bims-imicid 2025-02-09 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–02–09
nineteen papers selected by
Dylan Ryan, University of Cambridge

Impact of cryopreservation on immune cell metabolism as measured by SCENITH.
Thiamine deficiency aggravates experimental colitis in mice by promoting glycolytic reprogramming in macrophages.
Lipid metabolism in myeloid cell function and chronic inflammatory diseases.
Immunometabolism of Tregs: mechanisms, adaptability, and therapeutic implications in diseases.
Effects of natural products on macrophage immunometabolism: A new frontier in the treatment of metabolic diseases.
Longitudinal analysis of rhesus macaque metabolome during acute SIV infection reveals disruption in broad metabolite classes.
Effect of repurposed metabolic drugs on human macrophage polarization and antitumoral activity.
Harnessing amino acid pathways to influence myeloid cell function in tumor immunity.
Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma.
Lactylation-driven ALKBH5 diminishes macrophage NLRP3 inflammasome activation in patients with G6PT deficiency.
Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection.
IRG1/itaconate enhances efferocytosis by activating Nrf2-TIM4 signaling pathway to alleviate con A induced autoimmune liver injury.
Blimp-1 orchestrates macrophage polarization and metabolic homeostasis via purine biosynthesis in sepsis.
Preclinical insights into the potential of itaconate and its derivatives for liver disease therapy.
TEPP-46 inhibits glycolysis to promote M2 polarization of microglia after ischemic stroke.
FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy.
Tryptophan metabolism reprogramming contributes to the prothrombotic milieu in mice and humans infected with SARS-CoV-2.
GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome.
NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer's disease progression.

Oxf Open Immunol. 2025 ;6(1): iqae015

Impact of cryopreservation on immune cell metabolism as measured by SCENITH.

Curtis Luscombe, Eben Jones, Michaela Gregorova, Nicholas Jones, Laura Rivino.

  The dynamic functioning of immune cells is regulated by cellular metabolic processes, and there is growing interest in the study of immunometabolic correlates of dysfunctional immune responses. SCENITH is a novel flow cytometry-based technique that allows for ex vivo metabolic profiling of immune cells within heterogeneous samples. Cryopreservation of clinical samples is frequently undertaken to facilitate high throughput processing and longitudinal analyses of immune responses, but is thought to lead to cellular metabolic dysfunction. We aimed to investigate the impact of cryopreservation on immune cell metabolism, harnessing SCENITH's unique ability to describe the divergent bioenergetic characteristics of distinct immune cell subsets. We demonstrate that upon activation, T cells are unable to sufficiently/readily undergo metabolic reprogramming. Additionally, we find that cryopreservation introduces a time-dependent metabolic artefact that favours glycolysis and impairs oxidative phosphorylation, suggesting that cryopreservation results in mitochondrial dysfunction. Despite this artefact, SCENITH was still able to reveal the distinct bioenergetic profiles of contrasting immune cells populations following cryopreservation. Whilst SCENITH can provide valuable information about immune cell metabolism even in cryopreserved samples, our findings have important implications for the design of future studies. Investigators should carefully consider how to process and store clinical samples to ensure that cryopreservation does not confound analyses, particularly where longitudinal sampling is required.

Keywords:  Immunometabolism; SCENITH; T cell activation; aerobic glycolysis; cryopreservation; immune cell metabolism; oxidative phosphorylation; protein translation

DOI:  https://doi.org/10.1093/oxfimm/iqae015
Br J Pharmacol. 2025 Jan 31.

Thiamine deficiency aggravates experimental colitis in mice by promoting glycolytic reprogramming in macrophages.

Xiaohua Pan, Zhengnan Ren, Wenjie Liang, Xiaoliang Dong, Jiahong Li, Lili Wang, Madhav Bhatia, Li-Long Pan, Jia Sun.

