bims-imicid 2022-08-28 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–08–28
thirty-six papers selected by
Dylan Ryan, University of Cambridge

SPICE-Met: profiling and imaging energy metabolism at the single-cell level using a fluorescent reporter mouse.
Uropathogenic Escherichia coli subverts mitochondrial metabolism to enable intracellular bacterial pathogenesis in urinary tract infection.
Aconitate decarboxylase 1 is a mediator of polymicrobial sepsis.
Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation.
Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation.
Multi-omics analyses of airway host-microbe interactions in chronic obstructive pulmonary disease identify potential therapeutic interventions.
scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity.
CD4+ T cell metabolism, gut microbiota, and autoimmune diseases: implication in precision medicine of autoimmune diseases.
NAD+ metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity.
Metabolomic and transcriptomic signatures of influenza vaccine response in healthy young and older adults.
Mitochondrial Ultrastructure and Activity Are Differentially Regulated by Glycolysis-, Krebs Cycle-, and Microbiota-Derived Metabolites in Monocytes.
Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors.
A chromatin remodeling checkpoint of diet-induced macrophage activation in adipose tissue.
The Role of Immunometabolism in HIV-1 Pathogenicity: Links to Immune Cell Responses.
Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages.
mTOR regulation of metabolism limits LPS-induced monocyte inflammatory and procoagulant responses.
Obesity Dysregulates the Immune Response to Influenza Infection and Vaccination Through Metabolic and Inflammatory Mechanisms.
Postbiotics engage IRF4 in adipocytes to promote sex-dependent changes in blood glucose during obesity.
Macrophage Polarization Mediated by Mitochondrial Dysfunction Induces Adipose Tissue Inflammation in Obesity.
Understanding lactate sensing and signalling.
Metabolic rewiring directs melanoma immunology.
Influence of Microbial Metabolites and Itaconic Acid Involved in Bacterial Inflammation on the Activity of Mitochondrial Enzymes and the Protective Role of Alkalization.
Epigenetic perspectives of COVID-19: Virus infection to disease progression and therapeutic control.
Editorial: T cell metabolism in infection.
Macrophages take up VLDL-sized emulsion particles through caveolae-mediated endocytosis and excrete part of the internalized triglycerides as fatty acids.
SLC1A3 facilitates Newcastle disease virus replication by regulating glutamine catabolism.
Blocking CHOP-dependent TXNIP shuttling to mitochondria attenuates albuminuria and mitigates kidney injury in nephrotic syndrome.
Immunometabolism: An evolutionary perspective in obstructive sleep apnea.
Macrophages and neutrophils are necessary for ER stress-induced β cell loss.
DMGV Is a Rheostat of T Cell Survival and a Potential Therapeutic for Inflammatory Diseases and Cancers.
Multi-omics analysis identifies potential mechanisms by which high glucose accelerates macrophage foaming.
Malaria parasite evades mosquito immunity by glutaminyl cyclase-mediated posttranslational protein modification.
Development and validation of a method to deliver vitamin A to macrophages.
Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release.
Trophoblast-Derived Extracellular Vesicles Promote Preeclampsia by Regulating Macrophage Polarization.
Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl) homoserine lactone induces calcium signaling-dependent crosstalk between autophagy and apoptosis in human macrophages.

EMBO J. 2022 Aug 23. e111528

SPICE-Met: profiling and imaging energy metabolism at the single-cell level using a fluorescent reporter mouse.

Erica Russo, Fabrice Lemaître, Béatrice Corre, Aleksandra S Chikina, Francina Langa-Vives, Philippe Bousso.

