bims-imicid 2023-09-17 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–09–17
twenty-six papers selected by
Dylan Ryan, University of Cambridge

Metabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection.
Itaconate-producing neutrophils regulate local and systemic inflammation following trauma.
Nutrition impact on ILC3 maintenance and function centers on a cell-intrinsic CD71-iron axis.
Control of nutrient uptake by IRF4 orchestrates innate immune memory.
Editorial: Understanding the effects of metabolites and trace minerals on microbes during infection.
Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers.
Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model.
Novel XBP1s-independent function of IRE1 RNase in HIF-1α-mediated glycolysis upregulation in human macrophages upon stimulation with LPS or saturated fatty acid.
Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming.
Retinoid X receptor gamma dictates the activation threshold of group 2 innate lymphoid cells and limits type 2 inflammation in the small intestine.
Metabolism configures immune response across multi-systems: Lessons from COVID-19.
Itaconic acid and dimethyl itaconate exert antibacterial activity in carbon-enriched environments through the TCA cycle.
Cardiac macrophages and emerging roles for their metabolism after myocardial infarction.
LPS induces SGPP2 to participate metabolic reprogramming in endothelial cells.
Therapeutic targeting of adipose tissue macrophages ameliorates liver fibrosis in non-alcoholic fatty liver disease.
Metabolomics reveals that PS-NPs promote lung injury by regulating prostaglandin B1 through the cGAS-STING pathway.
Intermittent fasting promotes ILC3s secreting IL-22 contributing to the beigeing of white adipose tissue.
Vitamin D3 mitigates autoimmune inflammation caused by activation of myeloid dendritic cells in SLE.
Serum vitamin D deficiency is associated with increased risk of γδ T cell exhaustion in HBV-infected patients.
Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.
Multifaceted control of T cell differentiation by STIM1.
Identification of metabolism-related subtypes and feature genes in Alzheimer's disease.
pH sensing at the intersection of tissue homeostasis and inflammation.
Natural polysaccharides protect against diet-induced obesity by improving lipid metabolism and regulating the immune system.
Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation.
TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes.

Nat Commun. 2023 Sep 12. 14(1): 5627

Metabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection.

Graham A Heieis, Thiago A Patente, Luís Almeida, Frank Vrieling, Tamar Tak, Georgia Perona-Wright, Rick M Maizels, Rinke Stienstra, Bart Everts.

Tissue-resident macrophage populations constitute a mosaic of phenotypes, yet how their metabolic states link to the range of phenotypes and functions in vivo is still poorly defined. Here, using high-dimensional spectral flow cytometry, we observe distinct metabolic profiles between different organs and functionally link acetyl CoA carboxylase activity to efferocytotic capacity. Additionally, differences in metabolism are evident within populations from a specific site, corresponding to relative stages of macrophage maturity. Immune perturbation with intestinal helminth infection increases alternative activation and metabolic rewiring of monocyte-derived macrophage populations, while resident TIM4+ intestinal macrophages remain immunologically and metabolically hyporesponsive. Similar metabolic signatures in alternatively-activated macrophages are seen from different tissues using additional helminth models, but to different magnitudes, indicating further tissue-specific contributions to metabolic states. Thus, our high-dimensional, flow-based metabolic analyses indicates complex metabolic heterogeneity and dynamics of tissue-resident macrophage populations at homeostasis and during helminth infection.

DOI: https://doi.org/10.1038/s41467-023-41353-z
JCI Insight. 2023 Sep 14. pii: e169208. [Epub ahead of print]

Itaconate-producing neutrophils regulate local and systemic inflammation following trauma.

Janna L Crossley, Sonya Ostashevskaya-Gohstand, Stefano Comazzetto, Jessica S Hook, Lei Guo, Neda Vishlaghi, Conan Juan, Lin Xu, Alexander R Horswill, Gerta Hoxhaj, Jessica G Moreland, Robert J Tower, Benjamin Levi.

  Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries which undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate with the injury site. Subsequent single-cell RNA sequencing, molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury, potentially regulating immune cell production in the bone marrow, through delivery of endogenously produced itaconate and demonstrate a therapeutic potential for exogenous itaconate following tendon injury.

Keywords:  Immunology; Inflammation; Neutrophils

DOI:  https://doi.org/10.1172/jci.insight.169208
Nat Immunol. 2023 Sep 14.

Nutrition impact on ILC3 maintenance and function centers on a cell-intrinsic CD71-iron axis.

Lifeng Xiong, Eric Y Helm, Joseph W Dean, Na Sun, Felix R Jimenez-Rondan, Liang Zhou.

Iron metabolism is pivotal for cell fitness in the mammalian host; however, its role in group 3 innate lymphoid cells (ILC3s) is unknown. Here we show that transferrin receptor CD71 (encoded by Tfrc)-mediated iron metabolism cell-intrinsically controls ILC3 proliferation and host protection against Citrobacter rodentium infection and metabolically affects mitochondrial respiration by switching of oxidative phosphorylation toward glycolysis. Iron deprivation or Tfrc ablation in ILC3s reduces the expression and/or activity of the aryl hydrocarbon receptor (Ahr), a key ILC3 regulator. Genetic ablation or activation of Ahr in ILC3s leads to CD71 upregulation or downregulation, respectively, suggesting Ahr-mediated suppression of CD71. Mechanistically, Ahr directly binds to the Tfrc promoter to inhibit transcription. Iron overload partially restores the defective ILC3 compartment in the small intestine of Ahr-deficient mice, consistent with the compensatory upregulation of CD71. These data collectively demonstrate an under-appreciated role of the Ahr-CD71-iron axis in the regulation of ILC3 maintenance and function.

