bims-imicid 2023-08-27 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒08‒27
23 papers selected by
Dylan Ryan, University of Cambridge

Glutarate regulates T cell metabolism and anti-tumour immunity.
Glutarate tunes T cell fate.
Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.
Soluble epoxide hydrolase maintains steady-state lipid turnover linked with autocrine signaling in peritoneal macrophages.
Immunometabolic effects of lactate on B cell function in healthy individuals of different ages.
4-Octyl itaconate restricts STING activation by blocking its palmitoylation.
cDC1 craves glutamine for its glory.
Activated Lymphocyte-Derived DNA Drives Glucose Metabolic Adaptation for Inducing Macrophage Inflammatory Response in Systemic Lupus Erythematosus.
Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression.
Lipid oxidation dysregulation: an emerging player in the pathophysiology of sepsis.
C1q+ tumor-associated macrophages contribute to immunosuppression through fatty acid metabolic reprogramming in malignant pleural effusion.
Metabolic changes to host cells with Toxoplasma gondii infection.
MAVS Positively Regulates Mitochondrial Integrity and Metabolic Fitness in B Cells.
Triacylglycerol uptake and handling by macrophages: From fatty acids to lipoproteins.
Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.
lnc(RNA)-ing myeloid metabolism.
Influence of Maternal Immune Activation and Stressors on the Hippocampal Metabolome.
Mitochondrial Dysfunction in Bacterial Infections.
Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD.
Whole Blood and Plasma-Based Lipid Profiling Reveals Distinctive Metabolic Changes in Systemic Lupus Erythematosus and Systemic Sclerosis.
The Mechanisms of Action of Hyperbaric Oxygen in Restoring Host Homeostasis during Sepsis.
Microglial inflammatory signalling improves glucose tolerance.
Metabolic and Proteomic Divergence Is Present in Circulating Monocytes and Tissue-Resident Macrophages from Berkeley Sickle Cell Anemia and β-Thalassemia Mice.

Nat Metab. 2023 Aug 21.

Glutarate regulates T cell metabolism and anti-tumour immunity.

Eleanor Minogue, Pedro P Cunha, Brennan J Wadsworth, Guinevere L Grice, Shiv K Sah-Teli, Rob Hughes, David Bargiela, Alessandro Quaranta, Javier Zurita, Robin Antrobus, Pedro Velica, Laura Barbieri, Craig E Wheelock, Peppi Koivunen, James A Nathan, Iosifina P Foskolou, Randall S Johnson.

T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound is correlated with increased levels of both peripheral and intratumoural cytotoxic CD8+ T cells. These results demonstrate that glutarate is an important regulator of T cell metabolism and differentiation with a potential role in the improvement of T cell immunotherapy.

DOI: https://doi.org/10.1038/s42255-023-00855-2
Nat Metab. 2023 Aug 21.

Glutarate tunes T cell fate.

Francisco Yanqui-Rivera, Christiane A Opitz.

DOI: https://doi.org/10.1038/s42255-023-00878-9
Nat Commun. 2023 Aug 22. 14(1): 5114

Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.

Erika M Palmieri, Ronald Holewinski, Christopher L McGinity, Ciro L Pierri, Nunziata Maio, Jonathan M Weiss, Vincenzo Tragni, Katrina M Miranda, Tracey A Rouault, Thorkell Andresson, David A Wink, Daniel W McVicar.

M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex by using lipoate to generate nitroxyl (HNO). PDH E2-associated lipoate is modified in NO-rich macrophages while the PDH E3 enzyme, also known as dihydrolipoamide dehydrogenase (DLD), is irreversibly inhibited. Mechanistically, we show that lipoate facilitates NO-mediated production of HNO, which interacts with thiols forming irreversible modifications including sulfinamide. In addition, we reveal a macrophage signature of proteins with reduction-resistant modifications, including in DLD, and identify potential HNO targets. Consistently, DLD enzyme is modified in an HNO-dependent manner at Cys477 and Cys484, and molecular modeling and mutagenesis show these modifications impair the formation of DLD homodimers. In conclusion, our work demonstrates that HNO is produced physiologically. Moreover, the production of HNO is dependent on the lipoate-rich PDH complex facilitating irreversible modifications that are critical to NO-dependent metabolic rewiring.