  The regulation of cellular energy metabolism is central to most physiological and pathophysiological processes. However, most current methods have limited ability to functionally probe metabolic pathways in individual cells. Here, we describe SPICE-Met (Single-cell Profiling and Imaging of Cell Energy Metabolism), a method for profiling energy metabolism in single cells using flow cytometry or imaging. We generated a transgenic mouse expressing PercevalHR, a fluorescent reporter for cellular ATP:ADP ratio. Modulation of PercevalHR fluorescence with metabolic inhibitors was used to infer the dependence of energy metabolism on oxidative phosphorylation and glycolysis in defined cell populations identified by flow cytometry. We applied SPICE-Met to analyze T-cell memory development during vaccination. Finally, we used SPICE-Met in combination with real-time imaging to dissect the heterogeneity and plasticity of energy metabolism in single macrophages ex vivo and identify three distinct metabolic patterns. Functional probing of energy metabolism with single-cell resolution should greatly facilitate the study of immunometabolism at a steady state, during disease pathogenesis or in response to therapy.

Keywords:  OXPHOS; energy; glycolysis; imaging; immunometabolism

DOI:  https://doi.org/10.15252/embj.2022111528
Nat Microbiol. 2022 Sep;7(9): 1348-1360

Uropathogenic Escherichia coli subverts mitochondrial metabolism to enable intracellular bacterial pathogenesis in urinary tract infection.

Connor J Beebout, Gabriella L Robertson, Bradley I Reinfeld, Alexandra M Blee, Grace H Morales, John R Brannon, Walter J Chazin, W Kimryn Rathmell, Jeffrey C Rathmell, Vivian Gama, Maria Hadjifrangiskou.

Urinary tract infections are among the most common human bacterial infections and place a significant burden on healthcare systems due to associated morbidity, cost and antibiotic use. Despite being a facultative anaerobe, uropathogenic Escherichia coli, the primary cause of urinary tract infections, requires aerobic respiration to establish infection in the bladder. Here, by combining bacterial genetics with cell culture and murine models of infection, we demonstrate that the widely conserved respiratory quinol oxidase cytochrome bd is required for intracellular infection of urothelial cells. Through a series of genetic, biochemical and functional assays, we show that intracellular oxygen scavenging by cytochrome bd alters mitochondrial physiology by reducing the efficiency of mitochondrial respiration, stabilizing the hypoxia-inducible transcription factor HIF-1 and promoting a shift towards aerobic glycolysis. This bacterially induced rewiring of host metabolism antagonizes apoptosis, thereby protecting intracellular bacteria from urothelial cell exfoliation and preserving their replicative niche. These results reveal the metabolic basis for intracellular bacterial pathogenesis during urinary tract infection and identify subversion of mitochondrial metabolism as a bacterial strategy to facilitate persistence within the urinary tract.

DOI: https://doi.org/10.1038/s41564-022-01205-w
Sci Transl Med. 2022 Aug 24. 14(659): eabo2028

Aconitate decarboxylase 1 is a mediator of polymicrobial sepsis.

Runliu Wu, Jiao Liu, Nian Wang, Ling Zeng, Chunhua Yu, Feng Chen, Haichao Wang, Timothy R Billiar, Jianxin Jiang, Daolin Tang, Rui Kang.

Sepsis is a challenging clinical syndrome caused by a dysregulated host response to infection. Here, we identified an unexpected proseptic activity of aconitate decarboxylase 1 (ACOD1) in monocytes and macrophages. Previous studies have suggested that ACOD1, also known as immune-responsive gene 1, is an immunometabolic regulator that favors itaconate production to inhibit bacterial lipopolysaccharide-induced innate immunity. We used next-generation sequencing of lipopolysaccharide-activated THP1 cells to demonstrate that ACOD1 accumulation confers a robust proinflammation response by activating a cytokine storm, predominantly through the tumor necrosis factor signaling pathway. We further revealed that the phosphorylation of cyclin-dependent kinase 2 (CDK2) on threonine-160 mediates the activation of mitogen-activated protein kinase 8 through receptor for activated C kinase 1, leading to JUN-dependent transcription of ACOD1 in human and mouse macrophages or monocytes. Genetic deletion of CDK2 or ACOD1 in myeloid cells, or the administration of the CDK inhibitor dinaciclib, protected mice against polymicrobial sepsis and was associated with improved survival and decreased cytokine storm. The expression of the CDK2-ACOD1 axis also correlated with severity of illness in a cohort of 40 patients with bacterial sepsis. Thus, our findings provide evidence for a previously unrecognized function of ACOD1 in innate immunity and suggest it as a potential therapeutic target for the treatment of sepsis.

