bims-imicid 2024-10-20 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024‒10‒20
34 papers selected by
Dylan Ryan, University of Cambridge

Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.
Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.
Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation.
A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice.
Sex-specific phenotypical, functional and metabolic profiles of human term placenta macrophages.
Regulation of CD8+ T cells by lipid metabolism in cancer progression.
Immunometabolic Rewiring: A Tale of Macronutrients and Macrophages.
Metabolic reprogramming of macrophages in the context of type 2 diabetes.
Cholesterol sensing and metabolic adaptation in tissue immunity.
Metabolomic Profiling Reveals Potential of Fatty Acids as Regulators of Stem-like Exhausted CD8 T Cells During Chronic Viral Infection.
Itaconate induces tolerance of Staphylococcus aureus to aminoglycoside antibiotics.
Glutamine metabolism modulates microglial NLRP3 inflammasome activity through mitophagy in Alzheimer's disease.
Investigating the regulatory mechanism of glucose metabolism by ubiquitin-like protein MNSFβ.
CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation.
Glucose metabolism controls monocyte homeostasis and migration but has no impact on atherosclerosis development in mice.
Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling.
Bach2 repression of CD36 regulates lipid-metabolism-linked effector functions in follicular B cells.
Metabolic-epigenetic rewiring in CD8+ T cells via lactate-dependent histone lactylation.
Understanding Metabolic Pathway Rewiring by Oncogenic Gamma Herpesvirus.
Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity.
Glycolytic reprogramming in microglia: A potential therapeutic target for ischemic stroke.
Clostridium sporogenes-derived metabolites protect mice against colonic inflammation.
Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.
Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS.
Itaconate modulates mitochondria for antiviral IFN-β.
Modeling enzyme competition in Eicosanoid metabolism in macrophage cells using a cybernetic framework.
Host 5-HT affects Plasmodium transmission in mosquitoes via modulating mosquito mitochondrial homeostasis.
Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction.
The roles of arginases and arginine in immunity.
Tissue niche influences immune and metabolic profiles to Staphylococcus aureus biofilm infection.
Dynamic reciprocal interactions between activated T cells and tumor associated macrophages drive macrophage reprogramming and proinflammatory T cell migration within prostate tumor models.
Palmitoleate protects against Lipopolysaccharide-induced Inflammation and Inflammasome Activity.
Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1.
Immunometabolism and mitochondria in inflammatory bowel disease: a role for therapeutic intervention?

Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00103-5. [Epub ahead of print]389 67-103

Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.

Sanjay Pandey, Vandana Anang, Michelle M Schumacher.

  Understanding the intricacies of the metabolic phenotype in immune cells and its plasticity within the tumor microenvironment is pivotal in understanding the pathology and prognosis of cancer. Unfavorable conditions and cellular stress in the tumor microenvironment (TME) exert a profound impact on cellular functions in immune cells, thereby influencing both tumor progression and immune responses. Elevated AMP:ATP ratio, a consequence of limited glucose levels, activate AMP-activated protein kinase (AMPK) while concurrently repressing the activity of mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor 1-alpha (HIF-1α). The intricate balance between AMPK, mTOR, and HIF-1α activities defines the metabolic phenotype of immune cells in the TME. These Changes in metabolic phenotype are strongly associated with immune cell functions and play a crucial role in creating a milieu conducive to tumor progression. Insufficiency of nutrient and oxygen supply leads to a metabolic shift in immune cells characterized by a decrease in glycolysis and an increase in oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) rates. In most cases, this shift in metabolism is accompanied by a compromise in the effector functions of these immune cells. This metabolic adaptation prompts immune cells to turn down their effector functions, entering a quiescent or immunosuppressive state that may support tumor growth. This article discusses how tumor microenvironment alters the metabolism in immune cells leading to their tolerance and tumor progression, with emphasis on mitochondrial metabolism (OXPHOS and FAO).

Keywords:  AMPK; CAR-T; Fatty acid oxidation; Glycolysis; HIF1α; MTOR; Metabolism; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitochondrial metabolism; OXPHOS; T cell exhaustion; T cell metabolism

DOI:  https://doi.org/10.1016/bs.ircmb.2024.07.003
Nat Metab. 2024 Oct 15.

Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.

Shane M O'Carroll, Christian G Peace, Juliana E Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J O'Sullivan, Aline Zoller, Anne F Mcgettrick, Emily A Day, Maria Simarro, Neali Armstrong, Justin P Annes, Luke A J O'Neill.

Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.

DOI: https://doi.org/10.1038/s42255-024-01145-1
J Clin Invest. 2024 Oct 01. pii: e177242. [Epub ahead of print]

Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation.

Nowrin U Chowdhury, Jacqueline-Yvonne Cephus, Emely Henriquez Pilier, Melissa M Wolf, Matthew Z Madden, Shelby N Kuehnle, Kaitlin E McKernan, Erin Q Jennings, Emily N Arner, Darren R Heintzman, Channing Chi, Ayaka Sugiura, Matthew T Stier, Kelsey Voss, Xiang Ye, Kennedi L Scales, Evan S Krystofiak, Vivek D Gandhi, Robert D Guzy, Katherine N Cahill, Anne I Sperling, R Stokes Peebles, Jeffrey C Rathmell, Dawn C Newcomb.

  Females have an increased prevalence of many Th17 cell-mediated diseases, including asthma. Androgen signaling decreases Th17 cell-mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell-mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. Minimal reliance on glutamine uptake in male Th17 cells compared to female Th17 cells was also found in circulating T cells from patients with asthma. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.

Keywords:  Asthma; Immunology; Pulmonology; Sex hormones; T cells

DOI:  https://doi.org/10.1172/JCI177242
Cell Stem Cell. 2024 Oct 14. pii: S1934-5909(24)00324-2. [Epub ahead of print]

A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice.

Taylor S Mills, Bailee Kain, Matt A Burchill, Etienne Danis, Erin D Lucas, Rachel Culp-Hill, Courtney M Cowan, Wolfgang E Schleicher, Sweta B Patel, Brandon T Tran, Ruoqiong Cao, Andrew Goodspeed, Sarah Ferrara, Shaun Bevers, Beth A Jirón Tamburini, James R Roede, Angelo D'Alessandro, Katherine Y King, Eric M Pietras.

  Here, we investigate the contribution of long-term hematopoietic stem cells (HSCsLT) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased Mycobacterium avium killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI. However, these BMDMs exhibit reduced glycolytic activity and chromatin accessibility at metabolic genes while retaining elevated expression of TI-associated transcriptional regulators. Hence, HSC exposed to autoimmune inflammation can give rise to macrophages in which the functional and metabolic properties of TI are decoupled. Our data support a model in which TI is characterized by a spectrum of molecular and metabolic states driving augmented immune function.