   BACKGROUND AND PURPOSE: Inflammatory bowel disease (IBD) is closely associated with immune dysfunction, where nutrient-mediated metabolic flux dictates immune cell fate and function. Thiamine is a central water-soluble vitamin involved in cellular energy metabolism, and its deficiency has been reported in IBD patients. However, whether thiamine deficiency is a cause or consequence of IBD pathogenesis remains unclear. The current study aimed to reveal the immunometabolic regulation of macrophages and underlying mechanism of thiamine deficiency in colitis development.
EXPERIMENTAL APPROACH: Thiamine deficiency was induced in C57BL/6 mice and bone marrow-derived macrophages (BMDMs), by administering a thiamine-deficient diet/medium together with pyrithiamine hydrobromide. The frequency of macrophage phenotypes and their intracellular metabolism were detected using flow cytometry and non-targeted metabolomics, respectively.
KEY RESULTS: Thiamine deficiency aggravated ulcerative colitis in mice and promoted the infiltration of proinflammatory M1 macrophages in colonic lamina propria. Our mechanistic study revealed that thiamine deficiency impaired pyruvate dehydrogenase (PDH) activity, thereby reprogramming cellular glucose metabolism to enhance glycolysis and lactic acid accumulation in M1 macrophages. Using a well-established PDH inhibitor (CPI-613) and lactic acid dehydrogenase inhibitor (galloflavin), we further demonstrated that PDH inhibition mimics, while lactate dehydrogenase inhibition partially rescues, thiamine deficiency-induced proinflammatory macrophage infiltration and experimental colitis in mice.
CONCLUSION AND IMPLICATIONS: Our study provides evidence linking thiamine deficiency with proinflammatory macrophage activation and colitis aggravation, suggesting that monitoring thiamine status and adjusting thiamine intake is necessary to protect against colitis.

Keywords:  glycolysis; macrophage; metabolic reprogramming; thiamine deficiency; ulcerative colitis

DOI:  https://doi.org/10.1111/bph.17435
Front Immunol. 2024 ;15 1495853

Lipid metabolism in myeloid cell function and chronic inflammatory diseases.

Ayaka Ito, Takayoshi Suganami.

  Immune cells adapt their metabolism in response to their differentiation and activation status to meet the energy demands for an appropriate immune response. Recent studies have elucidated that during immune cell metabolic reprogramming, lipid metabolism, including lipid uptake, de novo lipid synthesis and fatty acid oxidation, undergoes significant alteration, resulting in dynamic changes in the quantity and quality of intracellular lipids. Given that lipids serve as an energy source and structural components of cellular membranes, they have important implications for physiological function. Myeloid cells, which are essential in bridging innate and adaptive immunity, are sensitive to these changes. Dysregulation of lipid metabolism in myeloid cells can result in immune dysfunction, chronic inflammation and impaired resolution of inflammation. Understanding the mechanism by which lipids regulate immune cell function might provide novel therapeutic insights into chronic inflammatory diseases, including metabolic diseases, autoimmune diseases and cancer. (143 words).

Keywords:  autoimmunity; cancer; immunometabolism; lipid metabolism; metabolic disease

DOI:  https://doi.org/10.3389/fimmu.2024.1495853
Front Immunol. 2025 ;16 1536020

Immunometabolism of Tregs: mechanisms, adaptability, and therapeutic implications in diseases.

Yuming Lu, Yifan Wang, Tiantian Ruan, Yihan Wang, Linling Ju, Mengya Zhou, Luyin Liu, Dengfu Yao, Min Yao.

  Immunometabolism is an emerging field that explores the intricate interplay between immune cells and metabolism. Regulatory T cells (Tregs), which maintain immune homeostasis in immunometabolism, play crucial regulatory roles. The activation, differentiation, and function of Tregs are influenced by various metabolic pathways, such as the Mammalian targets of rapamycin (mTOR) pathway and glycolysis. Correspondingly, activated Tregs can reciprocally impact these metabolic pathways. Tregs also possess robust adaptive capabilities, thus enabling them to adapt to various microenvironments, including the tumor microenvironment (TME). The complex mechanisms of Tregs in metabolic diseases are intriguing, particularly in conditions like MASLD, where Tregs are significantly upregulated and contribute to fibrosis, while in diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), they show downregulation and reduced anti-inflammatory capacity. These phenomena suggest that the differentiation and function of Tregs are influenced by the metabolic environment, and imbalances in either can lead to the development of metabolic diseases. Thus, moderate differentiation and inhibitory capacity of Tregs are critical for maintaining immune system balance. Given the unique immunoregulatory abilities of Tregs, the development of targeted therapeutic drugs may position them as novel targets in immunotherapy. This could contribute to restoring immune system balance, resolving metabolic dysregulation, and fostering innovation and progress in immunotherapy.

Keywords:  Tregs; immunometabolism; inflammation; metabolic diseases; metabolic pathways; microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1536020
Pharmacol Res. 2025 Jan 30. pii: S1043-6618(25)00059-3. [Epub ahead of print]213 107634

Effects of natural products on macrophage immunometabolism: A new frontier in the treatment of metabolic diseases.

Jiani Li, Chen Guo, Xiaofei Yang, Weinan Xie, Wenjing Mi, Chenglong Hua, Cheng Tang, Han Wang.

