bims-imicid 2024-05-12 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–05–12
25 papers selected by
Dylan Ryan, University of Cambridge

A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression.
Iron controls the development of airway hyperreactivity by regulating ILC2 metabolism and effector function.
Longitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer.
Glucose and trehalose metabolism through the cyclic pentose phosphate pathway shapes pathogen resistance and host protection in Drosophila.
Intermittent fasting influences immunity and metabolism.
Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.
Human CD4+ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses.
Nrf2 regulates the activation-driven expansion of CD4 + T-cells by differentially modulating glucose and glutamine metabolism.
Adiposity, immunity, and inflammation: interrelationships in health and disease: A report from 24th annual Harvard nutrition obesity symposium, June 2023.
miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signaling.
GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.
Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.
Adipose Tissue Immunometabolism: Unveiling the Intersection of Metabolic and Immune Regulation.
Functional regulation of microglia by vitamin B12 alleviates ischemic stroke-induced neuroinflammation in mice.
Cell metabolism: Functional and phenotypic single cell approaches.
TLR2 Supports γδ T cell IL-17A Response to ocular surface commensals by Metabolic Reprogramming.
GDF15 ameliorates sepsis-induced lung injury via AMPK-mediated inhibition of glycolysis in alveolar macrophage.
Itaconic acid inhibits nontuberculous mycobacterial growth in pH dependent manner while 4-octyl-itaconic acid enhances THP-1 clearance of nontuberculous mycobacteria in vitro.
The immunometabolic function of VGLL3 and female-biased autoimmunity.
Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.
LPS-induced monocarboxylate transporter-1 inhibition facilitates lactate accumulation triggering epithelial-mesenchymal transformation and pulmonary fibrosis.
Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke.
Effects of iron status on adaptive immunity and vaccine efficacy: a review.
MiR-106a-5p targets PFKFB3 and improves sepsis through regulating macrophage pyroptosis and inflammatory response.
Is Methylglyoxal a Potential Biomarker for the Warburg Effect Induced by the Lipopolysaccharide Neuroinflammation Model?

Sci Immunol. 2024 May 10. 9(95): eadi4191

A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression.

Michael P Plebanek, Yue Xue, Y-Van Nguyen, Nicholas C DeVito, Xueying Wang, Alisha Holtzhausen, Georgia M Beasley, Balamayooran Theivanthiran, Brent A Hanks.

Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8+ T cell activation and suppressed melanoma progression. CD63+ mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63+ mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.

DOI: https://doi.org/10.1126/sciimmunol.adi4191
Sci Transl Med. 2024 May 08. 16(746): eadk4728

Iron controls the development of airway hyperreactivity by regulating ILC2 metabolism and effector function.

Benjamin P Hurrell, Yoshihiro Sakano, Stephen Shen, Doumet Georges Helou, Meng Li, Pedram Shafiei-Jahani, Mohammad Hossein Kazemi, Kei Sakano, Xin Li, Christine Quach, Richard Barbers, Omid Akbari.

Group 2 innate lymphoid cells (ILC2s) rapidly induce a type 2 inflammation in the lungs in response to allergens. Here, we focused on the role of iron, a critical nutritional trace element, on ILC2 function and asthma pathogenesis. We found that transferrin receptor 1 (TfR1) is rapidly up-regulated and functional during ILC2 activation in the lungs, and blocking transferrin uptake reduces ILC2 expansion and activation. Iron deprivation reprogrammed ILC2 metabolism, inducing a HIF-1α-driven up-regulation of glycolysis and inhibition of oxidative mitochondrial activity. Consequently, we observed that in vivo iron chelation or induction of hypoferremia reduced the development of airway hyperreactivity in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s rapidly induced TfR1 during activation, whereas inhibition of iron uptake or iron deprivation reduced effector functions. Last, we found a negative relationship between circulating ILC2 TfR1 expression and airway function in cohorts of patients with asthma. Collectively, our studies define cellular iron as a critical regulator of ILC2 function.

DOI: https://doi.org/10.1126/scitranslmed.adk4728
Nat Commun. 2024 May 07. 15(1): 3837

Longitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer.

Kang Wang, Ioannis Zerdes, Henrik J Johansson, Dhifaf Sarhan, Yizhe Sun, Dimitris C Kanellis, Emmanouil G Sifakis, Artur Mezheyeuski, Xingrong Liu, Niklas Loman, Ingrid Hedenfalk, Jonas Bergh, Jiri Bartek, Thomas Hatschek, Janne Lehtiö, Alexios Matikas, Theodoros Foukakis.