Keywords:  autoimmune disease; bone marrow-derived macrophage; hematopoietic stem cell; inflammation; metabolism; trained immunity

DOI:  https://doi.org/10.1016/j.stem.2024.09.010
Biol Sex Differ. 2024 Oct 17. 15(1): 80

Sex-specific phenotypical, functional and metabolic profiles of human term placenta macrophages.

Daniel E Paparini, Esteban Grasso, Franco Aguilera, M Agustina Arslanian, Victoria Lella, Brenda Lara, Ana Schafir, Soledad Gori, Fátima Merech, Vanesa Hauk, Claudio Schuster, Marcelo Martí, Cesar Meller, Rosanna Ramhorst, Daiana Vota, Claudia Pérez Leirós.

  BACKGROUND: Placental macrophages, Hofbauer cells (HBC) are the only fetal immune cell population within the stroma of healthy placenta along pregnancy. They are central players in maintaining immune tolerance during pregnancy. Immunometabolism emerged a few years ago as a new field that integrates cellular metabolism with immune responses, however, the immunometabolism of HBC has not been explored yet. Here we studied the sex-specific differences in the phenotypic, functional and immunometabolic profile of HBC.METHODS: HBC were isolated from human term placentas (N = 31, 16 from male and 15 female neonates). Ex vivo assays were carried out to assess active metabolic and endoplasmic reticulum stress pathways by flow cytometry, confocal microscopy, gene expression and in silico approaches.
RESULTS: HBC from female placentas displayed a stronger M2 phenotype accompanied by high rates of efferocytosis majorly sustained on lipid metabolism. On the other hand, male HBC expressed a weaker M2 phenotype with higher glycolytic metabolism. LPS stimulation reinforced the glycolytic metabolism in male but not in female HBC. Physiological endoplasmic reticulum stress activates IRE-1 differently, since its pharmacological inhibition increased lipid mobilization, accumulation and efferocytosis only in female HBC. Moreover, differential sex-associated pathways accompanying the phenotypic and functional profiles of HBC appeared related to the placental villi environment.
CONCLUSIONS: These results support sex-associated effects on the immunometabolism of the HBC and adds another layer of complexity to the intricate maternal-fetal immune interaction.

Keywords:  Metabolism; Placental-macrophages; Sex-associated differences

DOI:  https://doi.org/10.1186/s13293-024-00652-w
Cell Mol Immunol. 2024 Oct 14.

Regulation of CD8+ T cells by lipid metabolism in cancer progression.

Yong Tang, Ziqing Chen, Qianying Zuo, Yibin Kang.

  Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment, where tumor cells utilize lipids for proliferation, survival, metastasis, and evasion of immune surveillance. Lipid metabolism has become a critical regulator of CD8+ T-cell-mediated antitumor immunity, with excess lipids in the tumor microenvironment impeding CD8+ T-cell activities. Considering the limited efficacy of immunotherapy in many solid tumors, targeting lipid metabolism to enhance CD8+ T-cell effector functions could significantly improve immunotherapy outcomes. In this review, we examine recent findings on how lipid metabolic processes, including lipid uptake, synthesis, and oxidation, regulate CD8+ T cells within tumors. We also assessed the impact of different lipids on CD8+ T-cell-mediated antitumor immunity, with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+ T cells. Furthermore, as cancer is a systemic disease, we examined systemic factors linking lipid metabolism to CD8+ T-cell effector function. Finally, we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy. Understanding the molecular and functional interplay between lipid metabolism and CD8+ T cells offers promising therapeutic opportunities for cancer treatment.

Keywords:  CD8+T cells; Immunotherapy; Lipid metabolism; Mitochondria; Oxidative phosphorylation

DOI:  https://doi.org/10.1038/s41423-024-01224-z
Results Probl Cell Differ. 2024 ;74 89-118

Immunometabolic Rewiring: A Tale of Macronutrients and Macrophages.

Gerasimos Anagnostopoulos, Camille Blériot, Nicolas Venteclef, Florent Ginhoux.

  Myeloid cells, including monocytes, macrophages, dendritic cells, and polymorphonuclear cells are key components of homeostasis maintenance and immune response. Among the myeloid lineage, macrophages stand out as highly versatile cells that safeguard tissue functions but also sense and respond to potentially harmful microenvironmental cues. Numerous studies have demonstrated that the nutritional status and macronutrient availability affect macrophage identity and function. However, the exact mechanistic links between macronutrient intake and cellular metabolic shifts are only beginning to be understood. In this chapter, we explore how dietary "macros"-carbohydrates, fats, and amino acids-impact the immunomodulatory activity of macrophages in healthy and inflamed tissues.

Keywords:  Immunometabolism; Macronutrient intake; Resident tissue macrophages (RTMs)

DOI:  https://doi.org/10.1007/978-3-031-65944-7_3
Eur J Med Res. 2024 Oct 16. 29(1): 497

Metabolic reprogramming of macrophages in the context of type 2 diabetes.

Leonel Witcoski Junior, Jordana Dinorá de Lima, Amanda Girardi Somensi, Lucas Brito de Souza Santos, Giulia Leonel Paschoal, Thalita Suemy Uada, Thais Sibioni Berti Bastos, André Guilherme Portela de Paula, Rebeca Bosso Dos Santos Luz, Andressa Pacheco Czaikovski, Mariana Rodrigues Davanso, Tarcio Teodoro Braga.

  Type 2 diabetes (T2D) is associated with insulin resistance and progressive dysfunction of β-pancreatic cells, leading to persistent hyperglycemia. Macrophages play a crucial role in this context, influencing both the development and progression of insulin resistance. These innate immune cells respond to inflammatory stimuli and reprogram their metabolism, directly impacting the pathophysiology of T2D. Macrophages are highly plastic and can adopt either pro-inflammatory or pro-resolutive phenotypic profiles. In T2D, pro-inflammatory macrophages, which rely on glycolysis, exacerbate insulin resistance through increased production of pro-inflammatory cytokines and nitric oxide. In contrast, pro-resolutive macrophages, which prioritize fatty acid metabolism, have different effects on glucose homeostasis. Metaflammation, a chronic low-grade inflammation, is induced by pro-inflammatory macrophages and significantly contributes to the progression of T2D, creating an environment conducive to metabolic dysfunction. This review aims to clarify the contribution of macrophages to the progression of T2D by detailing how their inflammatory responses and metabolic reprogramming influence insulin resistance and the disease's pathophysiology. The review seeks to deepen the understanding of the biochemical and metabolic mechanisms involved, offering broader insights into the impact on the quality of life for millions of patients worldwide.