DOI: https://doi.org/10.1038/s41467-023-40738-4
iScience. 2023 Aug 18. 26(8): 107465

Soluble epoxide hydrolase maintains steady-state lipid turnover linked with autocrine signaling in peritoneal macrophages.

Feng Liu, Xueying Diao, Haolun Cong, Eriko Suzuki, Keiji Hasumi, Hiroshi Takeshima.

  Soluble epoxide hydrolase is a widely distributed bifunctional enzyme that contains N-terminal phosphatase (N-phos) and C-terminal epoxide hydrolase (C-EH) domains. C-EH hydrolyzes anti-inflammatory epoxy-fatty acids to corresponding diols and contributes to various inflammatory conditions. However, N-phos has been poorly examined. In peritoneal macrophages, the N-phos inhibitor amino-hydroxybenzoic acid (AHBA) seemed to primarily interrupt the dephosphorylation of lysophosphatidates and broadly attenuated inflammation-related functions. AHBA activated intrinsic lysophosphatidate and thromboxane A2 receptors by altering lipid-metabolite distribution; downstream the signaling, phospholipase C was facilitated to dampen intracellular Ca2+ stores and AKT kinase (protein kinase B) was activated to presumably inhibit inflammatory gene expression. Our data suggest that N-phos maintains steady-state phospholipid turnover connecting autocrine signaling and is a prospective target for controlling inflammatory responses in macrophages.

Keywords:  Biochemistry; Biological sciences; Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2023.107465
medRxiv. 2023 Aug 09. pii: 2023.08.07.23293760. [Epub ahead of print]

Immunometabolic effects of lactate on B cell function in healthy individuals of different ages.

Maria Romero, Kate Miller, Andrew Gelsomini, Denisse Garcia, Kevin Li, Dhananjay Suresh, Daniela Frasca.

Aging is characterized by chronic systemic inflammation and metabolic changes. When we compared B cells from young and elderly donors, we found that aging induces higher oxygen consumption rates, and especially higher extracellular acidification rates, measures of oxidative phosphorylation and of anaerobic glycolysis, respectively. Importantly, this higher metabolic status, which reflects the age-associated expansion of pro-inflammatory B cell subsets, was found associated with higher secretion of lactate and autoimmune antibodies after in vitro stimulation. B cells from elderly individuals, induce in vitro generation of pro-inflammatory CD4+ T cells from young individuals through metabolic pathways mediated by lactate secretion. Lactate also induces immunosenescent B cells that are glycolytic and express transcripts for multiple pro-inflammatory molecules. These results altogether may have relevant clinical implications and suggest novel targets for therapeutic interventions in patients with inflammatory conditions and diseases.

DOI: https://doi.org/10.1101/2023.08.07.23293760
Cell Rep. 2023 Aug 24. pii: S2211-1247(23)01051-3. [Epub ahead of print]42(9): 113040

4-Octyl itaconate restricts STING activation by blocking its palmitoylation.

Chaofei Su, Tian Cheng, Jian Huang, Tuan Zhang, Hang Yin.

  The cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in defending foreign pathogens and maintaining immune homeostasis. While substantial advances have been made in understanding the metabolic changes that occur during macrophage activation, little is known about how these metabolic changes affect the cGAS-STING axis. In this study, we identify that 4-octyl itaconate (4-OI), a derivative of itaconate, inhibits the activation of cGAS-STING. Furthermore, we show that 4-OI inhibits cGAS-STING-related antiviral immune responses and autoimmune inflammation. However, we find that endogenous itaconate does not affect cGAS-STING activation, indicating that 4-OI and itaconate function differently. Mechanistically, we find that 4-OI directly alkylates STING at Cys91, blocking STING palmitoylation and oligomerization. The alkylation of STING by 4-OI represents another type of post-translational modifications (PTMs) of STING. Our findings reveal a mechanism by which cGAS-STING function is regulated through 4-OI alkylation and provide insights into the crosstalk between different kinds of PTMs.