Although metabolic reprogramming within tumor cells and tumor microenvironment (TME) is well described in breast cancer, little is known about how the interplay of immune state and cancer metabolism evolves during treatment. Here, we characterize the immunometabolic profiles of tumor tissue samples longitudinally collected from individuals with breast cancer before, during and after neoadjuvant chemotherapy (NAC) using proteomics, genomics and histopathology. We show that the pre-, on-treatment and dynamic changes of the immune state, tumor metabolic proteins and tumor cell gene expression profiling-based metabolic phenotype are associated with treatment response. Single-cell/nucleus RNA sequencing revealed distinct tumor and immune cell states in metabolism between cold and hot tumors. Potential drivers of NAC based on above analyses were validated in vitro. In summary, the study shows that the interaction of tumor-intrinsic metabolic states and TME is associated with treatment outcome, supporting the concept of targeting tumor metabolism for immunoregulation.

DOI: https://doi.org/10.1038/s41467-024-47932-y
PLoS Biol. 2024 May 07. 22(5): e3002299

Glucose and trehalose metabolism through the cyclic pentose phosphate pathway shapes pathogen resistance and host protection in Drosophila.

Michalina Kazek, Lenka Chodáková, Katharina Lehr, Lukáš Strych, Pavla Nedbalová, Ellen McMullen, Adam Bajgar, Stanislav Opekar, Petr Šimek, Martin Moos, Tomáš Doležal.

Activation of immune cells requires the remodeling of cell metabolism in order to support immune function. We study these metabolic changes through the infection of Drosophila larvae by parasitoid wasp. The parasitoid egg is neutralized by differentiating lamellocytes, which encapsulate the egg. A melanization cascade is initiated, producing toxic molecules to destroy the egg while the capsule also protects the host from the toxic reaction. We combined transcriptomics and metabolomics, including 13C-labeled glucose and trehalose tracing, as well as genetic manipulation of sugar metabolism to study changes in metabolism, specifically in Drosophila hemocytes. We found that hemocytes increase the expression of several carbohydrate transporters and accordingly uptake more sugar during infection. These carbohydrates are metabolized by increased glycolysis, associated with lactate production, and cyclic pentose phosphate pathway (PPP), in which glucose-6-phosphate is re-oxidized to maximize NADPH yield. Oxidative PPP is required for lamellocyte differentiation and resistance, as is systemic trehalose metabolism. In addition, fully differentiated lamellocytes use a cytoplasmic form of trehalase to cleave trehalose to glucose and fuel cyclic PPP. Intracellular trehalose metabolism is not required for lamellocyte differentiation, but its down-regulation elevates levels of reactive oxygen species, associated with increased resistance and reduced fitness. Our results suggest that sugar metabolism, and specifically cyclic PPP, within immune cells is important not only to fight infection but also to protect the host from its own immune response and for ensuring fitness of the survivor.

DOI: https://doi.org/10.1371/journal.pbio.3002299
Trends Endocrinol Metab. 2024 May 07. pii: S1043-2760(24)00097-3. [Epub ahead of print]

Intermittent fasting influences immunity and metabolism.

Daniel M Marko, Meghan O Conn, Jonathan D Schertzer.

  Intermittent fasting (IF) modifies cell- and tissue-specific immunometabolic responses that dictate metabolic flexibility and inflammation during obesity and type 2 diabetes (T2D). Fasting forces periods of metabolic flexibility and necessitates increased use of different substrates. IF can lower metabolic inflammation and improve glucose metabolism without lowering obesity and can influence time-dependent, compartmentalized changes in immunity. Liver, adipose tissue, skeletal muscle, and immune cells communicate to relay metabolic and immune signals during fasting. Here we review the connections between metabolic and immune cells to explain the divergent effects of IF compared with classic caloric restriction (CR) strategies. We also explore how the immunometabolism of metabolic diseases dictates certain IF outcomes, where the gut microbiota triggers changes in immunity and metabolism during fasting.

Keywords:  immunity; intermittent fasting; metabolism; obesity

DOI:  https://doi.org/10.1016/j.tem.2024.04.014
Cell Metab. 2024 May 07. pii: S1550-4131(24)00127-X. [Epub ahead of print]36(5): 884-886

Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.

Qiang Cai, Yihao Tian, Quazi T H Shubhra.

Tumors compromise T cell functionality through various mechanisms, including the induction of a nutrient-scarce microenvironment, leading to lipid accumulation and metabolic reprogramming. Hunt et al. elucidate acetyl-CoA carboxylase's crucial role in regulating lipid metabolism in CD8+ T cells, uncovering a novel metabolic strategy to potentiate antitumor immune responses.

DOI: https://doi.org/10.1016/j.cmet.2024.04.007
iScience. 2024 May 17. 27(5): 109775

Human CD4+ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses.

Nikhila S Bharadwaj, Nicholas A Zumwalde, Arvinder Kapur, Manish Patankar, Jenny E Gumperz.