Keywords:  Epigenetic modifications; Immunometabolism; Macrophage; T2D

DOI:  https://doi.org/10.1186/s40001-024-02069-y
Trends Immunol. 2024 Oct 17. pii: S1471-4906(24)00221-7. [Epub ahead of print]

Cholesterol sensing and metabolic adaptation in tissue immunity.

Eric V Dang, Andrea Reboldi.

  Cholesterol metabolites, particularly oxidized forms known as oxysterols, play crucial roles in modulating immune and metabolic processes across various tissues. Concentrations of local cholesterol and its metabolites influence tissue-specific immune responses by shaping the metabolic and spatial organization of immune cells in barrier organs like the small intestine (SI) and lungs. We explore recent molecular and cellular evidence supporting the metabolic adaptation of innate and adaptive immune cells in the SI and lung, driven by cholesterol and cholesterol metabolites. Further research should unravel the detailed molecular mechanisms and spatiotemporal adaptations involving cholesterol metabolites in distinct mucosal tissues in homeostasis or infection. We posit that pharmacological interventions targeting the generation or sensing of cholesterol metabolites might be leveraged to enhance long-term immune protection in mucosal tissues or prevent autoinflammatory states.

Keywords:  adaptive immunity; innate immunity; lung; mevalonate–cholesterol pathway; oxysterols; small intestine

DOI:  https://doi.org/10.1016/j.it.2024.09.013
bioRxiv. 2024 Oct 11. pii: 2024.10.07.617124. [Epub ahead of print]

Metabolomic Profiling Reveals Potential of Fatty Acids as Regulators of Stem-like Exhausted CD8 T Cells During Chronic Viral Infection.

Katelynn R Kazane, Lara Labarta-Bajo, Dina R Zangwill, Kalle Liimatta, Fernando Vargas, Kelly C Weldon, Pieter C Dorrestein, Elina I Zúñiga.

Chronic infections drive a CD8 T cell program termed T cell exhaustion, characterized by reduced effector functions. While cell-intrinsic mechanisms underlying CD8 T cell exhaustion have been extensively studied, the impact of the metabolic environment in which exhausted CD8 T cells (Tex) operate remains less clear. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model we investigated systemic metabolite changes early and late following acute versus chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the acute phase of the sustained infection. This included nutrient changes that were independent of viral loads and partially associated with CD8 T cell-induced anorexia and lipolysis. One remarkable observation was the elevation of medium- and long-chain fatty acid (FA) and acylcarnitines during the early phase after chronic infection. During this time, virus-specific CD8 T cells from chronically infected mice exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly stem-like Tex (Tex STEM ), a subset that generates effector-like Tex INT which directly limit viral replication. Notably, only Tex STEM increased oxidative metabolism and ATP production upon FA exposure. Consistently, short-term reintroduction of FA during late chronic infection exclusively improved Tex STEM mitochondrial fitness, percentages and numbers. This treatment, however, also reduced Tex INT , resulting in compromised viral control. Our study offers a valuable resource for investigating the role of specific metabolites in regulating immune responses during acute and chronic viral infections and highlights the potential of long-chain FA to influence Tex STEM and viral control during a protracted infection.Significance: This study examines systemic metabolite changes during acute and chronic viral infections. Notably, we identified an early, transient nutrient shift in chronic infection, marked by an increase in medium- and long-chain fatty acid related species. Concomitantly, a virus-specific stem-like T cell population, essential for maintaining other T cells, displayed high lipid avidity and was capable of metabolizing exogenous fatty acids. Administering fatty acids late in chronic infection, when endogenous lipid levels had normalized, expanded this stem-like T cell population and enhanced their mitochondrial fitness. These findings highlight the potential role of fatty acids in regulating stem-like T cells in chronic settings and offer a valuable resource for studying other metabolic signatures in both acute and persistent infections.

DOI: https://doi.org/10.1101/2024.10.07.617124
Front Microbiol. 2024 ;15 1450085

Itaconate induces tolerance of Staphylococcus aureus to aminoglycoside antibiotics.

Runping Zhao, Lei Xu, Jieyun Chen, Yanxian Yang, Xilong Guo, Min Dai, Guo-Bao Tian, Li-Na Qin.

  Introduction: Staphylococcus aureus is one of the chief pathogens that cause chronic and recurrent infections. Failure of the antibiotics to curb the infections contributes to relapse and is an important reason for the high mortality rate. Treatment failure may also be due to antibiotic tolerance. Accumulating evidence suggests that t the host immune environment plays an important role in inducing antibiotic tolerance of S. aureus, but research in this area has been limited.Methods: In this study,the minimum inhibitory concentration (MIC) of the antibiotics against S. aureus was determined using the standard broth microdilution method.The study evaluated whether itaconate induces antibiotic tolerance in S. aureus through an antibiotic bactericidal activity assay.The effect of itaconate on the growth of S. aureus was evaluated by monitoring the growth of S. aureus in medium supplemented with itaconate. Additionally, RNA sequencing and metabolomics analyses were used to determine transcriptional and metabolic changes in S. aureus when exposed to itaconate.
Results and discussion: According to the study,we found that the immune metabolite itaconate can induce tolerance in both methicillin-resistant and -susceptible S. aureus to aminoglycosides. When S. aureus was exposed to itaconate, its growth slowed down and transcriptomic and metabolomic alterations associated with decreased energy metabolism, including the tricarboxylate cycle, glycolysis, pyruvate metabolism, and arginine biosynthesis, were observed. These changes are associated with aminoglycoside tolerance. This study highlights the role of immune signaling metabolites in bacterial antibiotic tolerance and suggests new strategies to improve antibiotic treatment by modulating the host immune response and stimulating the metabolism of bacteria.

Keywords:  Staphylococcus aureus; aminoglycosides; antibiotic tolerance; immune metabolite; itaconate

DOI:  https://doi.org/10.3389/fmicb.2024.1450085
J Neuroinflammation. 2024 Oct 15. 21(1): 261

Glutamine metabolism modulates microglial NLRP3 inflammasome activity through mitophagy in Alzheimer's disease.

Zhixin Zhang, Miao Li, Xiang Li, Zhiyang Feng, Gan Luo, Ying Wang, Xiaoyan Gao.