Keywords:  4-OI; CP: Immunology; CP: Molecular biology; PTM; alkylation; cGAS-STING; palmitoylation

DOI:  https://doi.org/10.1016/j.celrep.2023.113040
Nat Immunol. 2023 Sep;24(9): 1405-1406

cDC1 craves glutamine for its glory.

Stefania Vilbois, Jaeoh Park, Ping-Chih Ho.

DOI: https://doi.org/10.1038/s41590-023-01598-8
Cells. 2023 Aug 18. pii: 2093. [Epub ahead of print]12(16):

Activated Lymphocyte-Derived DNA Drives Glucose Metabolic Adaptation for Inducing Macrophage Inflammatory Response in Systemic Lupus Erythematosus.

Hanqing Zhao, Zhenke Wen, Sidong Xiong.

  Activated lymphocyte-derived DNA (ALD-DNA) has been reported to drive the polarization of macrophages toward M2b, producing inflammatory cytokines and inducing inflammation, correspondingly playing an essential role in the development of systemic lupus erythematosus (SLE). Recently, accumulating evidence has pinpointed metabolic adaptation as the crucial cell-intrinsic determinant for inflammatory response, in which glucose metabolism is the key event. However, whether and how glucose metabolism was involved in ALD-DNA-induced macrophage inflammatory response and SLE development remains unclear. Herein, we performed glucose metabolomic analyses of ALD-DNA-stimulated macrophages and uncovered increased glycolysis and diminished pentose phosphate pathway (PPP), as well as enhanced glycogenesis. In ALD-DNA-stimulated macrophages, increased glycolysis resulted in higher lactate production, whereas diminished PPP efficiently led to lower levels of nicotinamide adenine dinucleotide phosphate (NADPH) with higher levels of reactive oxygen species (ROS). While blockade of lactate generation exerted no significant effect on macrophage inflammation in response to ALD-DNA, scavenging ROS fundamentally inhibited the inflammatory response of ALD-DNA-stimulated macrophages. Further, cyclic adenosine monophosphate (cAMP), a master for regulating glycogen metabolism, was downregulated by ALD-DNA in macrophages, which subsequently imbalanced glycogen metabolism toward glycogenesis but not glycogenolysis. Administration of cAMP effectively restored glycogenolysis and enhanced PPP, which correspondingly reduced ROS levels and inhibited the inflammatory response of ALD-DNA-stimulated macrophages. Finally, blocking glucose metabolism using 2-deoxy-D-glucose (2-DG) efficiently restricted macrophage inflammatory response and alleviated ALD-DNA-induced lupus disease. Together, our findings demonstrate that ALD-DNA drives the adaptation of glucose metabolism for inducing macrophage inflammatory response in SLE, which might further our understanding of disease pathogenesis and provide clues for interventive explorations.

Keywords:  ALD-DNA; SLE; cAMP; glucose metabolism; macrophage inflammatory response

DOI:  https://doi.org/10.3390/cells12162093
Proc Natl Acad Sci U S A. 2023 Aug 29. 120(35): e2208117120

Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression.

Sarah J Kierans, Raphael R Fagundes, Mykyta I Malkov, Ríona Sparkes, Eugène T Dillon, Albert Smolenski, Klaas Nico Faber, Cormac T Taylor.