  Immunometabolic variations in macrophages critically influence their differentiation into pro-inflammatory or anti-inflammatory phenotypes, thereby contributing to immune homeostasis, defense against infection, and tissue repair. Dysregulation of macrophage immunometabolism has been closely implicated in several metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), hypertension, atherosclerosis, and gout, which positions macrophages as potential therapeutic targets. Recently, several natural products that target macrophage metabolic pathways have shown significant efficacy in managing metabolic diseases; however, a systematic review of these findings has yet to be conducted. This study consolidates natural products with immunoregulatory properties, including flavonoids, phenols, terpenoids, and naphthoquinones, which can alleviate chronic inflammation associated with metabolic disorders by modulating macrophage metabolic pathways, such as aerobic glycolysis, oxidative phosphorylation (OXPHOS), and fatty acid oxidation (FAO). This review aims to elucidate the metabolic regulation of the immune system, analyze metabolic alterations in macrophage associated with metabolic diseases, and summarize the beneficial roles of natural products in immunometabolism, providing novel insights for the prevention and therapeutic management of metabolic diseases.

Keywords:  Immunometabolism; Macrophages; Metabolic diseases; Metabolic pathways; Natural products

DOI:  https://doi.org/10.1016/j.phrs.2025.107634
J Virol. 2025 Feb 06. e0163424

Longitudinal analysis of rhesus macaque metabolome during acute SIV infection reveals disruption in broad metabolite classes.

Andrew Hudson, Peng Wu, Kyle W Kroll, Brady Hueber, Griffin Woolley, Pixu Shi, R Keith Reeves.

  Persons living with HIV experience significant metabolic dysregulation, frequently resulting in immune and other cellular dysfunction. However, our understanding of metabolism and its relationship to immunity in the context of HIV remains incompletely understood, especially as it relates to the acute and early chronic phases of HIV infection. Herein, we employed mass spectrometry and a simian immunodeficiency virus (SIV)-infected rhesus macaque model to characterize changes in over 500 plasma metabolites throughout SIV infection. This broad metabolomic approach recapitulated known pathogenic signatures of HIV, such as a perturbed tryptophan/kynurenine ratio, but also identified novel metabolic changes. We observed a general decrease in plasma amino acid concentrations, with the notable exceptions of elevated aspartate and glutamate. Acute infection was marked by a transient increase in lactate dehydrogenase activity, indicating a shift toward anaerobic metabolism. Indoleamine 2,3-dioxygenase activity, defined by the kynurenine/tryptophan ratio, was significantly increased in both acute and chronic phases and strongly correlated with viral load. These results provide a comprehensive characterization of metabolic fluctuations during early lentiviral infection, furthering our understanding of the crucial interplay between metabolism and immune response. Our findings highlight systemic metabolic consequences of infection and provide potential targets for therapeutic intervention or biomarkers of disease progression.
IMPORTANCE: Despite significant advances in antiretroviral therapy and pre-exposure prophylaxis, HIV remains a global challenge. Understanding the underlying immune mechanisms is critical for improving HIV control and therapeutic development. Cellular metabolism represents a crucial yet underappreciated area of immune system function. Metabolite availability and metabolic pathway preferences directly influence the functional response capacity of immune cells and are highly dysregulated during HIV infection. To further the understanding of metabolic impacts of HIV infection, we utilized cutting-edge mass spectrometry-based metabolome interrogation to measure over 500 metabolites using an acute simian immunodeficiency virus infection model in rhesus macaques. Our comprehensive analysis provides insights into the dynamic metabolic landscape throughout early infection, revealing both known and novel metabolic signatures. These findings enhance our understanding of the complex interplay between metabolism and immunity in lentiviral infections, potentially informing new strategies for early detection, prevention, and treatment of HIV.

Keywords:  HIV; immunometabolism; proteomics

DOI:  https://doi.org/10.1128/jvi.01634-24
Clin Immunol. 2025 Jan 29. pii: S1521-6616(25)00015-4. [Epub ahead of print]272 110440

Effect of repurposed metabolic drugs on human macrophage polarization and antitumoral activity.

Ana Vizcaino-Castro, Shipeng Chen, Baukje Nynke Hoogeboom, Annemarie Boerma, Toos Daemen, Cesar Oyarce.