  The NLR family pyrin domain containing 3 (NLRP3) inflammasome in microglia is intimately linked to the pathogenesis of Alzheimer's disease (AD). Although NLRP3 inflammasome activity is regulated by cellular metabolism, the underlying mechanism remains elusive. Here, we found that under the pathological conditions of AD, the activation of NLRP3 inflammasome in microglia is accompanied by increased glutamine metabolism. Suppression of glutaminase, the rate limiting enzyme in glutamine metabolism, attenuated the NLRP3 inflammasome activation both in the microglia of AD mice and cultured inflammatory microglia. Mechanistically, inhibiting glutaminase blocked the anaplerotic flux of glutamine to the tricarboxylic acid cycle and amino acid synthesis, down-regulated mTORC1 signaling by phosphorylating AMPK, which stimulated mitophagy and limited the accumulation of intracellular reactive oxygen species, ultimately prevented the activation of NLRP3 inflammasomes in activated microglia during AD. Taken together, our findings suggest that glutamine metabolism regulates the activation of NLRP3 inflammasome through mitophagy in microglia, thus providing a potential therapeutic target for AD treatment.

Keywords:  Alzheimer’s disease; Glutamine metabolism; Microglia; Mitophagy; NLRP3 inflammasome

DOI:  https://doi.org/10.1186/s12974-024-03254-w
Mol Biol Rep. 2024 Oct 15. 51(1): 1053

Investigating the regulatory mechanism of glucose metabolism by ubiquitin-like protein MNSFβ.

Megumi Kono, Kyoko Yamasaki, Morihiko Nakamura.

  BACKGROUND: Monoclonal nonspecific suppressor factor β (MNSFβ), a ubiquitously expressed member of the ubiquitin-like protein family, is associated with diverse cell regulatory functions. It has been implicated in glycolysis regulation and cell proliferation enhancement in the macrophage-like cell line Raw264.7. This study aims to show that HIF-1α regulates MNSFβ-mediated metabolic reprogramming.METHODS AND RESULTS: In Raw264.7 cells, MNSFβ siRNA increased the oxygen consumption rate and reactive oxygen species (ROS) production but decreased ATP levels. Cells with MNSFβ knockdown showed a markedly increased ATP reduction rate upon the addition of oligomycin, a mitochondrial ATP synthase inhibitor. In addition, MNSFβ siRNA decreased the expression levels of mRNA and protein of HIF-1α-a regulator of glucose metabolism. Evaluation of the effect of MNSFβ on glucose metabolism in murine peritoneal macrophages revealed no changes in lactate production, glucose consumption, or ROS production.
CONCLUSION: MNSFβ affects both glycolysis and mitochondrial metabolism, suggesting HIF-1α involvement in the MNSFβ-regulated glucose metabolism in Raw264.7 cells.

Keywords:  HIF-1α; Metabolic reprogramming; Metabolism; Ubiquitin-like protein MNSFβ

DOI:  https://doi.org/10.1007/s11033-024-10009-6
Immunity. 2024 Oct 09. pii: S1074-7613(24)00457-6. [Epub ahead of print]

CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation.

Jana L Raynor, Nicholas Collins, Hao Shi, Cliff Guy, Jordy Saravia, Seon Ah Lim, Nicole M Chapman, Peipei Zhou, Yan Wang, Yu Sun, Isabel Risch, Haoran Hu, Anil Kc, Renqiang Sun, Sharad Shrestha, Hongling Huang, Jon P Connelly, Shondra M Pruett-Miller, Miguel Reina-Campos, Ananda W Goldrath, Yasmine Belkaid, Hongbo Chi.

  Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using in vivo CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8+ tissue-resident memory T (TRM) cell development. TRM cells depended on mitochondrial translation and respiration. Conversely, three nutrient-dependent lysosomal signaling nodes-Flcn, Ragulator, and Rag GTPases-inhibited intestinal TRM cell formation. Depleting these molecules or amino acids activated the transcription factor Tfeb, thereby linking nutrient stress to TRM programming. Further, Flcn deficiency promoted protective TRM cell responses in the small intestine. Mechanistically, the Flcn-Tfeb axis restrained retinoic acid-induced CCR9 expression for migration and transforming growth factor β (TGF-β)-mediated programming for lineage differentiation. Genetic interaction screening revealed that the mitochondrial protein Mrpl52 enabled early TRM cell formation, while Acss1 controlled TRM cell development under Flcn deficiency-associated lysosomal dysregulation. Thus, the interplay between nutrients, organelle signaling, and metabolic adaptation dictates tissue immunity.

Keywords:  CD8 T cell; adaptive immunity; dietary intervention; immunometabolism; lysosome; mitochondria; tissue-resident memory

DOI:  https://doi.org/10.1016/j.immuni.2024.09.013
Nat Commun. 2024 Oct 19. 15(1): 9027

Glucose metabolism controls monocyte homeostasis and migration but has no impact on atherosclerosis development in mice.

Alexandre Gallerand, Bastien Dolfi, Marion I Stunault, Zakariya Caillot, Alexia Castiglione, Axelle Strazzulla, Chuqiao Chen, Gyu Seong Heo, Hannah Luehmann, Flora Batoul, Nathalie Vaillant, Adélie Dumont, Thomas Pilot, Johanna Merlin, Fairouz N Zair, Jerome Gilleron, Adeline Bertola, Peter Carmeliet, Jesse W Williams, Rafael J Arguello, David Masson, David Dombrowicz, Laurent Yvan-Charvet, Denis Doyen, Arvand Haschemi, Yongjian Liu, Rodolphe R Guinamard, Stoyan Ivanov.

Monocytes directly contribute to atherosclerosis development by their recruitment to plaques in which they differentiate into macrophages. In the present study, we ask how modulating monocyte glucose metabolism could affect their homeostasis and their impact on atherosclerosis. Here we investigate how circulating metabolites control monocyte behavior in blood, bone marrow and peripheral tissues of mice. We find that serum glucose concentrations correlate with monocyte numbers. In diet-restricted mice, monocytes fail to metabolically reprogram from glycolysis to fatty acid oxidation, leading to reduced monocyte numbers in the blood. Mechanistically, Glut1-dependent glucose metabolism helps maintain CD115 membrane expression on monocytes and their progenitors, and regulates monocyte migratory capacity by modulating CCR2 expression. Results from genetic models and pharmacological inhibitors further depict the relative contribution of different metabolic pathways to the regulation of CD115 and CCR2 expression. Meanwhile, Glut1 inhibition does not impact atherosclerotic plaque development in mouse models despite dramatically reducing blood monocyte numbers, potentially due to the remaining monocytes having increased migratory capacity. Together, these data emphasize the role of glucose uptake and intracellular glucose metabolism in controlling monocyte homeostasis and functions.

DOI: https://doi.org/10.1038/s41467-024-53267-5
Nat Metab. 2024 Oct 18.

Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling.

Xiaomin Zhang, Yali Chen, Geng Sun, Yankang Fei, Ha Zhu, Yanfang Liu, Junyan Dan, Chunzhen Li, Xuetao Cao, Juan Liu.