  The metabolic adaptation of eukaryotic cells to hypoxia involves increasing dependence upon glycolytic adenosine triphosphate (ATP) production, an event with consequences for cellular bioenergetics and cell fate. This response is regulated at the transcriptional level by the hypoxia-inducible factor-1(HIF-1)-dependent transcriptional upregulation of glycolytic enzymes (GEs) and glucose transporters. However, this transcriptional upregulation alone is unlikely to account fully for the levels of glycolytic ATP produced during hypoxia. Here, we investigated additional mechanisms regulating glycolysis in hypoxia. We observed that intestinal epithelial cells treated with inhibitors of transcription or translation and human platelets (which lack nuclei and the capacity for canonical transcriptional activity) maintained the capacity for hypoxia-induced glycolysis, a finding which suggests the involvement of a nontranscriptional component to the hypoxia-induced metabolic switch to a highly glycolytic phenotype. In our investigations into potential nontranscriptional mechanisms for glycolytic induction, we identified a hypoxia-sensitive formation of complexes comprising GEs and glucose transporters in intestinal epithelial cells. Surprisingly, the formation of such glycolytic complexes occurs independent of HIF-1-driven transcription. Finally, we provide evidence for the presence of HIF-1α in cytosolic fractions of hypoxic cells which physically interacts with the glucose transporter GLUT1 and the GEs in a hypoxia-sensitive manner. In conclusion, we provide insights into the nontranscriptional regulation of hypoxia-induced glycolysis in intestinal epithelial cells.

Keywords:  HIF; glycolysis; hypoxia; metabolism

DOI:  https://doi.org/10.1073/pnas.2208117120
Front Immunol. 2023 ;14 1224335

Lipid oxidation dysregulation: an emerging player in the pathophysiology of sepsis.

Renan Muniz-Santos, Giovanna Lucieri-Costa, Matheus Augusto P de Almeida, Isabelle Moraes-de-Souza, Maria Alice Dos Santos Mascarenhas Brito, Adriana Ribeiro Silva, Cassiano Felippe Gonçalves-de-Albuquerque.

  Sepsis is a life-threatening organ dysfunction caused by abnormal host response to infection. Millions of people are affected annually worldwide. Derangement of the inflammatory response is crucial in sepsis pathogenesis. However, metabolic, coagulation, and thermoregulatory alterations also occur in patients with sepsis. Fatty acid mobilization and oxidation changes may assume the role of a protagonist in sepsis pathogenesis. Lipid oxidation and free fatty acids (FFAs) are potentially valuable markers for sepsis diagnosis and prognosis. Herein, we discuss inflammatory and metabolic dysfunction during sepsis, focusing on fatty acid oxidation (FAO) alterations in the liver and muscle (skeletal and cardiac) and their implications in sepsis development.

Keywords:  fatty acid oxidation (FAO); free fatty acid (FFA); inflammation; metabolic dysfunction; sepsis

DOI:  https://doi.org/10.3389/fimmu.2023.1224335
J Immunother Cancer. 2023 08;pii: e007441. [Epub ahead of print]11(8):

C1q+ tumor-associated macrophages contribute to immunosuppression through fatty acid metabolic reprogramming in malignant pleural effusion.

Siyu Zhang, Wenbei Peng, Haolei Wang, Xuan Xiang, Linlin Ye, Xiaoshan Wei, Zihao Wang, Qianqian Xue, Long Chen, Yuan Su, Qiong Zhou.

  BACKGROUND: Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop acquired resistance due to the existence of abundant immunosuppressive cells. Tumor-associated macrophages (TAMs), as the dominant immunosuppressive population, impede the antitumor immune response; however, the underlying mechanisms have not been fully elucidated yet.METHODS: Single-cell RNA sequencing analysis was performed to portray macrophage landscape and revealed the underlying mechanism of component 1q (C1q)+ TAMs. Malignant pleural effusion (MPE) of human and mouse was used to explore the phenotypes and functions of C1q+ TAMs.
RESULTS: C1q+ TAMs highly expressed multiple inhibitory molecules and their high infiltration was significantly correlated with poor prognosis. C1q+ TAMs promote MPE immunosuppression through impairing the antitumor effects of CD8+ T cells. Mechanistically, C1q+ TAMs enhance fatty acid binding protein 5 (FABP5)-mediated fatty acid metabolism, which activate transcription factor peroxisome proliferator-activated receptor-gamma, increasing the gene expression of inhibitory molecules. A high-fat diet increases the expression of inhibitory molecules in C1q+ TAMs and the immunosuppression of MPE microenvironment, whereas a low-fat diet ameliorates these effects. Moreover, FABP5 inhibition represses the expression of inhibitory molecules in TAMs and tumor progression, while enhancing the efficacy of ICB therapy in MPE and lung cancer.
CONCLUSIONS: C1q+ TAMs impede antitumor effects of CD8+ T cells promoting MPE immunosuppression. Targeting C1q+ TAMs effectively alleviates the immunosuppression and enhances the efficacy of ICB therapy. C1q+ TAMs subset has great potential to be a therapeutic target for cancer immunotherapy.