DOI: https://doi.org/10.1126/scitranslmed.abo2028
Nature. 2022 Aug 24.

Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation.

Che A Stafford, Alicia-Marie Gassauer, Carina C de Oliveira Mann, Maria C Tanzer, Evelyn Fessler, Benedikt Wefers, Dennis Nagl, Gunnar Kuut, Karolina Sulek, Catherine Vasilopoulou, Sophia J Schwojer, Andreas Wiest, Marie K Pfautsch, Wolfgang Wurst, Monica Yabal, Thomas Fröhlich, Matthias Mann, Nicolas Gisch, Lucas T Jae, Veit Hornung.

Bacterial cell wall components provide various unique molecular structures that are detected by pattern recognition receptors (PRRs) of the innate immune system as non-self. Most bacterial species form a cell wall that consists of peptidoglycan (PGN), a polymeric structure comprising alternating amino sugars that form strands cross-linked by short peptides. Muramyl dipeptide (MDP) has been well documented as a minimal immunogenic component of peptidoglycan1-3. MDP is sensed by the cytosolic nucleotide-binding oligomerization domain-containing protein 24 (NOD2). Upon engagement, it triggers pro-inflammatory gene expression, and this functionality is of critical importance in maintaining a healthy intestinal barrier function5. Here, using a forward genetic screen to identify factors required for MDP detection, we identified N-acetylglucosamine kinase (NAGK) as being essential for the immunostimulatory activity of MDP. NAGK is broadly expressed in immune cells and has previously been described to contribute to the hexosamine biosynthetic salvage pathway6. Mechanistically, NAGK functions upstream of NOD2 by directly phosphorylating the N-acetylmuramic acid moiety of MDP at the hydroxyl group of its C6 position, yielding 6-O-phospho-MDP. NAGK-phosphorylated MDP-but not unmodified MDP-constitutes an agonist for NOD2. Macrophages from mice deficient in NAGK are completely deficient in MDP sensing. These results reveal a link between amino sugar metabolism and innate immunity to bacterial cell walls.

DOI: https://doi.org/10.1038/s41586-022-05125-x
Cell Metab. 2022 Aug 20. pii: S1550-4131(22)00346-1. [Epub ahead of print]

Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation.

Chi Kin Wong, Bernardo Yusta, Jacqueline A Koehler, Laurie L Baggio, Brent A McLean, Dianne Matthews, Randy J Seeley, Daniel J Drucker.

  Gut intraepithelial lymphocytes (IELs) are thought to calibrate glucagon-like peptide 1 (GLP-1) bioavailability, thereby regulating systemic glucose and lipid metabolism. Here, we show that the gut IEL GLP-1 receptor (GLP-1R) is not required for enteroendocrine L cell GLP-1 secretion and glucose homeostasis nor for the metabolic benefits of GLP-1R agonists (GLP-1RAs). Instead, the gut IEL GLP-1R is essential for the full effects of GLP-1RAs on gut microbiota. Moreover, independent of glucose control or weight loss, the anti-inflammatory actions of GLP-1RAs require the gut IEL GLP-1R to selectively restrain local and systemic T cell-induced, but not lipopolysaccharide-induced, inflammation. Such effects are mediated by the suppression of gut IEL effector functions linked to the dampening of proximal T cell receptor signaling in a protein-kinase-A-dependent manner. These data reposition key roles of the L cell-gut IEL GLP-1R axis, revealing mechanisms linking GLP-1R activation in gut IELs to modulation of microbiota composition and control of intestinal and systemic inflammation.

Keywords:  GPCR; NASH; T cells; diabetes; glucagon-like peptide 1; immunology; inflammation; intestinal intraepithelial lymphocytes; microbiota; obesity

DOI:  https://doi.org/10.1016/j.cmet.2022.08.003
Nat Microbiol. 2022 Sep;7(9): 1361-1375

Multi-omics analyses of airway host-microbe interactions in chronic obstructive pulmonary disease identify potential therapeutic interventions.