Cellular metabolism modulates dendritic cell (DC) maturation and activation. Migratory dendritic cells (mig-DCs) travelling from the tissues to draining lymph nodes (dLNs) are critical for instructing adaptive immune responses. However, how lipid metabolites influence mig-DCs in autoimmunity remains elusive. Here, we demonstrate that farnesyl pyrophosphate (FPP), an intermediate of the mevalonate pathway, accumulates in mig-DCs derived from mice with systemic lupus erythematosus (SLE). FPP promotes mig-DC survival and germinal centre responses in the dLNs by coordinating protein geranylgeranylation and mitochondrial remodelling. Mechanistically, FPP-dependent RhoA geranylgeranylation promotes mitochondrial fusion and oxidative respiration through mitochondrial RhoA-MFN interaction, which subsequently facilitates the resolution of endoplasmic reticulum stress in mig-DCs. Simvastatin, a chemical inhibitor of the mevalonate pathway, restores mitochondrial function in mig-DCs and ameliorates systemic pathogenesis in SLE mice. Our study reveals a critical role for FPP in dictating mig-DC survival by reprogramming mitochondrial structure and metabolism, providing new insights into the pathogenesis of DC-dependent autoimmune diseases.

DOI: https://doi.org/10.1038/s42255-024-01149-x
Cell Rep. 2024 Oct 15. pii: S2211-1247(24)01229-4. [Epub ahead of print]43(11): 114878

Bach2 repression of CD36 regulates lipid-metabolism-linked effector functions in follicular B cells.

Eunkyeong Jang, ChangYeon Kim, Jeonghyun Noh, Hansol Yi, Sungsin Jo, Jin-Sil Park, Woochang Hwang, Ji-Young Cha, Mi-La Cho, Tae-Hwan Kim, Jeehee Youn.

  The transcription repressor Bach2 plays a crucial role in shaping humoral immunity, but its cell-autonomous function remains elusive. Here, we reveal the mechanism by which Bach2 regulates effector cell maturation in peripheral B cells. In response to Toll-like receptor (TLR) agonists, Bach2 deficiency promotes the differentiation of follicular, but not marginal zone, B cells into effector cells, producing interleukin (IL)-6 and antibodies. This phenomenon is associated with changes in lipid metabolism, such as increases in CD36 expression, lipid influx, and fatty acid oxidation. Consistent with this, Bach2-deficient B cells exhibit elevated levels of mitochondrial oxidative stress, lipid peroxidation, and p38 activation. Mechanistically, Bach2 acts as a repressor of Cd36, and inhibition of CD36 or fatty acid oxidation reduces the differentiation of naive B cells into IL-6- and antibody-secreting cells. These results indicate Bach2 as a key metabolic checkpoint regulator crucial for maintaining a functionally quiescent state of follicular B cells.

Keywords:  B cells; Bach2; CD36; CP: Immunology; CP: Metabolism; IL-6; follicular B cells; lipid metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114878
Nat Immunol. 2024 Oct 16.

Metabolic-epigenetic rewiring in CD8+ T cells via lactate-dependent histone lactylation.

Renqiang Sun, Hongbo Chi.

DOI: https://doi.org/10.1038/s41590-024-01991-x
J Microbiol Biotechnol. 2024 Aug 30. 34(11): 1-10

Understanding Metabolic Pathway Rewiring by Oncogenic Gamma Herpesvirus.

Un Yung Choi, Seung Hyun Lee.

  Gamma herpesviruses, including Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), are key contributors to the development of various cancers through their ability to manipulate host cellular pathways. This review explores the intricate ways these viruses rewire host metabolic pathways to sustain viral persistence and promote tumorigenesis. We look into how EBV and KSHV induce glycolytic reprogramming, alter mitochondrial function, and remodel nucleotide and amino acid metabolism, highlighting the crucial role of lipid metabolism in these oncogenic processes. By understanding these metabolic alterations, which confer proliferative and survival advantages to the virus-infected cells, we can identify potential therapeutic targets and develop innovative treatment strategies for gamma herpesvirus-associated malignancies. Ultimately, this review underscores the critical role of metabolic reprogramming in gamma herpesvirus oncogenesis and its implications for precision medicine in combating virus-driven cancers.

Keywords:  EBV; KSHV; Metabolic reprogramming; metabolic therapeutics; oncogenic virus

DOI:  https://doi.org/10.4014/jmb.2407.07039
Cell Death Dis. 2024 Oct 18. 15(10): 757

Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity.

Jean de Lima, Jefferson Antônio Leite, Paulo José Basso, Bruno Ghirotto, Eloisa Martins da Silva, Luisa Menezes-Silva, Meire Ioshie Hiyane, Carolina Purcell Goes, Luiz Lehmann Coutinho, Vinicius de Andrade Oliveira, Niels Olsen Saraiva Câmara.

Sirtuin 1 (SIRT1) is a class III histone deacetylase (HDAC3) that plays a crucial role in regulating the activation and differentiation of dendritic cells (DCs) as well as controlling the polarization and activation of T cells. Obesity, a chronic inflammatory condition, is characterized by the activation of immune cells in various tissues. We hypothesized that SIRT1 might influence the phenotype and functions of DCs through the Ido1 pathway, ultimately leading to the polarization towards pro-inflammatory T cells in obesity. In our study, we observed that SIRT1 activity was reduced in bone marrow-derived DCs (BMDCs) from obese animals. These BMDCs exhibited elevated oxidative phosphorylation (OXPHOS) and increased extracellular acidification rates (ECAR), along with enhanced expression of class II MHC, CD86, and CD40, and elevated secretion of IL-12p40, while the production of TGF-β was reduced. The kynurenine pathway activity was decreased in BMDCs from obese animals, particularly under SIRT1 inhibition. SIRT1 positively regulated the expression of Ido1 in DCs in a PPARγ-dependent manner. To support these findings, ATAC-seq analysis revealed that BMDCs from obese mice had differentially regulated open chromatin regions compared to those from lean mice, with reduced chromatin accessibility at the Sirt1 genomic locus in BMDCs from obese WT mice. Gene Ontology (GO) enrichment analysis indicated that BMDCs from obese animals had disrupted metabolic pathways, including those related to GTPase activity and insulin response. Differential expression analysis showed reduced levels of Pparg and Sirt1 in BMDCs from obese mice, which was challenged and confirmed using BMDCs from mice with conditional knockout of Sirt1 in dendritic cells (SIRT1∆). This study highlights that SIRT1 controls the metabolism and functions of DCs through modulation of the kynurenine pathway, with significant implications for obesity-related inflammation.