Keywords:  immunomodulation; immunotherapy; lymphocytes, tumor-infiltrating; macrophages; tumor microenvironment

DOI:  https://doi.org/10.1136/jitc-2023-007441
bioRxiv. 2023 Aug 10. pii: 2023.08.10.552811. [Epub ahead of print]

Metabolic changes to host cells with Toxoplasma gondii infection.

Gina M Gallego-López, Emmanuel Contreras Guzman, Laura J Knoll, Melissa Skala.

Toxoplasma gondii , the causative agent of toxoplasmosis, is an obligate intracellular parasite that infects warm-blooded vertebrates across the world. In humans, seropositivity rates of T. gondii range from 10% to 90%. Despite its prevalence, few studies address how T. gondii infection changes the metabolism of host cells. Here, we investigate how T. gondii manipulates the host cell metabolic environment by monitoring metabolic response over time using non-invasive autofluorescence lifetime imaging of single cells, seahorse metabolic flux analysis, reactive oxygen species (ROS) production, and metabolomics. Autofluorescence lifetime imaging indicates that infected host cells become more oxidized and have an increased proportion of bound NAD(P)H with infection. These findings are consistent with changes in mitochondrial and glycolytic function, decrease of intracellular glucose, fluctuations in lactate and ROS production in infected cells over time. We also examined changes associated with the pre-invasion "kiss and spit" process using autofluorescence lifetime imaging, which similarly showed a more oxidized host cell with an increased proportion of bound NAD(P)H over 48 hours. Glucose metabolic flux analysis indicated that these changes are driven by NADH and NADP+ in T. gondii infection. In sum, metabolic changes in host cells with T. gondii infection were similar during full infection, and kiss and spit. Autofluorescence lifetime imaging can non-invasively monitor metabolic changes in host cells over a microbial infection time-course.

DOI: https://doi.org/10.1101/2023.08.10.552811
Immunohorizons. 2023 Aug 01. 7(8): 587-599

MAVS Positively Regulates Mitochondrial Integrity and Metabolic Fitness in B Cells.

Hongsheng Wang, Wenxiang Sun, Javier Traba, Juan Wu, Chen-Feng Qi, Laura Amo, Hemanta K Kole, Bethany Scott, Komudi Singh, Michael N Sack, Silvia Bolland.

Activated B cells experience metabolic changes that require mitochondrial remodeling, in a process incompletely defined. In this study, we report that mitochondrial antiviral signaling protein (MAVS) is involved in BCR-initiated cellular proliferation and prolonged survival. MAVS is well known as a mitochondrial-tethered signaling adaptor with a central role in viral RNA-sensing pathways that induce type I IFN. The role of MAVS downstream of BCR stimulation was recognized in absence of IFN, indicative of a path for MAVS activation that is independent of viral infection. Mitochondria of BCR-activated MAVS-deficient mouse B cells exhibited a damaged phenotype including disrupted mitochondrial morphology, excess mitophagy, and the temporal progressive blunting of mitochondrial oxidative capacity with mitochondrial hyperpolarization and cell death. Costimulation of MAVS-deficient B cells with anti-CD40, in addition to BCR stimulation, partially corrected the mitochondrial structural defects and functionality. Our data reveal a (to our knowledge) previously unrecognized role of MAVS in controlling the metabolic fitness of B cells, most noticeable in the absence of costimulatory help.

DOI: https://doi.org/10.4049/immunohorizons.2300038
Prog Lipid Res. 2023 Aug 22. pii: S0163-7827(23)00040-1. [Epub ahead of print] 101250

Triacylglycerol uptake and handling by macrophages: From fatty acids to lipoproteins.

Lei Deng, Sander Kersten, Rinke Stienstra.