DOI: https://doi.org/10.1038/s41590-023-01612-z
Nat Immunol. 2023 Sep 11.

Control of nutrient uptake by IRF4 orchestrates innate immune memory.

Endi K Santosa, Hyunu Kim, Timo Rückert, Jean-Benoît Le Luduec, Aamna J Abbasi, Claire K Wingert, Lila Peters, Joe N Frost, Katharine C Hsu, Chiara Romagnani, Joseph C Sun.

Natural killer (NK) cells are innate cytotoxic lymphocytes with adaptive immune features, including antigen specificity, clonal expansion and memory. As such, NK cells share many transcriptional and epigenetic programs with their adaptive CD8+ T cell siblings. Various signals ranging from antigen, co-stimulation and proinflammatory cytokines are required for optimal NK cell responses in mice and humans during virus infection; however, the integration of these signals remains unclear. In this study, we identified that the transcription factor IRF4 integrates signals to coordinate the NK cell response during mouse cytomegalovirus infection. Loss of IRF4 was detrimental to the expansion and differentiation of virus-specific NK cells. This defect was partially attributed to the inability of IRF4-deficient NK cells to uptake nutrients required for survival and memory generation. Altogether, these data suggest that IRF4 is a signal integrator that acts as a secondary metabolic checkpoint to orchestrate the adaptive response of NK cells during viral infection.

DOI: https://doi.org/10.1038/s41590-023-01620-z
Front Cell Infect Microbiol. 2023 ;13 1276271

Editorial: Understanding the effects of metabolites and trace minerals on microbes during infection.

Thomas Naderer, Andre Mu, Andrew J Monteith, Tania Wong Fok Lung.



Keywords:  adenosine; bacterial metabolism; host-pathogen interaction; immunometabolism; itaconate; metabolic cross talk; microbial metabolic activity; microbiota-derived metabolites

DOI:  https://doi.org/10.3389/fcimb.2023.1276271
Mol Ther Nucleic Acids. 2023 Sep 12. 33 941-959

Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers.

Stephen Fitzsimons, María Muñoz-San Martín, Frances Nally, Eugene Dillon, Ifeolutembi A Fashina, Moritz J Strowitzki, Lluís Ramió-Torrentà, Jennifer K Dowling, Chiara De Santi, Claire E McCoy.

  The modulation of macrophage phenotype from a pro-inflammatory to an anti-inflammatory state holds therapeutic potential in the treatment of inflammatory disease. We have previously shown that arginase-2 (Arg2), a mitochondrial enzyme, is a key regulator of the macrophage anti-inflammatory response. Here, we investigate the therapeutic potential of Arg2 enhancement via target site blockers (TSBs) in human macrophages. TSBs are locked nucleic acid antisense oligonucleotides that were specifically designed to protect specific microRNA recognition elements (MREs) in human ARG2 3' UTR mRNA. TSBs targeting miR-155 (TSB-155) and miR-3202 (TSB-3202) MREs increased ARG2 expression in human monocyte-derived macrophages. This resulted in decreased gene expression and cytokine production of TNF-α and CCL2 and, for TSB-3202, in an increase in the anti-inflammatory macrophage marker, CD206. Proteomic analysis demonstrated that a network of pro-inflammatory responsive proteins was modulated by TSBs. In silico bioinformatic analysis predicted that TSB-3202 suppressed upstream pro-inflammatory regulators including STAT-1 while enhancing anti-inflammatory associated proteins. Proteomic data were validated by confirming increased levels of sequestosome-1 and decreased levels of phosphorylated STAT-1 and STAT-1 upon TSB treatment. In conclusion, upregulation of Arg2 by TSBs inhibits pro-inflammatory signaling and is a promising novel therapeutic strategy to modulate inflammatory signaling in human macrophages.

Keywords:  MT: Oligonucleotides: Therapies and Applications; arginase-2; inflammation; macrophages; miR-155; microRNA; multiple sclerosis; target site blockers

DOI:  https://doi.org/10.1016/j.omtn.2023.08.023
iScience. 2023 Oct 20. 26(10): 107713

Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model.

Riccardo Turchi, Francesca Sciarretta, Veronica Ceci, Marta Tiberi, Matteo Audano, Silvia Pedretti, Concetta Panebianco, Valentina Nesci, Valerio Pazienza, Alberto Ferri, Simone Carotti, Valerio Chiurchiù, Nico Mitro, Daniele Lettieri-Barbato, Katia Aquilano.

  Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNA-seq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes-like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.

Keywords:  Biological sciences; Natural sciences; Neuroscience; Pharmacology

DOI:  https://doi.org/10.1016/j.isci.2023.107713
Front Immunol. 2023 ;14 1204126

Novel XBP1s-independent function of IRE1 RNase in HIF-1α-mediated glycolysis upregulation in human macrophages upon stimulation with LPS or saturated fatty acid.

Margaud Iovino, Megan Colonval, Chloé Wilkin, Laurent L'homme, Cédric Lassence, Manon Campas, Olivier Peulen, Pascal de Tullio, Jacques Piette, Sylvie Legrand-Poels.