   AIM: This study aimed to investigate whether the polarization of monocyte-derived macrophages towards an anti-inflammatory phenotype could be hindered by modulating cellular metabolism. Several metabolic drugs were selected: Perhexiline (PerHx) and Nitazoxanide (NTZ) targeting fatty acid oxidation, CB839 (Telaglenastat) targeting glutaminolysis and Metformin (Metf) targeting the mitochondrial electron transport chain.
RESULTS: Our findings demonstrate that the presence of PerHx, NTZ, and CB839 during IL-4-mediated macrophages polarization impaired the acquisition of full anti-inflammatory phenotype, as evidenced by reduced expression of CD163 and CD209 and decreased secretion of CCL17 chemokine. Besides, CB839 induced tumoricidal activity in macrophages, comparable to that observed in macrophages activated by LPS and IFNγ.
CONCLUSION: This study reveals that targeting glutamine metabolism with CB839 effectively blocks the IL-4-induced anti-inflammatory phenotype in macrophages and enhances their tumor-killing capability. Our results provide a compelling rationale for repurposing metabolic drugs to create a pro-inflammatory tumor microenvironment, thereby potentially enhancing the efficacy of current immunotherapies.

Keywords:  Anti-inflammatory macrophages; Cancer; Glutaminolysis; Macrophage metabolism; Macrophage polarization; Repurposed drugs

DOI:  https://doi.org/10.1016/j.clim.2025.110440
Mol Med. 2025 Feb 04. 31(1): 44

Harnessing amino acid pathways to influence myeloid cell function in tumor immunity.

Jiongli Pan, Yi Lin, Xinyuan Liu, Xiaozhen Zhang, Tingbo Liang, Xueli Bai.

  Amino acids are pivotal regulators of immune cell metabolism, signaling pathways, and gene expression. In myeloid cells, these processes underlie their functional plasticity, enabling shifts between pro-inflammatory, anti-inflammatory, pro-tumor, and anti-tumor activities. Within the tumor microenvironment, amino acid metabolism plays a crucial role in mediating the immunosuppressive functions of myeloid cells, contributing to tumor progression. This review delves into the mechanisms by which specific amino acids-glutamine, serine, arginine, and tryptophan-regulate myeloid cell function and polarization. Furthermore, we explore the therapeutic potential of targeting amino acid metabolism to enhance anti-tumor immunity, offering insights into novel strategies for cancer treatment.

Keywords:  Amino acid metabolism; Cancer immunotherapy; Immunometabolism; Metabolic reprogramming; Myeloid cells

DOI:  https://doi.org/10.1186/s10020-025-01099-4
Nat Commun. 2025 Jan 31. 16(1): 1217

Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma.

Mengzhu Sun, Laure Garnier, Romane Chevalier, Martin Roumain, Chen Wang, Julien Angelillo, Julien Montorfani, Robert Pick, Dale Brighouse, Nadine Fournier, David Tarussio, Stéphanie Tissot, Jean-Marc Lobaccaro, Tatiana V Petrova, Camilla Jandus, Daniel E Speiser, Manfred Kopf, Caroline Pot, Christoph Scheiermann, Krisztian Homicsko, Giulio G Muccioli, Abhishek D Garg, Stéphanie Hugues.

In melanoma, lymphangiogenesis correlates with metastasis and poor prognosis and promotes immunosuppression. However, it also potentiates immunotherapy by supporting immune cell trafficking. We show in a lymphangiogenic murine melanoma that lymphatic endothelial cells (LECs) upregulate the enzyme Ch25h, which catalyzes the formation of 25-hydroxycholesterol (25-HC) from cholesterol and plays important roles in lipid metabolism, gene regulation, and immune activation. We identify a role for LECs as a source of extracellular 25-HC in tumors inhibiting PPAR-γ in intra-tumoral macrophages and monocytes, preventing their immunosuppressive function and instead promoting their conversion into proinflammatory myeloid cells that support effector T cell functions. In human melanoma, LECs also upregulate Ch25h, and its expression correlates with the lymphatic vessel signature, infiltration of pro-inflammatory macrophages, better patient survival, and better response to immunotherapy. We identify here in mechanistic detail an important LEC function that supports anti-tumor immunity, which can be therapeutically exploited in combination with immunotherapy.

DOI: https://doi.org/10.1038/s41467-025-55969-w
J Allergy Clin Immunol. 2025 Feb 01. pii: S0091-6749(25)00117-4. [Epub ahead of print]

Lactylation-driven ALKBH5 diminishes macrophage NLRP3 inflammasome activation in patients with G6PT deficiency.

Zexiong Su, Jiaoli Lan, Ying Wang, Ni Ma, Jing Yang, Danxia Liang, Hanshi Zeng, Min Yang.