Macrophages are essential innate immune cells and form our first line of immune defense. Also known as professional phagocytes, macrophages interact and take up various particles, including lipids. Defective lipid handling can drive excessive lipid accumulation leading to foam cell formation, a key feature of various cardiometabolic conditions such as atherosclerosis, non-alcoholic fatty liver disease, and obesity. At the same time, intracellular lipid storage and foam cell formation can also be viewed as a protective and anti-lipotoxic mechanism against a lipid-rich environment and associated elevated lipid uptake. Traditionally, foam cell formation has primarily been linked to cholesterol uptake via native and modified low-density lipoproteins. However, other lipids, including non-esterified fatty acids and triacylglycerol (TAG)-rich lipoproteins (very low-density lipoproteins and chylomicrons), can also interact with macrophages. Recent studies have identified multiple pathways mediating TAG uptake and processing by macrophages, including endocytosis and receptor/transporter-mediated internalization and transport. This review will present the current knowledge of how macrophages take up different lipids and lipoprotein particles and address how TAG-rich lipoproteins are processed intracellularly. Understanding how macrophages take up and process different lipid species such as TAG is necessary to design future therapeutic interventions to correct excessive lipid accumulation and associated co-morbidities.

DOI: https://doi.org/10.1016/j.plipres.2023.101250
Nat Commun. 2023 Aug 25. 14(1): 5197

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.

Jiyeon Lee, Julie M Dimitry, Jong Hee Song, Minsoo Son, Patrick W Sheehan, Melvin W King, G Travis Tabor, Young Ah Goo, Mitchell A Lazar, Leonard Petrucelli, Erik S Musiek.

Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

DOI: https://doi.org/10.1038/s41467-023-40927-1
Nat Immunol. 2023 Sep;24(9): 1396

lnc(RNA)-ing myeloid metabolism.

Stephanie Houston.

DOI: https://doi.org/10.1038/s41590-023-01615-w
Metabolites. 2023 Jul 25. pii: 881. [Epub ahead of print]13(8):

Influence of Maternal Immune Activation and Stressors on the Hippocampal Metabolome.

Bruce R Southey, Rodney W Johnson, Sandra L Rodriguez-Zas.

  Prenatal stress often results in maternal immune activation (MIA) that can impact prenatal brain development, molecular processes, and substrates and products of metabolism that participate in physiological processes at later stages of life. Postnatal metabolic and immunological stressors can affect brain metabolites later in life, independently or in combination with prenatal stressors. The effects of prenatal and postnatal stressors on hippocampal metabolites were studied using a pig model of viral MIA exposed to immunological and metabolic stressors at 60 days of age using gas chromatography mass spectrometry. Postnatal stress and MIA elicited effects (FDR-adjusted p-value < 0.1) on fifty-nine metabolites, while eight metabolites exhibited an interaction effect. The hippocampal metabolites impacted by MIA or postnatal stress include 4-aminobutanoate (GABA), adenine, fumarate, glutamate, guanine, inosine, ornithine, putrescine, pyruvate, and xanthine. Metabolites affected by MIA or postnatal stress encompassed eight significantly (FDR-adjusted p-value < 0.1) enriched Kyoto Encyclopedia of Genes and Genomes Database (KEGG) pathways. The enriched arginine biosynthesis and glutathione metabolism pathways included metabolites that are also annotated for the urea cycle and polyamine biosynthesis pathways. Notably, the prenatal and postnatal challenges were associated with disruption of the glutathione metabolism pathway and changes in the levels of glutamic acid, glutamate, and purine nucleotide metabolites that resemble patterns elicited by drugs of abuse and may underlie neuroinflammatory processes. The combination of MIA and postnatal stressors also supported the double-hit hypothesis, where MIA amplifies the impact of stressors later in life, sensitizing the hippocampus of the offspring to future challenges. The metabolites and pathways characterized in this study offer evidence of the role of immunometabolism in understanding the impact of MIA and stressors later in life on memory, spatial navigation, neuropsychiatric disorders, and behavioral disorders influenced by the hippocampus.