DOI: https://doi.org/10.1038/s41419-024-07125-3
Cell Signal. 2024 Oct 15. pii: S0898-6568(24)00439-X. [Epub ahead of print] 111466

Glycolytic reprogramming in microglia: A potential therapeutic target for ischemic stroke.

Guangming Zhang, Anliu Zhao, Xiaolu Zhang, Miao Zeng, Huayuan Wei, Xu Yan, Jie Wang, Xijuan Jiang, Yongna Dai.

  Ischemic stroke is currently the second leading cause of mortality worldwide, with limited treatment options available. As resident immune cells, microglia promptly respond to cerebral ischemic injury, influencing neuroinflammatory damage and neurorepair. Studies suggest that microglia undergo metabolic reprogramming from mitochondrial oxidative phosphorylation to glycolysis in response to ischemia, significantly impacting their function during ischemic stroke. Therefore, this study aims to investigate the roles and regulatory mechanisms involved in this process, aiming to identify a new therapeutic target or potential drug candidate.

Keywords:  Glycolysis; Ischemic stroke; Microglia; Neuroinflammation; Polarization

DOI:  https://doi.org/10.1016/j.cellsig.2024.111466
Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2412669

Clostridium sporogenes-derived metabolites protect mice against colonic inflammation.

Felix F Krause, Kira I Mangold, Anna-Lena Ruppert, Hanna Leister, Anne Hellhund-Zingel, Aleksandra Lopez Krol, Jelena Pesek, Bernhard Watzer, Sarah Winterberg, Hartmann Raifer, Kai Binder, Ralf Kinscherf, Alesia Walker, Wolfgang A Nockher, R Verena Taudte, Wilhelm Bertrams, Bernd Schmeck, Anja A Kühl, Britta Siegmund, Rossana Romero, Maik Luu, Stephan Göttig, Isabelle Bekeredjian-Ding, Ulrich Steinhoff, Burkhard Schütz, Alexander Visekruna.

  Gut microbiota-derived metabolites play a pivotal role in the maintenance of intestinal immune homeostasis. Here, we demonstrate that the human commensal Clostridium sporogenes possesses a specific metabolic fingerprint, consisting predominantly of the tryptophan catabolite indole-3-propionic acid (IPA), the branched-chain acids (BCFAs) isobutyrate and isovalerate and the short-chain fatty acids (SCFAs) acetate and propionate. Mono-colonization of germ-free mice with C. sporogenes (CS mice) affected colonic mucosal immune cell phenotypes, including up-regulation of Il22 gene expression, and increased abundance of transcriptionally active colonic tuft cells and Foxp3+ regulatory T cells (Tregs). In DSS-induced colitis, conventional mice suffered severe inflammation accompanied by loss of colonic crypts. These symptoms were absent in CS mice. In conventional, but not CS mice, bulk RNAseq analysis of the colon revealed an increase in inflammatory and Th17-related gene signatures. C. sporogenes-derived IPA reduced IL-17A protein expression by suppressing mTOR activity and by altering ribosome-related pathways in Th17 cells. Additionally, BCFAs and SCFAs generated by C. sporogenes enhanced the activity of Tregs and increased the production of IL-22, which led to protection from colitis. Collectively, we identified C. sporogenes as a therapeutically relevant probiotic bacterium that might be employed in patients with inflammatory bowel disease (IBD).

Keywords:  Colitis; commensal bacteria; indole-3-propionate; microbial metabolites

DOI:  https://doi.org/10.1080/19490976.2024.2412669
EMBO Rep. 2024 Oct 16.

Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.

Amelia M Knudsen-Clark, Daniel Mwangi, Juliana Cazarin, Kristina Morris, Cameron Baker, Lauren M Hablitz, Matthew N McCall, Minsoo Kim, Brian J Altman.

  Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.

Keywords:  Circadian Rhythms; Immuno-oncology; Immunology; Macrophage; Tumor Microenvironment

DOI:  https://doi.org/10.1038/s44319-024-00288-2
FASEB Bioadv. 2024 Sep;6(9): 337-350

Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS.

Signe Mosegaard, Krishna S Twayana, Simone W Denis, Jeffrey Kroon, Bauke V Schomakers, Michel van Weeghel, Riekelt H Houtkooper, Rikke K J Olsen, Christian K Holm.

  Stimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for subsequent release of pro-inflammatory cytokines. This has become particularly clear for enzymes of tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS-induced formation of IL-1β. If enzymes involved in beta-oxidation of fatty acids are important for sufficient responses to LPS is currently not clear. Using cells from various patients with inborn long-chain fatty acid oxidation disorders (lcFAOD), we report that disease-causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl-CoA Dehydrogenase (ACADVL), both cause insufficient inflammatory responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6. The insufficient responses to LPS were reproduced in cells from healthy controls by targeted loss-of-function of either ETFDH or ACADVL, supporting that the deleterious ETFDH and ACADVL variants cause the attenuated responses to LPS. ETFDH and ACADVL encode two distinct enzymes both involved in fatty acid beta-oxidation, and patients with these deficiencies cannot sufficiently metabolize long-chain fatty acids. We report that genes important for beta-oxidation of long-chain fatty acids are also important for inflammatory responses to an acute immunogen trigger like LPS, which may have important implications for understanding infection and other metabolic stress induced disease pathology in lcFAODs.

Keywords:  immunometabolism; lipopolyssacharide; long‐chain fatty acid oxidation disorders; toll‐like receptor 4

DOI:  https://doi.org/10.1096/fba.2024-00060
Nat Metab. 2024 Oct 15.

Itaconate modulates mitochondria for antiviral IFN-β.

Thekla Cordes, Karsten Hiller.

DOI: https://doi.org/10.1038/s42255-024-01146-0
J Lipid Res. 2024 Oct 10. pii: S0022-2275(24)00171-8. [Epub ahead of print] 100666

Modeling enzyme competition in Eicosanoid metabolism in macrophage cells using a cybernetic framework.

Sana Khanum, Shakti Gupta, Mano R Maurya, Rubesh Raja, Lina Aboulmouna, Shankar Subramaniam, Doraiswami Ramkrishna.