  In obesity, adipose tissue infiltrating macrophages acquire a unique pro-inflammatory polarization, thereby playing a key role in the development of chronic inflammation and Type 2 diabetes. Increased saturated fatty acids (SFAs) levels have been proposed to drive this specific polarization. Accordingly, we investigated the immunometabolic reprogramming in SFA-treated human macrophages. As expected, RNA sequencing highlighted a pro-inflammatory profile but also metabolic signatures including glycolysis and hypoxia as well as a strong unfolded protein response. Glycolysis upregulation was confirmed in SFA-treated macrophages by measuring glycolytic gene expression, glucose uptake, lactate production and extracellular acidification rate. Like in LPS-stimulated macrophages, glycolysis activation in SFA-treated macrophages was dependent on HIF-1α activation and fueled the production of pro-inflammatory cytokines. SFAs and LPS both induced IRE1α endoribonuclease activity, as demonstrated by XBP1 mRNA splicing, but with different kinetics matching HIF-1α activation and the glycolytic gene expression. Interestingly, the knockdown of IRE1α and/or the pharmacological inhibition of its RNase activity prevented HIF-1α activation and significantly decreased glycolysis upregulation. Surprisingly, XBP1s appeared to be dispensable, as demonstrated by the lack of inhibiting effect of XBP1s knockdown on glycolytic genes expression, glucose uptake, lactate production and HIF-1α activation. These experiments demonstrate for the first time a key role of IRE1α in HIF-1α-mediated glycolysis upregulation in macrophages stimulated with pro-inflammatory triggers like LPS or SFAs through XBP1s-independent mechanism. IRE1 could mediate this novel function by targeting other transcripts (mRNA or pre-miRNA) through a mechanism called regulated IRE1-dependent decay or RIDD. Deciphering the underlying mechanisms of this novel IRE1 function might lead to novel therapeutic targets to curtail sterile obesity- or infection-linked inflammation.

Keywords:  HIF-1α; IRE1α; glycolysis; inflammation; macrophages; saturated fatty acid

DOI:  https://doi.org/10.3389/fimmu.2023.1204126
Cell Mol Life Sci. 2023 Sep 09. 80(10): 283

Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming.

Xianmei Liu, Peng Yu, Yujun Xu, Yun Wang, Jin Chen, Fuzhou Tang, Zuquan Hu, Jing Zhou, Lina Liu, Wei Qiu, Yuannong Ye, Yi Jia, Weijuan Yao, Jinhua Long, Zhu Zeng.

  Dendritic cells (DCs) can mediate immune responses or immune tolerance depending on their immunophenotype and functional status. Remodeling of DCs' immune functions can develop proper therapeutic regimens for different immune-mediated diseases. In the immunopathology of autoimmune diseases (ADs), activated DCs notably promote effector T-cell polarization and exacerbate the disease. Recent evidence indicates that metformin can attenuate the clinical symptoms of ADs due to its anti-inflammatory properties. Whether and how the therapeutic effects of metformin on ADs are associated with DCs remain unknown. In this study, metformin was added to a culture system of LPS-induced DC maturation. The results revealed that metformin shifted DC into a tolerant phenotype, resulting in reduced surface expression of MHC-II, costimulatory molecules and CCR7, decreased levels of proinflammatory cytokines (TNF-α and IFN-γ), increased level of IL-10, upregulated immunomodulatory molecules (ICOSL and PD-L) and an enhanced capacity to promote regulatory T-cell (Treg) differentiation. Further results demonstrated that the anti-inflammatory effects of metformin in vivo were closely related to remodeling the immunophenotype of DCs. Mechanistically, metformin could mediate the metabolic reprogramming of DCs through FoxO3a signaling pathways, including disturbing the balance of fatty acid synthesis (FAS) and fatty acid oxidation (FAO), increasing glycolysis but inhibiting the tricarboxylic acid cycle (TAC) and pentose phosphate pathway (PPP), which resulted in the accumulation of fatty acids (FAs) and lactic acid, as well as low anabolism in DCs. Our findings indicated that metformin could induce tolerance in DCs by reprogramming their metabolic patterns and play anti-inflammatory roles in vitro and in vivo.

Keywords:  Autoimmune diseases; Dendritic cells; Immune metabolism; Immune tolerance; Metformin; Tolerant dendritic cells

DOI:  https://doi.org/10.1007/s00018-023-04932-3
Immunity. 2023 Sep 06. pii: S1074-7613(23)00375-8. [Epub ahead of print]

Retinoid X receptor gamma dictates the activation threshold of group 2 innate lymphoid cells and limits type 2 inflammation in the small intestine.

Yang Zang, Shaorui Liu, Zebing Rao, Yinsheng Wang, Boya Zhang, Hui Li, Yingjiao Cao, Jie Zhou, Zhuxia Shen, Shengzhong Duan, Danyang He, Heping Xu.

  Group 2 innate lymphoid cells (ILC2s) are crucial in promoting type 2 inflammation that contributes to both anti-parasite immunity and allergic diseases. However, the molecular checkpoints in ILC2s that determine whether to immediately launch a proinflammatory response are unknown. Here, we found that retinoid X receptor gamma (Rxrg) was highly expressed in small intestinal ILC2s and rapidly suppressed by alarmin cytokines. Genetic deletion of Rxrg did not impact ILC2 development but facilitated ILC2 responses and the tissue inflammation induced by alarmins. Mechanistically, RXRγ maintained the expression of its target genes that support intracellular cholesterol efflux, which in turn reduce ILC2 proliferation. Furthermore, RXRγ expression prevented ILC2 response to mild stimulations, including low doses of alarmin cytokine and mechanical skin injury. Together, we propose that RXRγ expression and its mediated lipid metabolic states function as a cell-intrinsic checkpoint that confers the threshold of ILC2 activation in the small intestine.