   BACKGROUND: Neutropenia represents an important clinical problem in patients with glycogen storage disease type Ib (GSD-Ib), characterized by genetic deficiency in glucose-6-phosphate translocase (G6PT/SLC37A4). However, the role of G6PT in macrophages has not been elucidated.
OBJECTIVE: We sought to investigate the function of G6PT in macrophage inflammation.
METHODS: Functional assays (including immunoblotting, real-time quantitative polymerase chain reaction, flow cytometry, immunofluorescence staining, and enzyme linked immunosorbent assay) and RNA sequencing were performed.
RESULTS: We find that macrophages from patients deficient in G6PT exhibited diminished NLRP3 inflammasome activation. Mechanistically, deficiency of G6PT promotes glycolysis and lactate production in macrophages. Lactate accumulation potently induces ALKBH5 upregulation via H3K18 lactylation. ALKBH5 decreases m6A modification on NLRP3 mRNA, attenuating its transcript stability and thus inhibiting inflammasome activation. Furtherly, treating G6PT-deficient macrophages with an inhibitor of the lactate dehydrogenase to lower their lactate levels restores NLRP3 inflammasome activation and rescues bacterial handling defect.
CONCLUSION: These findings unveil a previously unknown pathogenic mechanism of lactylation-driven defective NLRP3 inflammasome signaling and subsequent impaired antimicrobial activity as driving factors in these inflammatory disorders, and indicates glycolysis/lactate/histone lactylation cascade as a potential therapeutic target for GSD-Ib.

Keywords:  G6PT; Immune dysfunction; glycogen storage disease type Ib; inborn errors of immunity; inflammasome; lactylation; macrophages

DOI:  https://doi.org/10.1016/j.jaci.2025.01.028
Nat Commun. 2025 Feb 07. 16(1): 1460

Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection.

Trever T Greene, Yeara Jo, Carolina Chiale, Monica Macal, Ziyan Fang, Fawziyah S Khatri, Alicia L Codrington, Katelynn R Kazane, Elizabeth Akbulut, Shobha Swaminathan, Yu Fujita, Patricia Fitzgerald-Bocarsly, Thekla Cordes, Christian Metallo, David A Scott, Elina I Zúñiga.

Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.

DOI: https://doi.org/10.1038/s41467-025-56603-5
Cell Commun Signal. 2025 Feb 05. 23(1): 63

IRG1/itaconate enhances efferocytosis by activating Nrf2-TIM4 signaling pathway to alleviate con A induced autoimmune liver injury.

Liwu Zeng, Yaxin Wang, Yongzhou Huang, Wenchang Yang, Pei Zhou, Yaqi Wan, Kaixiong Tao, Ruidong Li.

  Immune response gene 1 (IRG1) is highly expressed in mitochondria of macrophages in a pro-inflammatory state. IRG1 and its metabolites play important roles in infection, immune-related diseases and tumor progression by exerting resistance of pathogens, attenuating inflammation and producing antioxidant substances through various pathways and mechanisms. IRG1 deficiency aggravates liver injury. Efferocytosis is a vital mechanism for preventing the progression of inflammatory tissue damage. However, the mechanism by how IRG1/itaconate regulates efferocytosis in autoimmune hepatitis has yet to be fully understood. Therefore, we explored the influence of IRG1-/- on efferocytosis and its effects on regulating the nuclear factor erythroid 2-associated factor 2 (Nrf2)-T-cell immunoglobulin domain and mucin domain 4 (TIM4) pathway and autoimmune liver injury. An autoimmune hepatitis model was established by injecting Con A into wild-type and IRG1-/- mice via the tail vein. Liver injury and inflammatory response were assessed. The efferocytosis role of IRG1-/- macrophages and its potential regulatory mechanisms were also analysed. Exogenous 4-octyl itaconate (OI) supplementation promoted the expression of Nrf2 and TIM4 and restored IRG1-/- bone marrow-derived macrophage (BMDM) efferocytosis, whereas inhibition of Nrf2 mediated by ML385 led to impaired efferocytosis of BMDMs, decreased expression of TIM4, and aggravated liver inflammation injury. Additionally, after supplementing Nrf2-/- BMDMs with exogenous OI, we evaluated the changes in its efferocytosis effect, efferocytosis did not change, and the protective effect of OI disappeared. However, when TIM4 was blocked, the efferocytotic effect of BMDMs was attenuated, inflammatory liver injury and oxidative stress were aggravated. OI promoted the transformation of macrophages into M2 macrophages, and this was inhibited when TIM4 was blocked. To our best understanding, this is the initial exploration to show that TIM4, a downstream molecule of the IRG1/itaconate-Nrf2 pathway, regulates macrophage efferocytosis. These findings suggest a new mechanism and potential treatment for promoting the resolution of inflammation and efferocytosis in autoimmune hepatitis.