Zhengzheng Yan, Boxuan Chen, Yuqiong Yang, Xinzhu Yi, Mingyuan Wei, Gertrude Ecklu-Mensah, Mary M Buschmann, Haiyue Liu, Jingyuan Gao, Weijie Liang, Xiaomin Liu, Junhao Yang, Wei Ma, Zhenyu Liang, Fengyan Wang, Dandan Chen, Lingwei Wang, Weijuan Shi, Martin R Stampfli, Pan Li, Shenhai Gong, Xia Chen, Wensheng Shu, Emad M El-Omar, Jack A Gilbert, Martin J Blaser, Hongwei Zhou, Rongchang Chen, Zhang Wang.

The mechanistic role of the airway microbiome in chronic obstructive pulmonary disease (COPD) remains largely unexplored. We present a landscape of airway microbe-host interactions in COPD through an in-depth profiling of the sputum metagenome, metabolome, host transcriptome and proteome from 99 patients with COPD and 36 healthy individuals in China. Multi-omics data were integrated using sequential mediation analysis, to assess in silico associations of the microbiome with two primary COPD inflammatory endotypes, neutrophilic or eosinophilic inflammation, mediated through microbial metabolic interaction with host gene expression. Hypotheses of microbiome-metabolite-host interaction were identified by leveraging microbial genetic information and established metabolite-human gene pairs. A prominent hypothesis for neutrophil-predominant COPD was altered tryptophan metabolism in airway lactobacilli associated with reduced indole-3-acetic acid (IAA), which was in turn linked to perturbed host interleukin-22 signalling and epithelial cell apoptosis pathways. In vivo and in vitro studies showed that airway microbiome-derived IAA mitigates neutrophilic inflammation, apoptosis, emphysema and lung function decline, via macrophage-epithelial cell cross-talk mediated by interleukin-22. Intranasal inoculation of two airway lactobacilli restored IAA and recapitulated its protective effects in mice. These findings provide the rationale for therapeutically targeting microbe-host interaction in COPD.

DOI: https://doi.org/10.1038/s41564-022-01196-8
Oncoimmunology. 2022 ;11(1): 2114740

scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity.

Genshen Zhong, Qi Wang, Ying Wang, Ying Guo, Meiqi Xu, Yaya Guan, Xiaoying Zhang, Minna Wu, Zhishan Xu, Weidong Zhao, Hongkai Lian, Hui Wang, Jianping Ye.

  ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein with an activity in inhibition of F1Fo-ATP synthase. ATPIF1 activity remains unknown in the control of immune activity of T cells. In this study, we identified ATPIF1 activity in the induction of CD8+ T cell function in tumor models through genetic approaches. ATPIF1 gene inactivation impaired the immune activities of CD8+ T cells leading to quick tumor growth (B16 melanoma and Lewis lung cancer) in ATPIF1-KO mice. The KO T cells exhibited a reduced activity in proliferation and IFN-γ secretion with metabolic reprogramming of increased glycolysis and decreased oxidative phosphorylation (OXPHOS) after activation. T cell exhaustion was increased in the tumor infiltrating leukocytes (TILs) of KO mice as revealed by the single-cell RNA sequencing (scRNA-seq) and confirmed by flow cytometry. In contrast, ATPIF1 overexpression in T cells increased expression of IFN-γ and Granzyme B, subset of central memory T cells in CAR-T cells, and survival rate of NALM-6 tumor-bearing mice. These data demonstrate that ATPIF1 deficiency led to tumor immune deficiency through induction of T cell exhaustion. ATPIF1 overexpression enhanced the T cell tumor immunity. Therefore, ATPIF1 is a potential molecular target in the modulation of antitumor immunity of CD8+ T cells in cancer immunotherapy. Induction of ATPIF1 activity may promote CAR-T activity in cancer therapy.