Keywords:  CUT&Tag; RNA-seq; activation threshold; allergy; group 2 innate lymphoid cells; lipid homeostasis; retinoid X receptor gamma; small intestine; type 2 inflammation

DOI:  https://doi.org/10.1016/j.immuni.2023.08.019
Adv Biol Regul. 2023 Aug 26. pii: S2212-4926(23)00023-4. [Epub ahead of print]90 100977

Metabolism configures immune response across multi-systems: Lessons from COVID-19.

Tinku Gupta, Najumuddin, Dhanya Rajendran, Akash Gujaral, Ashok Jangra.

  Several studies over the last decade demonstrate the recruitment of immune cells, increased inflammatory cytokines, and chemokine in patients with metabolic diseases, including heart failure, parenchymal inflammation, obesity, tuberculosis, and diabetes mellitus. Metabolic rewiring of immune cells is associated with the severity and prevalence of these diseases. The risk of developing COVID-19/SARS-CoV-2 infection increases in patients with metabolic dysfunction (heart failure, diabetes mellitus, and obesity). Several etiologies, including fatigue, dyspnea, and dizziness, persist even months after COVID-19 infection, commonly known as Post-Acute Sequelae of CoV-2 (PASC) or long COVID. A chronic inflammatory state and metabolic dysfunction are the factors that contribute to long COVID. Here, this study explores the potential link between pathogenic metabolic and immune alterations across different organ systems that could underlie COVID-19 and PASC. These interactions could be utilized for targeted future therapeutic approaches.

Keywords:  Immunity; Immunometabolism; Inflammation; Long COVID; Metabolic dysfunction; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.jbior.2023.100977
Biomed Pharmacother. 2023 Sep 13. pii: S0753-3322(23)01285-4. [Epub ahead of print]167 115487

Itaconic acid and dimethyl itaconate exert antibacterial activity in carbon-enriched environments through the TCA cycle.

L Y Xie, Y B Xu, X Q Ding, S Liang, D L Li, A K Fu, X A Zhan.

  Itaconic acid (IA), a metabolite generated by the tricarboxylic acid (TCA) cycle in eukaryotic immune cells, and its derivative dimethyl itaconate (DI) exert antibacterial functions in intracellular environments. Previous studies suggested that IA and DI only inhibit bacterial growth in carbon-limited environments; however, whether IA and DI maintain antibacterial activity in carbon-enriched environments remains unknown. Here, IA and DI inhibited the bacteria with minimum inhibitory concentrations of 24.02 mM and 39.52 mM, respectively, in a carbon-enriched environment. The reduced bacterial pathogenicity was reflected in cell membrane integrity, motility, biofilm formation, AI-2/luxS, and virulence. Mechanistically, succinate dehydrogenase (SDH) activity and fumaric acid levels decreased in the IA and DI treatments, while isocitrate lyase (ICL) activity was upregulated. Inhibited TCA circulation was also observed through untargeted metabolomics. In addition, energy-related aspartate metabolism and lysine degradation were suppressed. In summary, these results indicated that IA and DI reduced bacterial pathogenicity while exerting antibacterial functions by inhibiting TCA circulation. This study enriches knowledge on the inhibition of bacteria by IA and DI in a carbon-mixed environment, suggesting an alternative method for treating bacterial infections by immune metabolites.

Keywords:  Antibacterial activity; Bacterial pathogenicity; Dimethyl itaconate; Itaconic acid; TCA cycle

DOI:  https://doi.org/10.1016/j.biopha.2023.115487
J Clin Invest. 2023 Sep 15. pii: e171953. [Epub ahead of print]133(18):

Cardiac macrophages and emerging roles for their metabolism after myocardial infarction.

Edward B Thorp.

Interest in cardioimmunology has reached new heights as the experimental cardiology field works to tap the unrealized potential of immunotherapy for clinical care. Within this space is the cardiac macrophage, a key modulator of cardiac function in health and disease. After a myocardial infarction, myeloid macrophages both protect and harm the heart. To varying degrees, such outcomes are a function of myeloid ontogeny and heterogeneity, as well as functional cellular plasticity. Diversity is further shaped by the extracellular milieu, which fluctuates considerably after coronary occlusion. Ischemic limitation of nutrients constrains the metabolic potential of immune cells, and accumulating evidence supports a paradigm whereby macrophage metabolism is coupled to divergent inflammatory consequences, although experimental evidence for this in the heart is just emerging. Herein we examine the heterogeneous cardiac macrophage response following ischemic injury, with a focus on integrating putative contributions of immunometabolism and implications for therapeutically relevant cardiac injury versus cardiac repair.

DOI: https://doi.org/10.1172/JCI171953
Free Radic Biol Med. 2023 Sep 11. pii: S0891-5849(23)00625-1. [Epub ahead of print]

LPS induces SGPP2 to participate metabolic reprogramming in endothelial cells.

Xin Yi, Meng-Ling Chang, Zeng-Ding Zhou, Lei Yi, Hao Yuan, Jin Qi, Lei Yi, Jing-Ning Huan, Xiao-Qin Huang.