Keywords:  Autoimmune hepatitis; Efferocytosis; Itaconate; TIM4

DOI:  https://doi.org/10.1186/s12964-025-02075-5
Cell Death Dis. 2025 Feb 06. 16(1): 72

Blimp-1 orchestrates macrophage polarization and metabolic homeostasis via purine biosynthesis in sepsis.

Wenjuan Peng, Qiushi Qin, Rui Li, Yujia Liu, Lan Li, Yue Zhang, Liuluan Zhu.

Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection, leading to systemic inflammation and organ dysfunction. Macrophage polarization plays a critical role in pathogenesis of sepsis, and the influence of B lymphocyte-induced maturation protein-1 (Blimp-1) on this polarization is an underexplored yet pivotal aspect. This study aimed to elucidate the role of Blimp-1 in macrophage polarization and metabolism during sepsis. Using a murine cecal ligation and puncture model, we observed elevated Blimp-1 expression in M2 macrophages. Knockdown of Blimp-1 by macrophage-targeted adeno-associated virus in this model resulted in decreased survival rates, exacerbated tissue damage, and impaired M2 polarization, underscoring its protective role in sepsis. In vitro studies with bone marrow-derived macrophage (BMDM), RAW264.7, and THP-1 cells further demonstrated Blimp-1 promotes M2 polarization and modulates key metabolic pathways. Metabolomics and dual-luciferase assays revealed Blimp-1 significantly influences purine biosynthesis and the downstream Ornithine cycle, which are essential for M2 macrophage polarization. In vitro studies with BMDM further suggested that the purine biosynthesis and Ornithine cycle metabolic regulation is involved in Blimp-1's effects on M2 macrophage polarization, and mediates Blimp-1's impact on septic mice. Our findings unveil a novel mechanism by which Blimp-1 modulates macrophage polarization through metabolic regulation, presenting potential therapeutic targets for sepsis. This study highlights the significance of Blimp-1 in orchestrating macrophage responses and metabolic adaptations in sepsis, offering valuable insights into its role as a critical regulator of immune and metabolic homeostasis.

DOI: https://doi.org/10.1038/s41419-025-07405-6
Metabolism. 2025 Feb 03. pii: S0026-0495(25)00021-6. [Epub ahead of print]165 156152

Preclinical insights into the potential of itaconate and its derivatives for liver disease therapy.

Xiaodong Wu, Yanhong Song, Zhengwei Yuan, Shuodong Wu.

  Annually, approximately 3.5 % of the world's population dies of cirrhosis or liver cancer, and the burden of liver disease is steadily expanding owing to multiple factors such as alcohol consumption, irrational diets, viral transmission, and exposure to drugs and toxins. However, the lack of effective therapies and the adverse effects of some medications remain a threat to the management of liver disease. Recently, immunometabolism, as an emerging discipline, appears to be the focus of unprecedented research. As a natural metabolite that regulates cellular functions, itaconate is a crucial bridge connecting metabolism and immune response. Remodeling immune function through metabolic modulation may be a promising alternative for disease intervention strategies. In this review, we first briefly describe the historical origin of itaconate and the development of its derivatives. This was followed by a review of the molecular mechanisms by which itaconate regulated immune-metabolic responses. Furthermore, we analyzed the effects of itaconate regulation on immune cells of the hepatic system. Finally, we summarized the experimental evidence for itaconate and its derivatives in the therapeutic application of liver diseases. Itaconate is potentially an invaluable component of emerging therapeutic strategies for liver disease.

Keywords:  Immunity regulation; Itaconate; Liver diseases; Metabolism

DOI:  https://doi.org/10.1016/j.metabol.2025.156152
Int Immunopharmacol. 2025 Feb 03. pii: S1567-5769(25)00137-7. [Epub ahead of print]149 114148

TEPP-46 inhibits glycolysis to promote M2 polarization of microglia after ischemic stroke.

Xiaomei Xia, Wenli Chen, Ting Zhou, Fang Zhou, Can Lu, Zhenzhuang Yan, Qin Zhao, Qinglun Su.