  The transition of naive T lymphocytes into antigenically activated effector cells is associated with a metabolic shift from oxidative phosphorylation to aerobic glycolysis. This shift facilitates production of the key anti-tumor cytokine interferon (IFN)-γ; however, an associated loss of mitochondrial efficiency in effector T cells ultimately limits anti-tumor immunity. Memory phenotype (MP) T cells are a newly recognized subset that arises through homeostatic activation signals following hematopoietic transplantation. We show here that human CD4+ MP cell differentiation is associated with increased glycolytic and oxidative metabolic activity, but MP cells retain less compromised mitochondria compared to effector CD4+ T cells, and their IFN-γ response is less dependent on glucose and more reliant on glutamine. MP cells also produced IFN-γ more efficiently in response to weak T cell receptor (TCR) agonism than effectors and mediated stronger responses to transformed B cells. MP cells may thus be particularly well suited to carry out sustained immunosurveillance against neoplastic cells.

Keywords:  cell biology; immunity

DOI:  https://doi.org/10.1016/j.isci.2024.109775
bioRxiv. 2024 Apr 22. pii: 2024.04.18.590146. [Epub ahead of print]

Nrf2 regulates the activation-driven expansion of CD4 + T-cells by differentially modulating glucose and glutamine metabolism.

Aprajita Tripathi, Debolina Dasgupta, Anil Pant, Ashlyn Bugbee, Nanda Kumar Yellapu, Ben H Y Choi, Shailendra Giri, Kalyani Pyaram.

Upon antigenic stimulation, CD4 + T-cells undergo clonal expansion, elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4 + T-cells remains unexplored. Here, we elucidate the role of Nrf2 beyond the traditional antioxidation, in modulating activation-driven expansion of CD4 + T-cells by influencing their nutrient metabolism. T-cell-specific activation of Nrf2 enhances early activation and IL-2 secretion, upregulates TCR-signaling, and increases activation-driven proliferation of CD4 + T-cells. Mechanistically, high Nrf2 inhibits glucose metabolism through glycolysis but promotes glutamine metabolism via glutaminolysis to support increased T-cell proliferation. Further, Nrf2 expression is temporally regulated in activated CD4 + T-cells with elevated expression during the early activation, but decreased expression thereafter. Overall, our findings uncover a novel role of Nrf2 as a metabolic modulator of CD4 + T-cells, thus providing a framework for improving Nrf2-targeting therapies and T-cell immunotherapies.

DOI: https://doi.org/10.1101/2024.04.18.590146
Am J Clin Nutr. 2024 May 03. pii: S0002-9165(24)00455-6. [Epub ahead of print]

Adiposity, immunity, and inflammation: interrelationships in health and disease: A report from 24th annual Harvard nutrition obesity symposium, June 2023.

M Furkan Burak, Takara L Stanley, Elizabeth A Lawson, Sophia L Campbell, Lydia Lynch, Alyssa H Hasty, Ana I Domingos, Vishwa D Dixit, Gökhan S Hotamışlıgil, Frederick J Sheedy, Anne E Dixon, Tina E Brinkley, Joseph A Hill, Marc Y Donath, Steven K Grinspoon.

  The rapidly evolving field of immunometabolism explores how changes in local immune environments may affect the key metabolic and cellular processes, including that of adipose tissue. Importantly, these changes may contribute to low-grade systemic inflammation. In turn, chronic low-grade inflammation affecting adipose tissue may exacerbate the outcome of metabolic diseases. Novel advances in our understanding of immune-metabolic processes may critically lead to interventions to reduce disease severity and progression. An important example in this regard relates to obesity, which has a multifaceted effect on immunity activating the pro-inflammatory pathways such as inflammasome and disrupting cellular homeostasis. This multifaceted effect of obesity can be investigated through study of downstream conditions using cellular and systemic investigative techniques. To further explore this field, the NIH P30 Nutrition Obesity Research Center at Harvard in partnership with the Harvard Medical School assembled experts to present at its 24th annual Symposium entitled "Adiposity, Immunity, and Inflammation: Interrelationships in Health and Disease on June 07, 2023. This manuscript seeks to synthesize and present key findings from the symposium highlighting new research and novel disease-specific advances in the field. Better understanding the interaction between metabolism and immunity offers promising preventative and treatment therapies for obesity-related immunometabolic diseases.

Keywords:  Diet; Immunity; Immunometabolism; Inflammation; Obesity

DOI:  https://doi.org/10.1016/j.ajcnut.2024.04.029
Cardiovasc Res. 2024 May 04. pii: cvae102. [Epub ahead of print]

miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signaling.

Shruti Rawal, Vinay Randhawa, Syed Husain Mustafa Rizvi, Madhur Sachan, Akm Khyrul Wara, Daniel Pérez-Cremades, Robert M Weisbrod, Naomi M Hamburg, Mark W Feinberg.