  Cellular metabolism is a complex process involving the consumption and production of metabolites, as well as the regulation of enzyme synthesis and activity. Modeling of metabolic processes is important to understand the underlying mechanisms, with a wide range of applications in metabolic engineering and health sciences. Cybernetic modeling is a powerful technique that accounts for unknown intricate regulatory mechanisms in complex cellular processes. It models regulation as goal-oriented, where the levels and activities of enzymes are modulated by the cybernetic control variables to achieve the cybernetic objective. This study employed cybernetic model to study the enzyme competition between arachidonic acid (AA) and eicosapentaenoic acid (EPA) metabolism in murine macrophages. AA and EPA compete for the shared enzyme cyclooxygenase (COX). Upon external stimuli, AA produces pro-inflammatory 2-series prostaglandins (PGs) and EPA metabolizes to anti-inflammatory 3-series PGs, where pro- and anti- inflammatory responses are necessary for homeostasis. The cybernetic model adequately captured the experimental data for control and EPA-supplemented conditions. The model is validated by performing an F-test, conducting leave-one-out-metabolite cross-validation, and predicting an unseen experimental condition. The cybernetic variables provide insights into the competition between AA and EPA for the COX enzyme. Predictions from our model suggest that the system undergoes a switch from a predominantly pro-inflammatory state in the control to an anti-inflammatory state with EPA-supplementation. The model can also be used to analytically determine the AA and EPA concentrations required for the switch to occur. The quantitative outcomes enhance understanding of pro- and anti-inflammatory metabolism in RAW 264.7 macrophages.

Keywords:  Arachidonic acid; Cyclooxygenase; Eicosapentaenoic acid; Inflammation; Kinetic modeling; Lipidomics; Lipolysis and Fatty acid Metabolism; Omega-3 fatty acid; Prostaglandin

DOI:  https://doi.org/10.1016/j.jlr.2024.100666
PLoS Pathog. 2024 Oct 15. 20(10): e1012638

Host 5-HT affects Plasmodium transmission in mosquitoes via modulating mosquito mitochondrial homeostasis.

Li Gao, Benguang Zhang, Yuebiao Feng, Wenxu Yang, Shibo Zhang, Jingwen Wang.

Malaria parasites hijack the metabolism of their mammalian host during the blood-stage cycle. Anopheles mosquitoes depend on mammalian blood to lay eggs and to transmit malaria parasites. However, it remains understudied whether changes in host metabolism affect parasite transmission in mosquitoes. In this study, we discovered that Plasmodium infection significantly decreased the levels of the tryptophan metabolite, 5-hydroxytryptamine (5-HT), in both humans and mice. The reduction led to the decrease of 5-HT in mosquitoes. Oral supplementation of 5-HT to Anopheles stephensi enhanced its resistance to Plasmodium berghei infection by promoting the generation of mitochondrial reactive oxygen species. This effect was due to the accumulation of dysfunctional mitochondria caused by 5-HT-mediated inhibition of mitophagy. Elevating 5-HT levels in mouse serum significantly suppressed parasite infection in mosquitoes. In summary, our data highlight the critical role of metabolites in animal blood in determining the capacity of mosquitoes to control parasite infection.

DOI: https://doi.org/10.1371/journal.ppat.1012638
Res Sq. 2024 Sep 26. pii: rs.3.rs-4980210. [Epub ahead of print]

Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction.

Edward Wilson, Jacob Umans, Michelle Swarovski, Paras Minhas, Øivind Midttun, Arve Arve Ulvik, Marian Shahid-Besanti, Patricia Linortner, Siddhita Mhatre, Qian Wang, Divya Channappa, Nicole Corso, Lu Tian, Carolyn Fredericks, Geoffrey Kerchner, Edward Plowey, Brenna Cholerton, Per Ueland, Cyrus Zabetian, Nora Gray, Joseph Quinn, Thomas Montine, Sharon Sha, Frank Longo, David Wolk, Alice Chen-Plotkin, Victor Henderson, Tony Wyss-Coray, Anthony Wagner, Elizabeth Mormino, Nima Aghaeepour, Kathleen Poston, Katrin Andreasson.

Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). This multicenter study used highly sensitive liquid chromatography-tandem mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. Results indicate that increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau and severity of both motor and non-motor PD clinical dysfunction. Importantly, plasma and CSF kynurenine metabolites classified PD participants with a high degree of accuracy (AUC = 0.897). Finally, analysis of metabolite data revealed subgroups with distinct KP profiles, and these were subsequently found to display distinct PD clinical features. Together, these data further support the hypothesis that the KP serves as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

DOI: https://doi.org/10.21203/rs.3.rs-4980210/v1
Nat Rev Immunol. 2024 Oct 17.

The roles of arginases and arginine in immunity.

Stefania Canè, Roger Geiger, Vincenzo Bronte.

Arginase activity and arginine metabolism in immune cells have important consequences for health and disease. Their dysregulation is commonly observed in cancer, autoimmune disorders and infectious diseases. Following the initial description of a role for arginase in the dysfunction of T cells mounting an antitumour response, numerous studies have broadened our understanding of the regulation and expression of arginases and their integration with other metabolic pathways. Here, we highlight the differences in arginase compartmentalization and storage between humans and rodents that should be taken into consideration when assessing the effects of arginase activity. We detail the roles of arginases, arginine and its metabolites in immune cells and their effects in the context of cancer, autoimmunity and infectious disease. Finally, we explore potential therapeutic strategies targeting arginases and arginine.

DOI: https://doi.org/10.1038/s41577-024-01098-2
Nat Commun. 2024 Oct 17. 15(1): 8965

Tissue niche influences immune and metabolic profiles to Staphylococcus aureus biofilm infection.

Zachary Van Roy, Prabakar Arumugam, Blake P Bertrand, Dhananjay D Shinde, Vinai C Thomas, Tammy Kielian.

Infection is a devastating post-surgical complication, often requiring additional procedures and prolonged antibiotic therapy. This is especially relevant for craniotomy and prosthetic joint infections (PJI), both of which are characterized by biofilm formation on the bone or implant surface, respectively, with S. aureus representing a primary cause. The local tissue microenvironment likely has profound effects on immune attributes that can influence treatment efficacy, which becomes critical to consider when developing therapeutics for biofilm infections. However, the extent to which distinct tissue niches influence immune function during biofilm development remains relatively unknown. To address this, we compare the metabolomic, transcriptomic, and functional attributes of leukocytes in mouse models of S. aureus craniotomy and PJI complemented with patient samples from both infection modalities, which reveals profound tissue niche-dependent differences in nucleic acid, amino acid, and lipid metabolism with links to immune modulation. These signatures are both spatially and temporally distinct, differing not only between infection sites but evolving over time within a single model. Collectively, this demonstrates that biofilms elicit unique immune and metabolic responses that are heavily influenced by the local tissue microenvironment, which will likely have important implications when designing therapeutic approaches targeting these infections.

DOI: https://doi.org/10.1038/s41467-024-53353-8
Sci Rep. 2024 10 16. 14(1): 24230

Dynamic reciprocal interactions between activated T cells and tumor associated macrophages drive macrophage reprogramming and proinflammatory T cell migration within prostate tumor models.

Erika Heninger, Matthew Thomas Breneman, Emma Elizabeth Recchia, Sheena Catherine Kerr, Reyna Elvan Dogru, Marina Nasrin Sharifi, Aaron Matthew LeBeau, David Kosoff.