  Following an ischemic stroke, neuroinflammation is triggered and is often typified by microglial activation. According to recent research, increased glycolysis metabolism frequently occurs when microglia become activated in an inflammatory response. In this study, we found that the PKM2 expression of microglia was gradually increased during the activation of microglia in ischemic stroke. TEPP-46, the activator of PKM2, enhanced the M2 polarization and promoted phagocytosis of microglia both in vivo and in vitro. Meanwhile, TEPP-46 administration ameliorated neuroinflammation and neuronal injuries and reduced the infarct volume of tMCAO mice. Mechanistically, we demonstrated that TEPP-46 suppressed the nuclear translocation of PKM2 and the interaction of PKM2 and HIF-1α, and inhibited glycolysis of microglia. According to our research, PKM2 modulation in microglia may be a viable therapeutic approach to lessen neuroinflammation following ischemic stroke, and TEPP-46 may be able to polarize microglia from an M1 to an M2 phenotype after ischemia/reperfusion damage.

Keywords:  Glycolysis; Ischemic stroke; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1016/j.intimp.2025.114148
Nat Cancer. 2025 Feb 05.

FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy.

Haiwei Ni, Zachary J Reitman, Wei Zou, Md Naushad Akhtar, Ritama Paul, Menggui Huang, Duo Zhang, Hao Zheng, Ruitao Zhang, Ruiying Ma, Gina Ngo, Lin Zhang, Eric S Diffenderfer, S Azar Oliaei Motlagh, Michele M Kim, Andy J Minn, Jay F Dorsey, Jessica B Foster, James Metz, Constantinos Koumenis, David G Kirsch, Yanqing Gong, Yi Fan.

FLASH radiotherapy holds promise for treating solid tumors given the potential lower toxicity in normal tissues but its therapeutic effects on tumor immunity remain largely unknown. Using a genetically engineered mouse model of medulloblastoma, we show that FLASH radiation stimulates proinflammatory polarization in tumor macrophages. Single-cell transcriptome analysis shows that FLASH proton beam radiation skews macrophages toward proinflammatory phenotypes and increases T cell infiltration. Furthermore, FLASH radiation reduces peroxisome proliferator-activated receptor-γ (PPARγ) and arginase 1 expression and inhibits immunosuppressive macrophage polarization under stimulus-inducible conditions. Mechanistically, FLASH radiation abrogates lipid oxidase expression and oxidized low-density lipid generation to reduce PPARγ activity, while standard radiation induces reactive oxygen species-dependent PPARγ activation in macrophages. Notably, FLASH radiotherapy improves infiltration and activation of chimeric antigen receptor (CAR) T cells and sensitizes medulloblastoma to GD2 CAR-T cell therapy. Thus, FLASH radiotherapy reprograms macrophage lipid metabolism to reverse tumor immunosuppression. Combination FLASH-CAR radioimmunotherapy may offer exciting opportunities for solid tumor treatment.

DOI: https://doi.org/10.1038/s43018-025-00905-6
bioRxiv. 2025 Jan 30. pii: 2025.01.17.633602. [Epub ahead of print]

Tryptophan metabolism reprogramming contributes to the prothrombotic milieu in mice and humans infected with SARS-CoV-2.

Saravanan Subramaniam, Marc Arthur Napoleon, Saran Lotfollahzadeh, Mohamed Hassan Kamal, Helena Kurniawan, Murad Elsadawi, Devin Kenney, Florian Douam, Markus Bosmann, Stephen Whelan, Howard Cabral, Eric J Burks, Grace Zhao, Vijay Kolachalama, Katya Ravid, Vipul Chitalia.

SARS-CoV-2 infection disturbs the coagulation balance in the blood, triggering thrombosis and contributing to organ failure. The role of prothrombotic metabolites in COVID-19-associated coagulopathy remains elusive. Leveraging K18-hACE2 mice infected with SARS-CoV-2, we observed higher levels of the tryptophan metabolite, kynurenine, compared to controls. SARS CoV-2 infected mice showed a significant upregulation of enzymes controlling Kynurenine biogenesis, such as indoleamine 2,3-dioxygenase (IDO-1) and tryptophan 2,3-dioxygenase levels in kidneys and liver, respectively, as well as changes in the enzymes involved in kynurenine catabolism, including kynurenine monooxygenase and kynurinase. Consistent with the agonistic role of these metabolites in Aryl Hydrocarbon Receptor (AHR) signaling, AHR activation and its downstream mediator, tissue factor (TF), a highly potent procoagulant factor, was observed in endothelial cells (ECs) of lungs and kidneys of infected mice. These findings were validated in humans, where compared to controls, sera of COVID-19 patients showed increased levels of Kynurenine, kynurenic acid, anthranilic acid, and quinolinic acid. Activation of the AHR-TF axis was noted in the kidneys and lungs of COVID-19 patients, and COVID-19 sera showed higher IDO-1 activity than controls. Levels of Kyn in COVID-19 patients correlated strongly with the TF inducing activity of COVID-19 sera on ECs. A specific IDO-1 inhibitor or AHR inhibitor separately or in combination suppressed COVID-19 sera-induced TF activity in ECs. Together, we identified IDO-1 as upregulated by SARS-CoV-2 infection, resulting in augmented Kyn and its prothrombotic catabolites, thereby suggesting the Kyn AHR-TF axis as possibly a new diagnostic and/or therapeutic target.