Keywords:  gas chromatography; hippocampus; immunometabolism; mass spectrometry; maternal immune activation; metabolite; metabolomics

DOI:  https://doi.org/10.3390/metabo13080881
Pathogens. 2023 Aug 01. pii: 1005. [Epub ahead of print]12(8):

Mitochondrial Dysfunction in Bacterial Infections.

Nicholas M Maurice, Ruxana T Sadikot.

  Mitochondria are critical in numerous cellular processes, including energy generation. Bacterial pathogens target host cell mitochondria through various mechanisms to disturb the host response and improve bacterial survival. We review recent advances in the understanding of how bacteria cause mitochondrial dysfunction through perturbations in mitochondrial cell-death pathways, energy production, mitochondrial dynamics, mitochondrial quality control, DNA repair, and the mitochondrial unfolded protein response. We also briefly highlight possible therapeutic approaches aimed at restoring the host mitochondrial function as a novel strategy to enhance the host response to bacterial infection.

Keywords:  bacterial infection; innate immunity; metabolism; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.3390/pathogens12081005
JCI Insight. 2023 Aug 22. pii: e163403. [Epub ahead of print]8(16):

Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD.

Li-Chao Fan, Keith McConn, Maria Plataki, Sarah Kenny, Niamh C Williams, Kihwan Kim, Jennifer A Quirke, Yan Chen, Maor Sauler, Matthias E Möbius, Kuei-Pin Chung, Estela Area Gomez, Augustine Mk Choi, Jin-Fu Xu, Suzanne M Cloonan.

  Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid-containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.

Keywords:  COPD; Intermediary metabolism; Metabolism; Pulmonary surfactants; Pulmonology

DOI:  https://doi.org/10.1172/jci.insight.163403
J Proteome Res. 2023 Aug 22.

Whole Blood and Plasma-Based Lipid Profiling Reveals Distinctive Metabolic Changes in Systemic Lupus Erythematosus and Systemic Sclerosis.

Helena Beatriz Ferreira, Tânia Melo, Inês M S Guerra, Ana S P Moreira, Paula Laranjeira, Artur Paiva, Laura Goracci, Stefano Bonciarelli, Pedro Domingues, M Rosário Domingues.

  Autoimmune diseases (AID), such as systemic lupus erythematosus (SLE) and systemic sclerosis (SS), are complex conditions involving immune system dysregulation. Diagnosis is challenging, requiring biomarkers for improved detection and prediction of relapses. Lipids have emerged as potential biomarkers due to their role in inflammation and immune response. This study uses an untargeted C18 RP-LC-MS lipidomics approach to comprehensively assess changes in lipid profiles in patients with SLE and SS. By analyzing whole blood and plasma, the study aims to simplify the lipidomic analysis, explore cellular-level lipids, and compare lipid signatures of SLE and SS with healthy controls. Our findings showed variations in the lipid profile of SLE and SS. Sphingomyelin and ceramide molecular species showed significant increases in plasma samples from SS patients, suggesting an atherosclerotic profile and potentially serving as lipid biomarkers. Phosphatidylserine species in whole blood from SLE patients exhibited elevated levels supporting previously reported dysregulated processes of cell death and defective clearance of dying cells in this AID. Moreover, decreased phospholipids bearing PUFA were observed, potentially attributed to the degradation of these species through lipid peroxidation processes. Further studies are needed to better understand the role of lipids in the pathological mechanisms underlying SLE and SS.

Keywords:  autoimmune diseases; lipid metabolism; lipidomic signature; lipidomics; mass spectrometry; systemic lupus erythematosus; systemic sclerosis

DOI:  https://doi.org/10.1021/acs.jproteome.3c00321
Biomolecules. 2023 Aug 07. pii: 1228. [Epub ahead of print]13(8):

The Mechanisms of Action of Hyperbaric Oxygen in Restoring Host Homeostasis during Sepsis.

Julie Vinkel, Bjoern Arenkiel, Ole Hyldegaard.