Keywords:  ATPIF1; CD19 CAR-T; CD8+ T cells; single cell RNA sequencing

DOI:  https://doi.org/10.1080/2162402X.2022.2114740
Precis Clin Med. 2022 Sep;5(3): pbac018

CD4+ T cell metabolism, gut microbiota, and autoimmune diseases: implication in precision medicine of autoimmune diseases.

Wenjing Yang, Tianming Yu, Yingzi Cong.

  CD4+ T cells are critical to the development of autoimmune disorders. Glucose, fatty acids, and glutamine metabolisms are the primary metabolic pathways in immune cells, including CD4+ T cells. The distinct metabolic programs in CD4+ T cell subsets are recognized to reflect the bioenergetic requirements, which are compatible with their functional demands. Gut microbiota affects T cell responses by providing a series of antigens and metabolites. Accumulating data indicate that CD4+ T cell metabolic pathways underlie aberrant T cell functions, thereby regulating the pathogenesis of autoimmune disorders, including inflammatory bowel diseases, systemic lupus erythematosus, and rheumatoid arthritis. Here, we summarize the current progress of CD4+ T cell metabolic programs, gut microbiota regulation of T cell metabolism, and T cell metabolic adaptions to autoimmune disorders to shed light on potential metabolic therapeutics for autoimmune diseases.

Keywords:  autoimmune disorders; gut microbiota; immunometabolism; metabolic adaption

DOI:  https://doi.org/10.1093/pcmedi/pbac018
Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2211310119

NAD+ metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity.

Tom Meyer, Dor Shimon, Sawsan Youssef, Gal Yankovitz, Adi Tessler, Tom Chernobylsky, Anat Gaoni-Yogev, Rita Perelroizen, Noga Budick-Harmelin, Lawrence Steinman, Lior Mayo.

  Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Astrocytes are the most abundant glial cells in the CNS, and their dysfunction contributes to the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Recent advances highlight the pivotal role of cellular metabolism in programming immune responses. However, the underlying immunometabolic mechanisms that drive astrocyte pathogenicity remain elusive. Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme involved in cellular redox reactions and a substrate for NAD+-dependent enzymes. Cellular NAD+ levels are dynamically controlled by synthesis and degradation, and dysregulation of this balance has been associated with inflammation and disease. Here, we demonstrate that cell-autonomous generation of NAD+ via the salvage pathway regulates astrocyte immune function. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the salvage pathway, results in depletion of NAD+, inhibits oxidative phosphorylation, and limits astrocyte inflammatory potential. We identified CD38 as the main NADase up-regulated in reactive mouse and human astrocytes in models of neuroinflammation and MS. Genetic or pharmacological blockade of astrocyte CD38 activity augmented NAD+ levels, suppressed proinflammatory transcriptional reprogramming, impaired chemotactic potential to inflammatory monocytes, and ameliorated EAE. We found that CD38 activity is mediated via calcineurin/NFAT signaling in mouse and human reactive astrocytes. Thus, NAMPT-NAD+-CD38 circuitry in astrocytes controls their ability to meet their energy demands and drives the expression of proinflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, MS. Our results identify candidate therapeutic targets in MS.

Keywords:  Nicotinamide adenine dinucleotide; astrocyte; multiple sclerosis; neuroinflammation; tryptophan catabolism

DOI:  https://doi.org/10.1073/pnas.2211310119
Aging Cell. 2022 Aug 23. e13682

Metabolomic and transcriptomic signatures of influenza vaccine response in healthy young and older adults.

Chih-Hung Chou, Subhasis Mohanty, Heather A Kang, Lingjia Kong, Julian Avila-Pacheco, Samit R Joshi, Ikuyo Ueda, Lesley Devine, Khadir Raddassi, Kerry Pierce, Sarah Jeanfavre, Kevin Bullock, Hailong Meng, Clary Clish, Fabio R Santori, Albert C Shaw, Ramnik J Xavier.