  Sepsis often causes organ dysfunction and is manifested in increased endothelial cell permeability in blood vessels. Early-stage inflammation is accompanied by metabolic changes, but it is unclear how the metabolic alterations in the endothelial cells following lipopolysaccharide (LPS) stimulation affect endothelial cell function. In this study, the effects of 1 μg/ml of LPS on the metabolism of human umbilical vein endothelial cells (HUVECs) were investigated, and the metabolic changes after LPS stimulation were explained from the perspective of mRNA expression, chromatin openness and metabolic flux. We found changes in the central metabolism of endothelial cells after LPS stimulation, such as enhanced glycolysis function, decreased mitochondrial membrane potential, and increased production of reactive oxygen species (ROS). Sphingolipid metabolic pathways change at the transcriptome level, and sphingosine-1-phosphatase 2 (SGPP2) was upregulated in LPS-stimulated endothelial cells and zebrafish models. Overexpression of SGPP2 improved cell barrier function, enhanced mitochondrial respiration capacity, but also produced oxidative respiration chain uncoupling. In addition, SGPP2 overexpression inhibited the degradation of HIF-1α protein. The molecular and biochemical processes identified in this study are not only beneficial for understanding the metabolic-related mechanisms of LPS-induced endothelial injury, but also for the discovery of general therapeutic targets for inflammation and inflammation-related diseases.

Keywords:  HUVEC; LPS; Metabolic reprogramming; ROS; Warburg effect

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.007
JHEP Rep. 2023 Oct;5(10): 100830

Therapeutic targeting of adipose tissue macrophages ameliorates liver fibrosis in non-alcoholic fatty liver disease.

Celia Martínez-Sánchez, Octavi Bassegoda, Hongping Deng, Xènia Almodóvar, Ainitze Ibarzabal, Ana de Hollanda, Raquel-Adela Martínez García de la Torre, Delia Blaya, Silvia Ariño, Natalia Jiménez-Esquivel, Beatriz Aguilar-Bravo, Julia Vallverdú, Carla Montironi, Oscar Osorio-Conles, Yiliam Fundora, Francisco Javier Sánchez Moreno, Alicia G Gómez-Valadés, Laia Aguilar-Corominas, Anna Soria, Elisa Pose, Adrià Juanola, Marta Cervera, Martina Perez, Virginia Hernández-Gea, Silvia Affò, Kelly S Swanson, Joana Ferrer-Fàbrega, Jose Maria Balibrea, Pau Sancho-Bru, Josep Vidal, Pere Ginès, Andrew M Smith, Isabel Graupera, Mar Coll.

   Background & Aims: : The accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the contribution of ATMs to hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in patients with patients with NAFLD and evaluate the impact of modulation of ATMs over hepatic fibrosis in an experimental non-alcoholic steatohepatitis (NASH) model.
Methods: Adipose tissue and liver biopsies from 42 patients with NAFLD with different fibrosis stages were collected. ATMs were characterised by immunohistochemistry and flow cytometry and the correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of the ATM phenotype was achieved by i.p. administration of dextran coupled with dexamethasone in diet-induced obesity and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. In vitro crosstalk between human ATMs and hepatic stellate cells (HSCs) and liver spheroids was performed.
Results: Patients with NAFLD presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long-term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. In vitro, the reduction of the pro-inflammatory phenotype of human ATMs with dextran-dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSCs and liver spheroids.
Conclusions: Pro-inflammatory ATMs increase in parallel with fibrosis degree in patients with NAFLD and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD.
Impact and implications: We report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Furthermore, the modulation of adipose tissue macrophages (ATMs) by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATMs to an anti-inflammatory phenotype in an experimental murine model of non-alcoholic steatohepatitis. This shift ameliorates adipose tissue inflammation, hepatic inflammation, and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD.

Keywords:  Adipose tissue inflammation; Dextran dexamethasone conjugates; Drug delivery; Liver injury; Nanomedicine; Nanoparticle; Non-alcoholic steatohepatitis; Targeted therapy

DOI:  https://doi.org/10.1016/j.jhepr.2023.100830
Chemosphere. 2023 Sep 13. pii: S0045-6535(23)02378-0. [Epub ahead of print] 140108

Metabolomics reveals that PS-NPs promote lung injury by regulating prostaglandin B1 through the cGAS-STING pathway.

Lihui Xuan, Yin Wang, Can Qu, Yuhui Yan, Wensen Yi, Jingjing Yang, Magdalena Skonieczna, Cuimei Chen, Justyna Miszczyk, Dmitry S Ivanov, Hesham M H Zakaly, Vladimir Markovic, Ruixue Huang.

  Nanoplastics have been widely studied as environmental pollutants, which can accumulate in the human body through the food chain or direct contact. Research has shown that nanoplastics can affect the immune system and mitochondrial function, but the underlying mechanisms are unclear. Lungs and macrophages have important immune and metabolic functions. This study explored the effects of 100 nm PS-NPs on innate immunity, mitochondrial function, and cellular metabolism-related pathways in lung (BEAS-2B) cells and macrophages (RAW264.7). The results had shown that PS-NPs exposure caused a decrease in mitochondrial membrane potential, intracellular ROS accumulation, and Ca2+ overload, and activated the cGAS-STING signaling pathway related to innate immunity. These changes had been observed at concentrations of PS-NPs as low as 60 μg/mL, which might have been comparable to environmental levels. Non-target metabolomics and Western Blotting results confirmed that PS-NPs regulated prostaglandin B1 and other metabolites to cause cell damage through the cGAS-STING pathway. Supplementation of prostaglandin B1 alleviated the immune activation and metabolic disturbance caused by PS-NPs exposure. This study identified PS-NPs-induced innate immune activation, mitochondrial dysfunction, and metabolic toxicity pathways, providing new insights into the potential for adverse outcomes of NPs in human life.