   AIMS: Diabetes leads to dysregulated macrophage immunometabolism, contributing to accelerated atherosclerosis progression. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet goal. MicroRNAs (miRs) orchestrate multiple signaling events in macrophages, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear.
METHODS AND RESULTS: MiRNA profiling revealed significantly lower miR-369-3p expression in aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose containing (HFSC) diet for 12 weeks. miR-369-3p was also reduced in peripheral blood mononuclear cells (PBMCs) from diabetic patients with coronary artery disease (CAD). Cell-type expression profiling showed miR-369-3p enrichment in aortic macrophages. In vitro, oxLDL treatment reduced miR-369-3p expression in mouse bone marrow-derived macrophages (BMDMs). Metabolic profiling in BMDMs revealed that miR-369-3p overexpression blocked the oxLDL-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation (lL-1β, TNF-a, IL-6). Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signaling pathways. Therapeutic administration of miR-369-3p mimics in HFSC-fed Ldlr-/- mice reduced GPR91 expression in lesional macrophages and diabetes-accelerated atherosclerosis, evident by a decrease in plaque size and pro-inflammatory Ly6Chi monocytes. RNA-seq analyses showed more pro-resolving pathways in plaque macrophages from miR-369-3p treated mice, consistent with an increase in macrophage efferocytosis in lesions. Finally, a GPR91 antagonist attenuated oxLDL-induced inflammation in primary monocytes from human subjects with diabetes.
CONCLUSION: These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism.

Keywords:  GPR91; atherosclerosis; diabetes; macrophage; microRNA; succinate

DOI:  https://doi.org/10.1093/cvr/cvae102
Mol Ther. 2024 May 07. pii: S1525-0016(24)00303-4. [Epub ahead of print]

GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.

Yuzhe Shi, Ivan S Kotchetkov, Anton Dobrin, Sophie A Hanina, Vinagolu K Rajasekhar, John H Healey, Michel Sadelain.

The tumor microenvironment presents many obstacles to effective CAR T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Rα2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes Tscm formation and prolongs survival. RNA sequencing of these CAR T cells reveals that overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR T cells improve tumor control and response to rechallenge in an RCC patient derived xenograft model. Furthermore, IL13Rα2-BBz CAR T cells overexpressing GLUT1 prolong survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR T cells in harsh tumor environments where glucose is limiting.

DOI: https://doi.org/10.1016/j.ymthe.2024.05.006
bioRxiv. 2024 Apr 28. pii: 2024.04.25.591150. [Epub ahead of print]

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.

David R Ziehr, Fei Li, K Mark Parnell, Nathan M Krah, Kevin J Leahy, Christelle Guillermier, Jack Varon, Rebecca M Baron, Bradley A Maron, Nancy J Philp, Lida P Hariri, Edy Y Kim, Matthew L Steinhauser, Rachel S Knipe, Jared Rutter, William M Oldham.

Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGFβ-stimulated pulmonary myofibroblast differentiation in vitro and decreases bleomycin-induced pulmonary fibrosis in vivo . Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist.
SUMMARY: Small molecule inhibitors of lactate transporters, including the novel MCT4 inhibitor VB253, reprogram fibroblast metabolism to prevent myofibroblast differentiation and decrease bleomycin-induced pulmonary fibrosis.

DOI: https://doi.org/10.1101/2024.04.25.591150
Rev Invest Clin. 2024 ;76(2): 65-79

Adipose Tissue Immunometabolism: Unveiling the Intersection of Metabolic and Immune Regulation.

Medina-Urrutia Aida X, Torre-Villalvazo Ivan, Juárez-Rojas Juan G.

   UNASSIGNED: Excess body weight has become a global epidemic and a significant risk factor for developing chronic diseases, which are the leading causes of worldwide morbidities. Adipose tissue (AT), primarily composed of adipocytes, stores substantial amounts of energy and plays a crucial role in maintaining whole-body glucose and lipid metabolism. This helps prevent excessive body fat accumulation and lipotoxicity in peripheral tissues. In addition, AT contains endothelial cells and a substantial population of immune cells (constituting 60-70% of non-adipocyte cells), including macrophages, T and B lymphocytes, and natural killer cells. These resident immune cells engage in crosstalk with adipocytes, contributing to the maintenance of metabolic and immune homeostasis in AT. An exacerbated inflammatory response or inadequate immune resolution can lead to chronic systemic low-grade inflammation, triggering the development of metabolic alterations and the onset of chronic diseases. This review aims to elucidate the regulatory mechanisms through which immune cells influence AT function and energy homeostasis. We also focus on the interactions and functional dynamics of immune cell populations, highlighting their role in maintaining the delicate balance between metabolic health and obesity-related inflammation. Finally, understanding immunometabolism is crucial for unraveling the pathogenesis of metabolic diseases and developing targeted immunotherapeutic strategies. These strategies may offer innovative avenues in the rapidly evolving field of immunometabolism. (Rev Invest Clin. 2024;76(2):65-79).