  Seasonal influenza causes mild to severe respiratory infections and significant morbidity, especially in older adults. Transcriptomic analysis in populations across multiple flu seasons has provided insights into the molecular determinants of vaccine response. Still, the metabolic changes that underlie the immune response to influenza vaccination remain poorly characterized. We performed untargeted metabolomics to analyze plasma metabolites in a cohort of younger and older subjects before and after influenza vaccination to identify vaccine-induced molecular signatures. Metabolomic and transcriptomic data were combined to define networks of gene and metabolic signatures indicative of high and low antibody response in these individuals. We observed age-related differences in metabolic baselines and signatures of antibody response to influenza vaccination and the abundance of α-linolenic and linoleic acids, sterol esters, fatty-acylcarnitines, and triacylglycerol metabolism. We identified a metabolomic signature associated with age-dependent vaccine response, finding increased tryptophan and decreased polyunsaturated fatty acids (PUFAs) in young high responders (HRs), while fatty acid synthesis and cholesteryl esters accumulated in older HRs. Integrated metabolomic and transcriptomic analysis shows that depletion of PUFAs, which are building blocks for prostaglandins and other lipid immunomodulators, in young HR subjects at Day 28 is related to a robust immune response to influenza vaccination. Increased glycerophospholipid levels were associated with an inflammatory response in older HRs to flu vaccination. This multi-omics approach uncovered age-related molecular markers associated with influenza vaccine response and provides insight into vaccine-induced metabolic responses that may help guide development of more effective influenza vaccines.

Keywords:  immune response; influenza; metabolomics; systems biology; systems vaccinology; transcriptomics; vaccine

DOI:  https://doi.org/10.1111/acel.13682
Biology (Basel). 2022 Jul 28. pii: 1132. [Epub ahead of print]11(8):

Mitochondrial Ultrastructure and Activity Are Differentially Regulated by Glycolysis-, Krebs Cycle-, and Microbiota-Derived Metabolites in Monocytes.

C Angélica Pérez-Hernández, M Maximina Bertha Moreno-Altamirano, Edgar O López-Villegas, Egle Butkeviciute, Mohammad Ali, Barbara Kronsteiner, Susanna J Dunachie, Hazel M Dockrell, Steven G Smith, F Javier Sánchez-García.

  Several intermediate metabolites harbour cell-signalling properties, thus, it is likely that specific metabolites enable the communication between neighbouring cells, as well as between host cells with the microbiota, pathogens, and tumour cells. Mitochondria, a source of intermediate metabolites, participate in a wide array of biological processes beyond that of ATP production, such as intracellular calcium homeostasis, cell signalling, apoptosis, regulation of immune responses, and host cell-microbiota crosstalk. In this regard, mitochondria's plasticity allows them to adapt their bioenergetics status to intra- and extra-cellular cues, and the mechanisms driving such plasticity are currently a matter of intensive research. Here, we addressed whether mitochondrial ultrastructure and activity are differentially shaped when human monocytes are exposed to an exogenous source of lactate (derived from glycolysis), succinate, and fumarate (Krebs cycle metabolic intermediates), or butyrate and acetate (short-chain fatty acids produced by intestinal microbiota). It has previously been shown that fumarate induces mitochondrial fusion, increases the mitochondrial membrane potential (Δψm), and reshapes the mitochondrial cristae ultrastructure. Here, we provide evidence that, in contrast to fumarate, lactate, succinate, and butyrate induce mitochondrial fission, while acetate induces mitochondrial swelling. These traits, along with mitochondrial calcium influx kinetics and glycolytic vs. mitochondrial ATP-production rates, suggest that these metabolites differentially shape mitochondrial function, paving the way for the understanding of metabolite-induced metabolic reprogramming of monocytes and its possible use for immune-response intervention.

Keywords:  Krebs cycle; glycolysis; innate immunity; mitochondria; mitochondrial reprogramming; short-chain fatty acids

DOI:  https://doi.org/10.3390/biology11081132
FEBS Lett. 2022 Aug 23.

Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors.