DOI: https://doi.org/10.1101/2025.01.17.633602
Clin Mol Hepatol. 2025 Feb 05.

GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome.

Sheng-Tao Cheng, Wei-Xian Chen, Hai-Jun Deng, Xin He, Hui Zhang, Ming Tan, Hai-Bo Yu, Zhen-Zhen Zhang, Ji-Hua Ren, Min-Li Yang, Da-Peng Zhang, Zhi-Hong Li, Juan Chen.

   Background: Hepatitis B virus (HBV) hijacks host cell metabolism, especially host glutamine metabolism, to support its replication. Glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme crucial for glutamine metabolism, can interact with histone demethylases to regulate gene expression through histone methylation. However, the mechanisms underlying GDH1-mediated glutamine metabolism reprogramming and the roles of key metabolites during HBV infection remain unclear.
Methods: Transcriptomic and metabolomic analyses of HBV-infected cell were performed. Both HBV-infected cells and humanized liver chimeric mice were used to elucidate the effect of glutamine metabolism on HBV.
Results: HBV infection leads to the abnormal activation of glutamine metabolism, including upregulation of key enzymes and metabolites involved in glutamine metabolism. The viral core protein (HBc) mediates the translocation of GDH1 into the nucleus, where GDH1 activates covalently closed circular DNA (cccDNA) transcription by converting glutamate to α-ketoglutarate (αKG). Mechanistically, the promoting effect of GDH1-derived αKG on cccDNA transcription is independent of its conventional role. Rather, αKG directly interacts with the lysine-specific demethylase KDM4A and enhances KDM4A demethylase activity to regulate αKG-dependent histone demethylation, controlling cccDNA transcription.
Conclusions: Our findings highlight the importance of glutamine metabolism in HBV transcription and suggest that glutamine deprivation is a potential strategy for silencing cccDNA transcription.

Keywords:   GDH1; Methylation; cccDNA; αKG; Glutamine

DOI:  https://doi.org/10.3350/cmh.2024.0694
Immunity. 2025 Jan 31. pii: S1074-7613(25)00032-9. [Epub ahead of print]

NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer's disease progression.

Róisín M McManus, Max P Komes, Angelika Griep, Francesco Santarelli, Stephanie Schwartz, Juan Ramón Perea, Johannes C M Schlachetzki, David S Bouvier, Michelle-Amirah Khalil, Mario A Lauterbach, Lea Heinemann, Titus Schlüter, Mehran Shaban Pour, Marta Lovotti, Rainer Stahl, Fraser Duthie, Juan F Rodríguez-Alcázar, Susanne V Schmidt, Jasper Spitzer, Peri Noori, Alberto Maillo, Andreas Boettcher, Brian Herron, John McConville, David Gomez-Cabrero, Jesper Tegnér, Christopher K Glass, Karsten Hiller, Eicke Latz, Michael T Heneka.

  Activation of the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer's disease (AD) via the release of IL-1β and ASC specks. However, whether NLRP3 is involved in pathways beyond this remained unknown. Here, we found that Aβ deposition in vivo directly triggered NLRP3 activation in APP/PS1 mice, which model many features of AD. Loss of NLRP3 increased glutamine- and glutamate-related metabolism and increased expression of microglial Slc1a3, which was associated with enhanced mitochondrial and metabolic activity. The generation of α-ketoglutarate during this process impacted cellular function, including increased clearance of Aβ peptides as well as epigenetic and gene transcription changes. This pathway was conserved between murine and human cells. Critically, we could mimic this effect pharmacologically using NLRP3-specific inhibitors, but only with chronic NLRP3 inhibition. Together, these data demonstrate an additional role for NLRP3, where it can modulate mitochondrial and metabolic function, with important downstream consequences for the progression of AD.

Keywords:  Alzheimer’s disease; NLRP3; amyloid-β; dementia; glutamine metabolism; inflammasome; microglia; phagocytosis; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.immuni.2025.01.007