Keywords:  Adipose tissue functionality; Immunometabolism; Inflammation

DOI:  https://doi.org/10.24875/RIC.23000231
iScience. 2024 Apr 19. 27(4): 109480

Functional regulation of microglia by vitamin B12 alleviates ischemic stroke-induced neuroinflammation in mice.

Yong Ge, Changjun Yang, Mojgan Zadeh, Shane M Sprague, Yang-Ding Lin, Heetanshi Sanjay Jain, Brenden Fitzgerald Determann, William H Roth, Juan Pablo Palavicini, Jonathan Larochelle, Eduardo Candelario-Jalil, Mansour Mohamadzadeh.

  Ischemic stroke is the second leading cause of death and disability worldwide, and efforts to prevent stroke, mitigate secondary neurological damage, and promote neurological recovery remain paramount. Recent findings highlight the critical importance of microbiome-related metabolites, including vitamin B12 (VB12), in alleviating toxic stroke-associated neuroinflammation. Here, we showed that VB12 tonically programmed genes supporting microglial cell division and activation and critically controlled cellular fatty acid metabolism in homeostasis. Intriguingly, VB12 promoted mitochondrial transcriptional and metabolic activities and significantly restricted stroke-associated gene alterations in microglia. Furthermore, VB12 differentially altered the functions of microglial subsets during the acute phase of ischemic stroke, resulting in reduced brain damage and improved neurological function. Pharmacological depletion of microglia before ischemic stroke abolished VB12-mediated neurological improvement. Thus, our preclinical studies highlight the relevance of VB12 in the functional programming of microglia to alleviate neuroinflammation, minimize ischemic injury, and improve host neurological recovery after ischemic stroke.

Keywords:  Immunology; Neuroscience; Omics; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.109480
Methods Cell Biol. 2024 ;pii: S0091-679X(24)00055-4. [Epub ahead of print]186 151-187

Cell metabolism: Functional and phenotypic single cell approaches.

Sara De Biasi, Julien Paul Gigan, Rebecca Borella, Elena Santacroce, Domenico Lo Tartaro, Anita Neroni, Nikolaos Paschalidis, Katarzyna Piwocka, Rafael José Argüello, Lara Gibellini, Andrea Cossarizza.

  Several metabolic pathways are essential for the physiological regulation of immune cells, but their dysregulation can cause immune dysfunction. Hypermetabolic and hypometabolic states represent deviations in the magnitude and flexibility of effector cells in different contexts, for example in autoimmunity, infections or cancer. To study immunometabolism, most methods focus on bulk populations and rely on in vitro activation assays. Nowadays, thanks to the development of single-cell technologies, including multiparameter flow cytometry, mass cytometry, RNA cytometry, among others, the metabolic state of individual immune cells can be measured in a variety of samples obtained in basic, translational and clinical studies. Here, we provide an overview of different single-cell approaches that are employed to investigate both mitochondrial functions and cell dependence from mitochondria metabolism. Moreover, besides the description of the appropriate experimental settings, we discuss the strengths and weaknesses of different approaches with the aim to suggest how to study cell metabolism in the settings of interest.

Keywords:  Function; Metabolism; Multiparametric flow cytometry; Single-cell

DOI:  https://doi.org/10.1016/bs.mcb.2024.02.024
bioRxiv. 2024 Apr 01. pii: 2024.04.01.587519. [Epub ahead of print]

TLR2 Supports γδ T cell IL-17A Response to ocular surface commensals by Metabolic Reprogramming.

Wenjie Zhu, Xiaoyan Xu, Vijayaraj Nagarajan, Jing Guo, Zixuan Peng, Amy Zhang, Jie Liu, Mary J Mattapallil, Yingyos Jittayasothorn, Reiko Horai, Anthony J St Leger, Rachel R Caspi.

The ocular surface is a mucosal barrier tissue colonized by commensal microbes, which tune local immunity by eliciting IL-17 from conjunctival γδ T cells to prevent pathogenic infection. The commensal Corynebacterium mastitidis ( C. mast ) elicits protective IL-17 responses from conjunctival Vγ4 T cells through a combination of γδ TCR ligation and IL-1 signaling. Here, we identify Vγ6 T cells as a major C. mast -responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that Vγ6 cells require not only extrinsic (via dendritic cells) but also intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes responsible for metabolic shift to fatty acid oxidation to support Il17a transcription. We identify one key transcription factor, IκBζ, which is upregulated by TLR2 stimulation and is essential for this program. Our study highlights the importance of intrinsic TLR2 signaling in driving metabolic reprogramming and production of IL-17A in microbiome-specific mucosal γδ T cells.
Summary: The ocular commensal Corynebacterium mastitidis ( C. mast ) induces the IL-17 responses from γδ T cells by activating TLR2 signaling. γδ T cell-intrinsic TLR2 stimulation promotes fatty acid oxidation and increases IL-17A transcription, favoring IL-17A responses.
Highlights: (1) TLR2-deficient mice exhibit reduced γδ T cell responses to ocular commensal bacteria.(2) γδ T cell-intrinsic TLR2 deficiency causes defects of fatty acid oxidation and IL-17A production in a γδ subset-specific manner.(3) The transcription factor, IκBζ is upregulated by TLR2 stimulation and supports γδ IL-17A production through fatty acid oxidation.