  The perception of sepsis has shifted over time; however, it remains a leading cause of death worldwide. Sepsis is now recognized as an imbalance in host cellular functions triggered by the invading pathogens, both related to immune cells, endothelial function, glucose and oxygen metabolism, tissue repair and restoration. Many of these key mechanisms in sepsis are also targets of hyperbaric oxygen (HBO2) treatment. HBO2 treatment has been shown to improve survival in clinical studies on patients with necrotizing soft tissue infections as well as experimental sepsis models. High tissue oxygen tension during HBO2 treatment may affect oxidative phosphorylation in mitochondria. Oxygen is converted to energy, and, as a natural byproduct, reactive oxygen species are produced. Reactive oxygen species can act as mediators, and both these and the HBO2-mediated increase in oxygen supply have the potential to influence the cellular processes involved in sepsis. The pathophysiology of sepsis can be explained comprehensively through resistance and tolerance to infection. We argue that HBO2 treatment may protect the host from collateral tissue damage during resistance by reducing neutrophil extracellular traps, inhibiting neutrophil adhesion to vascular endothelium, reducing proinflammatory cytokines, and halting the Warburg effect, while also assisting the host in tolerance to infection by reducing iron-mediated injury and upregulating anti-inflammatory measures. Finally, we show how inflammation and oxygen-sensing pathways are connected on the cellular level in a self-reinforcing and detrimental manner in inflammatory conditions, and with support from a substantial body of studies from the literature, we conclude by demonstrating that HBO2 treatment can intervene to maintain homeostasis.

Keywords:  host immune response; hyperbaric oxygen treatment; hypoxia; hypoxia-inducible factor 1-alpha; inflammation; nuclear factor kappa-light-chain-enhancer of activated B cells; oxygen; sepsis; systemic infectious diseases; tolerance to infection

DOI:  https://doi.org/10.3390/biom13081228
Nat Rev Endocrinol. 2023 Aug 21.

Microglial inflammatory signalling improves glucose tolerance.

Claire Greenhill.

DOI: https://doi.org/10.1038/s41574-023-00892-7
J Proteome Res. 2023 Aug 22.

Metabolic and Proteomic Divergence Is Present in Circulating Monocytes and Tissue-Resident Macrophages from Berkeley Sickle Cell Anemia and β-Thalassemia Mice.

Christina Lisk, Francesca Cendali, Saini Setua, Kiruphararan Thangaraju, David I Pak, Delaney Swindle, Monika Dzieciatkowska, Fabia Gamboni, Kathryn Hassell, Rachelle Nuss, Gemlyn George, Pavel Davizon-Castillo, Paul W Buehler, Angelo D'Alessandro, David C Irwin.

  Sickle cell disease and β-thalassemia represent hemoglobinopathies arising from dysfunctional or underproduced β-globin chains, respectively. In both diseases, red blood cell injury and anemia are the impetus for end organ injury. Because persistent erythrophagocytosis is a hallmark of these genetic maladies, it is critical to understand how macrophage phenotype polarizations in tissue compartments can inform on disease progression. Murine models of sickle cell disease and β-thalassemia allow for a basic understanding of the mechanisms and provide for translation to human disease. A multi-omics approach to understanding the macrophage metabolism and protein changes in two murine models of β-globinopathy was performed on peripheral blood mononuclear cells as well as spleen and liver macrophages isolated from Berkley sickle cell disease (Berk-ss) and heterozygous B1/B2 globin gene deletion (Hbbth3/+) mice. The results from these experiments revealed that the metabolome and proteome of macrophages are polarized to a distinct phenotype in Berk-ss and Hbbth3/+ compared with each other and their common-background mice (C57BL6/J). Further, spleen and liver macrophages revealed distinct disease-specific phenotypes, suggesting that macrophages become differentially polarized and reprogrammed within tissue compartments. We conclude that tissue recruitment, polarization, and metabolic and proteomic reprogramming of macrophages in Berk-ss and Hbbth3/+ mice may be relevant to disease progression in other tissue.

Keywords:  PBMCs; macrophage; metabolomics; polarization; proteomics; pulmonary hypertension; sickle cell disease; β-thalassemia

DOI:  https://doi.org/10.1021/acs.jproteome.3c00224