  Tumor-associated macrophages (TAMs) have been implicated as a tumor microenvironment (TME) cell population, which may be playing a vital role in the inhibition of effective T cell responses in the prostate TME. In this manuscript, we leverage a novel microscale cell culture platform, known as Stacks, to investigate mono-, co-, and tri-culture TME models comprised of prostate tumor cell lines, primary macrophages, and autologous T cells from patients with prostate cancer. Through multiplexed analysis of these multi-cellular prostate tumor models, we capture a dynamic interaction between primary TAMs and activated T cells that resulted in reciprocal proinflammatory activation of both cell populations upon interaction. These findings suggest that activated T cells are capable of reprogramming immunosuppressive TAMs in the context of prostate tumor models and that TAM reprogramming may play a key supportive role in restoring proinflammatory T cell tumor responses in the prostate TME.

Keywords:  Co-culture; Macrophage; T cells; TAM; Tumor microenvironment

DOI:  https://doi.org/10.1038/s41598-024-75265-9
J Lipid Res. 2024 Oct 11. pii: S0022-2275(24)00177-9. [Epub ahead of print] 100672

Palmitoleate protects against Lipopolysaccharide-induced Inflammation and Inflammasome Activity.

Prakash Kumar Sahoo, Aiswariya Ravi, Baolong Liu, Jiujiu Yu, Sathish Kumar Natarajan.

  Inflammation is part of natural immune defense mechanism against any form of infection or injury. However, prolonged inflammation could perturb cell homeostasis and contribute to the development of metabolic and inflammatory diseases including maternal obesity, diabetes, cardiovascular diseases, and metabolic dysfunction-associated steatotic liver diseases. Polyunsaturated fatty acids have been shown to mitigate inflammatory response by generating specialized pro-resolving lipid mediators which take part in resolution of inflammation. Here, we show that palmitoleate, an omega-7 monounsaturated fatty acid exerts anti-inflammatory properties in response to lipopolysaccharide (LPS)-mediated inflammation. Exposure of bone-marrow derived macrophages (BMDMs) to LPS or TNFα induces robust increase in the expression of pro-inflammatory cytokines and supplementation of palmitoleate inhibited LPS-mediated upregulation of pro-inflammatory cytokines. We also observed that palmitoleate was able to block LPS+ATP-induced inflammasome activation mediated cleavage of pro-caspase 1 and pro-interleukin (IL)-1β. Further, treatment of palmitoleate protects against LPS-induced inflammation in human THP-1 derived macrophages and trophoblasts. Co-exposure of LPS and palmitate (saturated free fatty acid) induces inflammasome and cell death in BMDMs, however, treatment of palmitoleate blocked LPS and palmitate-induced cell death in BMDMs. Further, LPS and palmitate together results in the activation of mitogen activated protein kinases (MAPK) and pretreatment of palmitoleate inhibited the activation of MAPKs and nuclear translocation of nuclear factor kappa B (NF-kB) in BMDMs. In conclusion, palmitoleate shows anti-inflammatory properties against LPS-induced inflammation and LPS+palmitate/ATP-induced inflammasome activity and cell death.

Keywords:  Mono-unsaturated fatty acids; macrophages; mitogen-activated protein kinase; obesity; placenta; pregnancy; trophoblasts

DOI:  https://doi.org/10.1016/j.jlr.2024.100672
bioRxiv. 2024 Oct 11. pii: 2024.10.10.617691. [Epub ahead of print]

Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1.

Tyron Chang, Jessica Alvarez, Sruthi Chappidi, Stacey Crockett, Mahsa Sorouri, Robert C Orchard, Dustin C Hancks.

Interferon (IFN) induced activities are critical, early determinants of immune responses and infection outcomes. A key facet of IFN responses is the upregulation of hundreds of mRNAs termed interferon-stimulated genes (ISGs) that activate intrinsic and cell-mediated defenses. While primary interferon signaling is well-delineated, other layers of regulation are less explored but implied by aberrant ISG expression signatures in many diseases in the absence of infection. Consistently, our examination of tonic ISG levels across uninfected human tissues and individuals revealed three ISG subclasses. As tissue identity and many comorbidities with increased virus susceptibility are characterized by differences in metabolism, we characterized ISG responses in cells grown in media known to favor either aerobic glycolysis (glucose) or oxidative phosphorylation (galactose supplementation). While these conditions over time had a varying impact on the expression of ISG RNAs, the differences were typically greater between treatments than between glucose/galactose. Interestingly, extended interferon-priming led to divergent expression of two ISG proteins: upregulation of IRF1 in IFN-γ/glucose and increased IFITM3 in galactose by IFN-α and IFN-γ. In agreement with a hardwired response, glucose/galactose regulation of interferon-γ induced IRF1 is conserved in unrelated mouse and cat cell types. In galactose conditions, proteasome inhibition restored interferon-γ induced IRF1 levels to that of glucose/interferon-γ. Glucose/interferon-γ decreased replication of the model poxvirus vaccinia at low MOI and high MOIs. Vaccinia replication was restored by IRF1 KO. In contrast, but consistent with differential regulation of IRF1 protein by glucose/galactose, WT and IRF1 KO cells in galactose media supported similar levels of vaccinia replication regardless of IFN-γ priming. Also associated with glucose/galactose is a seemingly second block at a very late stage in viral replication which results in reductions in herpes- and poxvirus titers but not viral protein expression. Collectively, these data illustrate a novel layer of regulation for the key ISG protein, IRF1, mediated by glucose/galactose and imply unappreciated subprograms embedded in the interferon response. In principle, such cellular circuitry could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.

DOI: https://doi.org/10.1101/2024.10.10.617691
Dis Model Mech. 2024 Oct 01. pii: dmm050895. [Epub ahead of print]17(10):

Immunometabolism and mitochondria in inflammatory bowel disease: a role for therapeutic intervention?

Claire E Adams, Duncan G Rutherford, Gareth R Jones, Gwo-Tzer Ho.

Inflammatory bowel diseases (IBDs), incurable conditions characterised by recurrent episodes of immune-mediated gut inflammation and damage of unknown aetiology, are common. Current advanced therapies target key leukocyte-trafficking and cytokine-signalling hubs but are only effective in 50% of patients. With growing evidence of mitochondrial dysfunction in IBD and advances in our understanding of the role of metabolism in inflammation, we provide an overview of novel metabolic approaches to IBD therapy, challenging the current 'therapeutic ceiling', identifying critical pathways for intervention and re-imagining metabolic biomarkers for the 21st century.

DOI: https://doi.org/10.1242/dmm.050895