DOI: https://doi.org/10.1101/2024.04.01.587519
Respir Res. 2024 May 09. 25(1): 201

GDF15 ameliorates sepsis-induced lung injury via AMPK-mediated inhibition of glycolysis in alveolar macrophage.

Shasha Lu, Ranran Li, Yunxin Deng, Ju Bai, Bangqi Ji, Yufeng Chu, Yan Xu, Hongping Qu, Xiaosun Guo, Pibao Li, Mei Meng.

  Growth differentiation factor 15 (GDF15) as a stress response cytokine is involved in the development and progression of several diseases associated with metabolic disorders. However, the regulatory role and the underlying mechanisms of GDF15 in sepsis remain poorly defined. Our study analyzed the levels of GDF15 and its correlations with the clinical prognosis of patients with sepsis. In vivo and in vitro models of sepsis were applied to elucidate the role and mechanisms of GDF15 in sepsis-associated lung injury. We observed strong correlations of plasma GDF15 levels with the levels of C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), and lactate as well as Sequential Organ Failure Assessment (SOFA) scores in patients with sepsis. In the mouse model of lipopolysaccharide-induced sepsis, recombinant GDF15 inhibited the proinflammatory responses and alleviated lung tissue injury. In addition, GDF15 decreased the levels of cytokines produced by alveolar macrophages (AMs). The anti-inflammatory effect of glycolysis inhibitor 2-DG on AMs during sepsis was mediated by GDF15 via inducing the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α) and the expression of activating transcription factor 4 (ATF4). Furthermore, we explored the mechanism underlying the beneficial effects of GDF15 and found that GDF15 inhibited glycolysis and mitogen-activated protein kinases (MAPK)/nuclear factor-κB (NF-κB) signaling via promoting AMPK phosphorylation. This study demonstrated that GDF15 inhibited glycolysis and NF-κB/MAPKs signaling via activating AMP-activated protein kinase (AMPK), thereby alleviating the inflammatory responses of AMs and sepsis-associated lung injury. Our findings provided new insights into novel therapeutic strategies for treating sepsis.

Keywords:  Alveolar macrophage; Glycolysis; Growth differentiation factor 15(GDF15); Inflammation; sepsis

DOI:  https://doi.org/10.1186/s12931-024-02824-z
PLoS One. 2024 ;19(5): e0303516

Itaconic acid inhibits nontuberculous mycobacterial growth in pH dependent manner while 4-octyl-itaconic acid enhances THP-1 clearance of nontuberculous mycobacteria in vitro.

Paul Breen, Madsen Zimbric, Lindsay J Caverly.

Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum identified lower levels of the host metabolite itaconate in those infected with NTM. Itaconate can inhibit the growth of M. tuberculosis (MTB) in vitro via the inhibition of the glyoxylate cycle enzyme (ICL), but its impact on NTM is unclear. To test itaconic acid's (IA) effect on NTM growth, laboratory and CF clinical strains of Mycobacterium abscessus and Mycobacterium avium were cultured in 7H9 minimal media supplemented with 1-10 mM of IA and short-chain fatty acids (SCFA). M. avium and M. abscessus grew when supplemented with SCFAs, whereas the addition of IA (≥ 10 mM) completely inhibited NTM growth. NTM supplemented with acetate or propionate and 5 mM IA displayed slower growth than NTM cultured with SCFA and ≤ 1 mM of IA. However, IA's inhibition of NTM was pH dependent; as similar and higher quantities (100 mM) of pH adjusted IA (pH 7) did not inhibit growth in vitro, while in an acidic minimal media (pH 6.1), 1 to 5 mM of non-pH adjusted IA inhibited growth. None of the examined isolates displayed the ability to utilize IA as a carbon source, and IA added to M. abscessus isocitrate lyase (ICL) decreased enzymatic activity. Lastly, the addition of cell-permeable 4-octyl itaconate (4-OI) to THP-1 cells enhanced NTM clearance, demonstrating a potential role for IA/itaconate in host defense against NTM infections.

DOI: https://doi.org/10.1371/journal.pone.0303516
Immunometabolism (Cobham). 2024 Apr;6(2): e00041

The immunometabolic function of VGLL3 and female-biased autoimmunity.

Kameron Kennicott, Yun Liang.