Keywords:  Cytotoxicity; Innate immunity; Metabolic toxicity; Mitochondrial damage; Nanoplastics

DOI:  https://doi.org/10.1016/j.chemosphere.2023.140108
bioRxiv. 2023 Aug 30. pii: 2023.08.29.555436. [Epub ahead of print]

Intermittent fasting promotes ILC3s secreting IL-22 contributing to the beigeing of white adipose tissue.

Hong Chen, Lijun Sun, Lu Feng, Xue Han, Yunhua Zhang, Wenbo Zhai, Zehe Zhang, Michael Mulholland, Weizhen Zhang, Yue Yin.

Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted IL-22 production by ILC3s and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell‒cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells (DCs) and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.

DOI: https://doi.org/10.1101/2023.08.29.555436
Exp Dermatol. 2023 Sep 13.

Vitamin D3 mitigates autoimmune inflammation caused by activation of myeloid dendritic cells in SLE.

Mingfang Li, Li Luo, Chuanchuan Lin, Bing Ni, Liyun Zou, Zhiqiang Song, Fei Hao, Yi Wu, Na Luo.

  Systemic lupus erythematosus (SLE) is an autoimmune disease in which defective T cells, immune complex deposition and other immune system alterations contribute to pathological changes of multiple organ systems. The vitamin D metabolite c is a critical immunomodulator playing pivotal roles in the immune system. Epidemiological evidence indicates that vitamin D deficiency is correlated with the severity of SLE. Our aim is to investigate the effects of 1,25(OH)2D3 (VitD3) on the activation of myeloid dendritic cells (mDCs) by autologous DNA-containing immune complex (DNA-ICs), and the effects of VitD3 on immune system balance during SLE. We purified DNA-ICs from the serum of SLE patients and isolated mDCs from normal subjects. In vitro studies showed that DNA-ICs were internalized and consumed by mDCs. VitD3 blocked the effects of DNA-ICs on RelB, IL-10 and TNF-α in mDCs. Further analysis indicated that DNA-ICs stimulated histone acetylation in the RelB promoter region, which was inhibited by VitD3. Knockdown of the histone deacetylase 3 gene (HDAC3) blocked these VitD3-mediated effects. Co-culture of mDCs and CD4+ T cells showed that VitD3 inhibited multiple processes mediated by DNA-ICs, including proliferation, downregulation of IL-10, TGF-β and upregulation of TNF-α. Moreover, VitD3 could also reverse the effects of DNA-IC-induced imbalance of CD4+ CD127- Foxp3+ T cells and CD4+ IL17+ T cells. Taken together, our results indicated that autologous DNA-ICs stimulate the activation of mDCs in the pathogenesis of SLE, and VitD3 inhibits this stimulatory effects of DNA-ICs by negative transcriptional regulation of RelB gene and maintaining the Treg/Th17 immune cell balance. These results suggest that vitamin D may have therapeutic value for the treatment of SLE.

Keywords:  1,25(OH)2D3; DNA-containing immune complexes; Treg/Th17 immune balance; autoimmune inflammation; myeloid dendritic cells; systemic lupus erythematosus

DOI:  https://doi.org/10.1111/exd.14926
Immunology. 2023 Sep 13.

Serum vitamin D deficiency is associated with increased risk of γδ T cell exhaustion in HBV-infected patients.

Ke Li, Eying Lu, Qian Wang, Ruirong Xu, Wenhui Yuan, Ruan Wu, Ligong Lu, Peng Li.

  Previous studies have demonstrated that T cell exhaustion is associated with poor clearance of Hepatitis B virus (HBV). However, whether the expression of exhaustion markers on innate-like circulating γδ T cells derived from patients with HBV infection correlates with the serum level of vitamin D is not completely understood. In this study, we found that the frequency of circulating Vδ2+ T cell and serum levels of vitamin 25(OH)D3 were significantly decreased in patients with HBV. And serum 25(OH)D3 levels in HBV-infected patients were negatively correlated with HBV DNA load and PD-1 expression on γδ T cells. Interestingly, 1α,25(OH)2 D3 alleviated the exhaustion phenotype of Vδ2 T cells in HBV-infected patients and promoted IFN-β expression in human cytotoxic Vδ2 T cells in vitro. Collectively, these findings demonstrate that vitamin D plays a pivotal role in reversing γδ T-cell exhaustion and is highly promising target for ameliorating HBV infection.

Keywords:  hepatitis B virus; immune exhaustion; vitamin D; γδ T cell

DOI:  https://doi.org/10.1111/imm.13696
Cell Rep. 2023 Sep 13. pii: S2211-1247(23)01143-9. [Epub ahead of print]42(9): 113131

Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.

Mueez U-Din, Vanessa D de Mello, Marjo Tuomainen, Juho Raiko, Tarja Niemi, Tobias Fromme, Anton Klåvus, Nadine Gautier, Kimmo Haimilahti, Marko Lehtonen, Karsten Kristiansen, John W Newman, Kirsi H Pietiläinen, Jussi Pihlajamäki, Ez-Zoubir Amri, Martin Klingenspor, Pirjo Nuutila, Eija Pirinen, Kati Hanhineva, Kirsi A Virtanen.

