords:  Bis[monoacylglycerol]phosphates; Enzymology/Enzyme mechanisms; Glycerophospholipids; Inflammation; Lipotoxicity; Macrophage; Phospholipids/Phosphatidic acid

DOI:  https://doi.org/10.1016/j.jlr.2024.100730
Inflammation. 2024 Dec 19.

5-Aminolevulinic Acid (5-ALA) Plays an Important Role in the Function of Innate Immune Cells.

Shinichi Saitoh, Yuji Takeda, Akemi Araki, Yusuke Nouchi, Risako Yamaguchi, Osamu Nakajima, Hironobu Asao.

  5-aminolevulinic acid (5-ALA) is an amino acid essential for the synthesis of heme, which is important for various cellular functions, including the mitochondrial electron transport chain. We previously established heterozygous knockout mice (Alas1+/-) for 5-ALA synthase 1 (ALAS1), the rate-limiting enzyme for 5-ALA synthesis, and reported that the mice developed non-obese insulin-resistant diabetes. In the present study, we used these mice to analyze the role of 5-ALA in the immune system. Using a lipopolysaccharide (LPS)-induced septic shock model, Alas1+/- mice showed reduced mortality compared to wild-type (WT) mice. In this model experiment, the plasma concentration of inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), and the chemokine monocyte chemoattractant protein-1 (MCP1) decreased in Alas1+/- mice compared that in WT mice, and inflammatory cell infiltration into the peritoneal cavity was also decreased. In ex vivo experiments, exogenous 5-ALA pretreatment enhanced LPS-induced TNFα and IL-6 production from peripheral blood leukocytes of Alas1+/- mice. Additionally, 5-ALA pretreatment enhanced LPS-induced activation of inflammatory cytokine genes in innate immune cells. Interestingly, the phagocytosis and reactive oxygen species (ROS) producing abilities of neutrophils were clearly hampered in Alas1+/- mice compared to WT mice, but after 2 weeks of 5-ALA administration to Alas1+/- mice, both abilities were significantly recovered up to the level in WT mice. These results reveal that 5-ALA is essential for the function of innate immune cells. Because 5-ALA can be supplemented orally, it has the potential to be used as a drug to restore innate immune function.

Keywords:  5-ALA (5-aminolevulinic acid); ALAS1; Cytokine; Innate immunity; LPS; Neutrophil

DOI:  https://doi.org/10.1007/s10753-024-02212-1
Res Sq. 2024 Dec 05. pii: rs.3.rs-5278203. [Epub ahead of print]

Mitochondrial metabolism and epigenetic crosstalk drive the SASP.

Joao Passos, Helene Martini, Jodie Birch, Francisco Marques, Stella Victorelli, Anthony Lagnado, Nicholas Pirius, Ana Franco, Gung Lee, Yeaeun Han, Jennifer Rowsey, Alexandre Gaspar-Maia, Aaron Havas, Rabi Murad, Xue Lei, Rebecca Porritt, Oliver Maddocks, Diana Jurk, Sundeep Khosla, Peter Adams.

Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.

DOI: https://doi.org/10.21203/rs.3.rs-5278203/v1
Cell Commun Signal. 2024 Dec 18. 22(1): 599

STING exerts antiviral innate immune response by activating pentose phosphate pathway.

Dan-Hui Wu, Zi-Long Zhao, Wei-Tao Yin, Huai Liu, Xiong-Yan Xiang, Ling-Jun Zhu, Jun-Qi Li, Zhen-Hua Yan, Yu-Jia Li, Yong-Ping Jian, Zhi-Xiang Xu.

   BACKGROUND: The innate immune system serves as the host's first line of defense against invading pathogens. Stimulator of interferon genes (STING) is a key component of this system, yet its relationship with glucose metabolism, particularly in antiviral immunity, remains underexplored.
METHODS: Metabolomics analysis was used for detecting metabolic alterations in spleens from STING knockout (KO) and wild-type (WT) mice. Co-immunoprecipitation was employed for determining ubiquitination of TKT. Mass spectrometry was used for detecting interaction proteins of STING. Enzyme activity kits were used for detecting the activities of TKT and G6PD.
RESULTS: In this study, we demonstrate that herpes simplex virus (HSV) infection activates the pentose phosphate pathway (PPP) in host cells, thereby initiating an antiviral immune response. Using STING-manipulated cells and systemic knockout mice, we show that STING positively regulates PPP, which, in turn, limits HSV infection. Inhibition of the PPP significantly reduced the production of antiviral immune factors and dampened STING-induced innate immune responses. Mechanistically, we discovered that STING interacts with transketolase (TKT), a key enzyme in the non-oxidative branch of the PPP, and reduces its ubiquitination via the E3 ubiquitin ligase UBE3A, stabilizing TKT. Silencing TKT or inhibiting its activity with oxythiamine diminished antiviral immune factor production.
CONCLUSION: Our findings reveal that the PPP plays a synergistic role in generating antiviral immune factors during viral infection and suggest that PPP activation could serve as an adjunct strategy for antiviral therapy.

Keywords:  Antiviral immune response; Inflammatory factors; PPP; STING; Transketolase

DOI:  https://doi.org/10.1186/s12964-024-01983-2