  Autoimmune diseases exhibit a pronounced yet unexplained prevalence among women. Vestigial-like family member 3 (VGLL3), a female-biased factor that promotes autoimmunity, has recently been discovered to assist cells in sensing and adapting to nutritional stress. This role of VGLL3 may confer a selective advantage during the evolution of placental mammals. However, the excessive activation of the VGLL3-mediated energy-sensing pathway can trigger inflammatory cell death and the exposure of self-antigens, leading to the onset of autoimmunity. These observations have raised the intriguing perspective that nutrient sensing serves as a double-edged sword in immune regulation. Mechanistically, VGLL3 intersects with Hippo signaling and activates multiple downstream, immune-associated genes that play roles in metabolic regulation. Understanding the multifaceted roles of VGLL3 in nutrient sensing and immune modulation provides insight into the fundamental question of sexual dimorphism in immunometabolism and sheds light on potential therapeutic targets for autoimmune diseases.

Keywords:  autoimmunity; immunometabolism; nutrient sensing; sexual dimorphism

DOI:  https://doi.org/10.1097/IN9.0000000000000041
Immunity. 2024 Apr 30. pii: S1074-7613(24)00211-5. [Epub ahead of print]

Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.

Alessandra De Leo, Alessio Ugolini, Xiaoqing Yu, Fabio Scirocchi, Delia Scocozza, Barbara Peixoto, Angelica Pace, Luca D'Angelo, James K C Liu, Arnold B Etame, Aurelia Rughetti, Marianna Nuti, Antonio Santoro, Michael A Vogelbaum, Jose R Conejo-Garcia, Paulo C Rodriguez, Filippo Veglia.

  Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.

Keywords:  ER stress; PERK; brain cancer; glioblastoma; glycolysis; histone lactylation; immunosuppression; metabolism; myeloid cells; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.immuni.2024.04.006
Cell Mol Life Sci. 2024 May 06. 81(1): 206

LPS-induced monocarboxylate transporter-1 inhibition facilitates lactate accumulation triggering epithelial-mesenchymal transformation and pulmonary fibrosis.

Jinhua Feng, Han Zhong, Shuya Mei, Ri Tang, Yang Zhou, Shunpeng Xing, Yuan Gao, Qiaoyi Xu, Zhengyu He.

  The epithelial-mesenchymal transformation (EMT) process of alveolar epithelial cells is recognized as involved in the development of pulmonary fibrosis. Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung tissue and elevated lactate concentration are associated with the pathogenesis of sepsis-associated pulmonary fibrosis. However, it is uncertain whether LPS promotes the development of sepsis-associated pulmonary fibrosis by promoting lactate accumulation in lung tissue, thereby initiating EMT process. We hypothesized that monocarboxylate transporter-1 (MCT1), as the main protein for lactate transport, may be crucial in the pathogenic process of sepsis-associated pulmonary fibrosis. We found that high concentrations of lactate induced EMT while moderate concentrations did not. Besides, we demonstrated that MCT1 inhibition enhanced EMT process in MLE-12 cells, while MCT1 upregulation could reverse lactate-induced EMT. LPS could promote EMT in MLE-12 cells through MCT1 inhibition and lactate accumulation, while this could be alleviated by upregulating the expression of MCT1. In addition, the overexpression of MCT1 prevented LPS-induced EMT and pulmonary fibrosis in vivo. Altogether, this study revealed that LPS could inhibit the expression of MCT1 in mouse alveolar epithelial cells and cause lactate transport disorder, which leads to lactate accumulation, and ultimately promotes the process of EMT and lung fibrosis.

Keywords:  Epithelial-mesenchymal transformation; Lactate; Lipopolysaccharide; Monocarboxylate transporter-1; Pulmonary fibrosis

DOI:  https://doi.org/10.1007/s00018-024-05242-y
Cell Death Differ. 2024 May 08.

Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke.

Chao Wei, Zhongnan Xiao, Yanling Zhang, Zhaoli Luo, Dongyang Liu, Liye Hu, Danmin Shen, Meng Liu, Lei Shi, Xiaotong Wang, Ting Lan, Qingqing Dai, Jing Liu, Wen Chen, Yurui Zhang, Qingyu Sun, Weihua Wu, Peipei Wang, Chenguang Zhang, Junchi Hu, Chu Wang, Fei Yang, Qian Li.

Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4's enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH.

DOI: https://doi.org/10.1038/s41418-024-01303-8
Adv Nutr. 2024 May 08. pii: S2161-8313(24)00072-3. [Epub ahead of print] 100238

Effects of iron status on adaptive immunity and vaccine efficacy: a review.

Nicole U Stoffel, Hal Drakesmith.