  Cold-induced brown adipose tissue (BAT) activation is considered to improve metabolic health. In murine BAT, cold increases the fundamental molecule for mitochondrial function, nicotinamide adenine dinucleotide (NAD+), but limited knowledge of NAD+ metabolism during cold in human BAT metabolism exists. We show that cold increases the serum metabolites of the NAD+ salvage pathway (nicotinamide and 1-methylnicotinamide) in humans. Additionally, individuals with cold-stimulated BAT activation have decreased levels of metabolites from the de novo NAD+ biosynthesis pathway (tryptophan, kynurenine). Serum nicotinamide correlates positively with cold-stimulated BAT activation, whereas tryptophan and kynurenine correlate negatively. Furthermore, the expression of genes involved in NAD+ biosynthesis in BAT is related to markers of metabolic health. Our data indicate that cold increases serum tryptophan conversion to nicotinamide to be further utilized by BAT. We conclude that NAD+ metabolism is activated upon cold in humans and is probably regulated in a coordinated fashion by several tissues.

Keywords:  BAT; CP: Metabolism; NAD(+); cold exposure; human brown adipose tissue; nicotinamide; tryptophan

DOI:  https://doi.org/10.1016/j.celrep.2023.113131
Trends Biochem Sci. 2023 Sep 09. pii: S0968-0004(23)00209-8. [Epub ahead of print]

Multifaceted control of T cell differentiation by STIM1.

Scott Gross, Lauren Womer, Dietmar J Kappes, Jonathan Soboloff.

  In T cells, stromal interaction molecule (STIM) and Orai are dispensable for conventional T cell development, but critical for activation and differentiation. This review focuses on novel STIM-dependent mechanisms for control of Ca2+ signals during T cell activation and its impact on mitochondrial function and transcriptional activation for control of T cell differentiation and function. We highlight areas that require further work including the roles of plasma membrane Ca2+ ATPase (PMCA) and partner of STIM1 (POST) in controlling Orai function. A major knowledge gap also exists regarding the independence of T cell development from STIM and Orai, despite compelling evidence that it requires Ca2+ signals. Resolving these and other outstanding questions ensures that the field will remain active for many years to come.

Keywords:  STIM1; T cells; calcium; differentiation; mitochondria

DOI:  https://doi.org/10.1016/j.tibs.2023.08.006
J Transl Med. 2023 Sep 15. 21(1): 628

Identification of metabolism-related subtypes and feature genes in Alzheimer's disease.

Piaopiao Lian, Xing Cai, Cailin Wang, Ke Liu, Xiaoman Yang, Yi Wu, Zhaoyuan Zhang, Zhuoran Ma, Xuebing Cao, Yan Xu.

   BACKGROUND: Owing to the heterogeneity of Alzheimer's disease (AD), its pathogenic mechanisms are yet to be fully elucidated. Evidence suggests an important role of metabolism in the pathophysiology of AD. Herein, we identified the metabolism-related AD subtypes and feature genes.
METHODS: The AD datasets were obtained from the Gene Expression Omnibus database and the metabolism-relevant genes were downloaded from a previously published compilation. Consensus clustering was performed to identify the AD subclasses. The clinical characteristics, correlations with metabolic signatures, and immune infiltration of the AD subclasses were evaluated. Feature genes were screened using weighted correlation network analysis (WGCNA) and processed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Furthermore, three machine-learning algorithms were used to narrow down the selection of the feature genes. Finally, we identified the diagnostic value and expression of the feature genes using the AD dataset and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis.
RESULTS: Three AD subclasses were identified, namely Metabolism Correlated (MC) A (MCA), MCB, and MCC subclasses. MCA contained signatures associated with high AD progression and may represent a high-risk subclass compared with the other two subclasses. MCA exhibited a high expression of genes related to glycolysis, fructose, and galactose metabolism, whereas genes associated with the citrate cycle and pyruvate metabolism were downregulated and associated with high immune infiltration. Conversely, MCB was associated with citrate cycle genes and exhibited elevated expression of immune checkpoint genes. Using WGCNA, 101 metabolic genes were identified to exhibit the strongest association with poor AD progression. Finally, the application of machine-learning algorithms enabled us to successfully identify eight feature genes, which were employed to develop a nomogram model that could bring distinct clinical benefits for patients with AD. As indicated by the AD datasets and qRT-PCR analysis, these genes were intimately associated with AD progression.
CONCLUSION: Metabolic dysfunction is associated with AD. Hypothetical molecular subclasses of AD based on metabolic genes may provide new insights for developing individualized therapy for AD. The feature genes highly correlated with AD progression included GFAP, CYB5R3, DARS, KIAA0513, EZR, KCNC1, COLEC12, and TST.

Keywords:  Alzheimer’s disease; Characteristic genes; Immune infiltration; Machine learning; Metabolic subclass

DOI:  https://doi.org/10.1186/s12967-023-04324-y
Trends Immunol. 2023 Sep 14. pii: S1471-4906(23)00162-X. [Epub ahead of print]

pH sensing at the intersection of tissue homeostasis and inflammation.

Stephanie Hajjar, Xu Zhou.

  pH is tightly maintained at cellular, tissue, and systemic levels, and altered pH - particularly in the acidic range - is associated with infection, injury, solid tumors, and physiological and pathological inflammation. However, how pH is sensed and regulated and how it influences immune responses remain poorly understood at the tissue level. Applying conceptual frameworks of homeostatic and inflammatory circuitries, we categorize cellular and tissue components engaged in pH regulation, drawing parallels from established cases in physiology. By expressing various intracellular (pHi) and extracellular pH (pHe)-sensing receptors, the immune system may integrate information on tissue and cellular states into the regulation of homeostatic and inflammatory programs. We introduce the novel concept of resistance and adaptation responses to rationalize pH-dependent immunomodulation intertwined with homeostatic equilibrium and inflammatory control. We discuss emerging challenges and opportunities in understanding the immunological roles of pH sensing, which might reveal new strategies to combat inflammation and restore tissue homeostasis.

Keywords:  acidic environment; adaptation; inflammatory response; pH homeostasis; pH sensing; resistance

DOI:  https://doi.org/10.1016/j.it.2023.08.008
Food Res Int. 2023 10;pii: S0963-9969(23)00737-8. [Epub ahead of print]172 113192

Natural polysaccharides protect against diet-induced obesity by improving lipid metabolism and regulating the immune system.

Chao Tang, Yuxin Wang, Dan Chen, Man Zhang, Jingguo Xu, Chen Xu, Jun Liu, Juan Kan, Changhai Jin.

  Unhealthy dietary patterns-induced obesity and obesity-related complications pose a great threat to human health all over the world. Accumulating evidence suggests that the pathophysiology of obesity and obesity-associated metabolic disorders is closely associated with dysregulation of lipid and energy metabolism, and metabolic inflammation. In this review, three potential anti-obesity mechanisms of natural polysaccharides are introduced. Firstly, natural polysaccharides protect against diet-induced obesity directly by improving lipid and cholesterol metabolism. Since the immunity also affects lipid and energy metabolism, natural polysaccharides improve lipid and energy metabolism by regulating host immunity. Moreover, diet-induced mitochondrial dysfunction, prolonged endoplasmic reticulum stress, defective autophagy and microbial dysbiosis can disrupt lipid and/or energy metabolism in a direct and/or inflammation-induced manner. Therefore, natural polysaccharides also improve lipid and energy metabolism and suppress inflammation by alleviating mitochondrial dysfunction and endoplasmic reticulum stress, promoting autophagy and regulating gut microbiota composition. Specifically, this review comprehensively summarizes underlying anti-obesity mechanisms of natural polysaccharides and provides a theoretical basis for the development of functional foods. For the first time, this review elucidates anti-obesity mechanisms of natural polysaccharides from the perspectives of their hypolipidemic, energy-regulating and immune-regulating mechanisms.

Keywords:  Energy metabolism; Immune-regulating activities; Lipid metabolism; Metabolic diseases; Natural polysaccharides

DOI:  https://doi.org/10.1016/j.foodres.2023.113192
PLoS Pathog. 2023 Sep 11. 19(9): e1011138

Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation.

Yongxing Wang, Vikram V Kulkarni, Jezreel Pantaleón García, Miguel M Leiva-Juárez, David L Goldblatt, Fahad Gulraiz, Lisandra Vila Ellis, Jichao Chen, Michael K Longmire, Sri Ramya Donepudi, Philip L Lorenzi, Hao Wang, Lee-Jun Wong, Michael J Tuvim, Scott E Evans.

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.

DOI: https://doi.org/10.1371/journal.ppat.1011138
Proc Natl Acad Sci U S A. 2023 Sep 19. 120(38): e2218150120

TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes.

Nabil E Boutagy, Joseph W Fowler, Kariona A Grabinska, Rebecca Cardone, Qiushi Sun, Kyla R Vazquez, Michael B Whalen, Xiaolong Zhu, Raja Chakraborty, Kathleen A Martin, Michael Simons, Casey E Romanoski, Richard G Kibbey, William C Sessa.

  The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure of endothelial cells (EC) to proinflammatory stimuli leads to an increase in mitochondrial metabolism; however, the function and regulation of elevated mitochondrial metabolism in EC in response to proinflammatory cytokines remain unclear. Studies using high-resolution metabolomics and 13C-glucose and 13C-glutamine labeling flux techniques showed that pyruvate dehydrogenase activity (PDH) and oxidative tricarboxylic acid cycle (TCA) flux are elevated in human umbilical vein ECs in response to overnight (16 h) treatment with TNFα (10 ng/mL). Mechanistic studies indicated that TNFα mediated these metabolic changes via mitochondrial-specific protein degradation of pyruvate dehydrogenase kinase 4 (PDK4, inhibitor of PDH) by the Lon protease via an NF-κB-dependent mechanism. Using RNA sequencing following siRNA-mediated knockdown of the catalytically active subunit of PDH, PDHE1α (PDHA1 gene), we show that PDH flux controls the transcription of approximately one-third of the genes that are up-regulated by TNFα stimulation. Notably, TNFα-induced PDH flux regulates a unique signature of proinflammatory mediators (cytokines and chemokines) but not inducible adhesion molecules. Metabolomics and ChIP sequencing for acetylated modification on lysine 27 of histone 3 (H3K27ac) showed that TNFα-induced PDH flux promotes histone acetylation of specific gene loci via citrate accumulation and ATP-citrate lyase-mediated generation of acetyl CoA. Together, these results uncover a mechanism by which TNFα signaling increases oxidative TCA flux of glucose to support TNFα-induced gene transcription through extramitochondrial acetyl CoA generation and histone acetylation.

Keywords:  TNF; endothelium; gene expression; inflammation; vascular

DOI:  https://doi.org/10.1073/pnas.2218150120