  Vaccines can prevent infectious diseases, but their efficacy varies, and factors impacting vaccine effectiveness remain unclear. Iron deficiency is the most common nutrient deficiency, affecting over 2 billion individuals. It is particularly common in areas with high infectious disease burden and in groups that are routinely vaccinated, such as infants, pregnant women, and the elderly. Recent evidence suggests that iron deficiency and low serum iron (hypoferremia) not only cause anemia, but also may impair adaptive immunity and vaccine efficacy. A report of human immunodeficiency caused by defective iron transport underscored the necessity of iron for adaptive immune responses and spurred research in this area. Sufficient iron is essential for optimal production of plasmablasts and IgG responses by human B cells in vitro and in vivo. The increased metabolism of activated lymphocytes depends on high iron acquisition, and hypoferremia, especially when occurring during lymphocyte expansion, adversely affects multiple facets of adaptive immunity, and may lead to prolonged inhibition of T cell memory. In mice, hypoferremia suppresses adaptive immune response to influenza infection, resulting in more severe pulmonary disease. In African infants, anemia and/or iron deficiency at time of vaccination predict decreased response to diphtheria, pertussis and pneumococcal vaccines, and response to measles vaccine may be increased by iron supplementation. In this review, we examine the emerging evidence that iron deficiency may limit adaptive immunity and vaccine responses. We discuss the molecular mechanisms and evidence from animal and human studies, highlight important unknowns, and propose a framework of key research questions to better understand iron-vaccine interactions.

Keywords:  B cells; T cells; adaptive immunity; deficiency; hepcidin; iron; lymphocytes; vaccination

DOI:  https://doi.org/10.1016/j.advnut.2024.100238
J Biol Chem. 2024 May 03. pii: S0021-9258(24)01835-0. [Epub ahead of print] 107334

MiR-106a-5p targets PFKFB3 and improves sepsis through regulating macrophage pyroptosis and inflammatory response.

Yixin Chen, Ping Zhang, Fangwei Han, Yanying Zhou, Juexian Wei, Cailing Wang, Mingchuan Song, Shaopeng Lin, Yiming Xu, Xiaohui Chen.

  The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) is a critical regulator of glycolysis and plays a key role in modulating the inflammatory response, thereby contributing to the development of inflammatory diseases such as sepsis. Despite its importance, the development of strategies to target PFKFB3 in the context of sepsis remains challenging. In this study, we employed a microRNA-based approach to decrease PFKFB3 expression. Through multiple meta-analyses, we observed a downregulation of miR-106a-5p expression and an upregulation of PFKFB3 expression in clinical sepsis samples. These changes were also confirmed in blood monocytes from patients with early sepsis and from a mouse model of lipopolysaccharide (LPS)-induced sepsis. Overexpression of miR-106a-5p significantly decreased the LPS-induced increase in glycolytic capacity, inflammatory response, and pyroptosis in macrophages. Mechanistically, we identified PFKFB3 as a direct target protein of miR-106a-5p and demonstrated its essential role in LPS-induced pyroptosis and inflammatory response in macrophages. Furthermore, treatment with agomir-miR-106a-5p conferred a protective effect in an LPS mouse model of sepsis, but this effect was attenuated in myeloid-specific Pfkfb3 knockout mice. These findings indicate that miR-106a-5p inhibits macrophage pyroptosis and inflammatory response in sepsis by regulating PFKFB3-mediated glucose metabolism, representing a potential therapeutic option for the treatment of sepsis.

Keywords:  PFKFB3; glycolysis; inflammation; macrophage; miRNA-106a-5p; pyroptosis; sepsis

DOI:  https://doi.org/10.1016/j.jbc.2024.107334
Neurochem Res. 2024 May 10.

Is Methylglyoxal a Potential Biomarker for the Warburg Effect Induced by the Lipopolysaccharide Neuroinflammation Model?

Adriana Fernanda Kuckartz Vizuete, Carlos-Alberto Gonçalves.

  Methylglyoxal (MG) is considered a classical biomarker of diabetes mellitus and its comorbidities. However, a role for this compound in exacerbated immune responses, such as septicemia, is being increasingly observed and requires clarification, particularly in the context of neuroinflammatory responses. Herein, we used two different approaches (in vivo and acute hippocampal slice models) to investigate MG as a biomarker of neuroinflammation and the neuroimmunometabolic shift to glycolysis in lipopolysaccharide (LPS) inflammation models. Our data reinforce the hypothesis that LPS-induced neuroinflammation stimulates the cerebral innate immune response by increasing IL-1β, a classical pro-inflammatory cytokine, and the astrocyte reactive response, via elevating S100B secretion and GFAP levels. Acute neuroinflammation promotes an early neuroimmunometabolic shift to glycolysis by elevating glucose uptake, lactate release, PFK1, and PK activities. We observed high serum and cerebral MG levels, in association with a reduction in glyoxalase 1 detoxification activity, and a close correlation between serum and hippocampus MG levels with the systemic and neuroinflammatory responses to LPS. Findings strongly suggest a role for MG in immune responses.

Keywords:  Aerobic glycolysis; LPS; Methylglyoxal; Neuroinflammation; Warburg effect

DOI:  https://doi.org/10.1007/s11064-024-04142-8