Ulrich Stifel, Giorgio Caratti, Jan Tuckermann.

  Regulation of cellular catabolic metabolism in immune cells has recently become a major concept for resolution of inflammation. Nuclear receptors (NRs), including peroxisome proliferator activator receptors (PPARs), 1,25-dihydroxyvitamin D(3) receptor (VDR), liver X receptors (LXRs), glucocorticoid receptors (GRs), estrogen-related receptor α (ERRα) and Nur77, have been identified as major modulators of inflammation, affecting innate immune cells, such as macrophages. Evidence emerges on how NRs regulate cellular metabolism in macrophages during inflammatory processes and contribute to the resolution of inflammation. This could have new implications for our understanding of how NRs shape immune responses and inform anti-inflammatory drug design. This review will highlight the recent developments about NRs and their role in cellular metabolism in macrophages.

Keywords:  Cellular Metabolism; ERRα; GR; Immunometabolism; Inflammation; LXR; Macrophages; Nuclear Receptors; Nur77; PPAR; VDR

DOI:  https://doi.org/10.1002/1873-3468.14474
Metabol Open. 2022 Sep;15 100204

A chromatin remodeling checkpoint of diet-induced macrophage activation in adipose tissue.

Maria Dalamaga, Junli Liu.

  The interplay between the environment and the immune cells is linked to metabolic homeostasis under physiologic and pathophysiologic conditions. Diabetes mellitus type 2 (T2D) is considered an immune-related inflammatory disorder, in which the adipose tissue macrophages (ATMs) are key players orchestrating metabolic chronic meta-inflammation and contributing to the pathogenesis of metabolic disease. However, the molecular regulators that integrate the environmental signals to control ATM activation and adipose inflammation during obesity and T2D remain unclear. Epigenetic mechanisms constitute important parameters in metabolic homeostasis, obesity and T2D via the integration of the environmental factors to the transcriptional regulation of gene programs. In a very recent study published in Diabetes by Kong et al., BAF60a has been identified as a key chromatin remodeling checkpoint factor that associates obesity-associated stress signals with meta-inflammation and systemic homeostasis. Furthermore, this work uncovers Atf3 as an important downstream effector in BAF60a-mediated chromatin remodeling and transcriptional reprogramming of macrophage activation in adipose tissue. The findings of this research may contribute to the development of new therapeutic approaches for obesity-induced metabolic inflammation and associated metabolic disorders.

Keywords:  Adipose tissue; BAF60a; Diabetes; Inflammation; Macrophage; Obesity

DOI:  https://doi.org/10.1016/j.metop.2022.100204
Viruses. 2022 Aug 18. pii: 1813. [Epub ahead of print]14(8):

The Role of Immunometabolism in HIV-1 Pathogenicity: Links to Immune Cell Responses.

Eman Teer, Nyasha C Mukonowenzou, M Faadiel Essop.

  With the successful roll-out of combination antiretroviral treatment, HIV is currently managed as a chronic illness. Of note, immune activation and chronic inflammation are hallmarks of HIV-1 infection that persists even though patients are receiving treatments. Despite strong evidence linking immune activation and low-grade inflammation to HIV-1 pathogenesis, the underlying mechanisms remain less well-understood. As intracellular metabolism is emerging as a crucial factor determining the fate and activity of immune cells, this review article focuses on how links between early immune responses and metabolic reprograming may contribute to HIV pathogenicity. Here, the collective data reveal that immunometabolism plays a key role in HIV-1 pathogenesis. For example, the shift from quiescent immune cells to its activation leads to perturbed metabolic circuits that are major drivers of immune cell dysfunction and an altered phenotype. These findings suggest that immunometabolic perturbations play a key role in the onset of non-AIDS-associated comorbidities and that they represent an attractive target to develop improved diagnostic tools and novel therapeutic strategies to help blunt HIV-1 pathogenesis.

Keywords:  HIV; immunometabolism; inflammation; mitochondria; non-AIDS-associated comorbidities

DOI:  https://doi.org/10.3390/v14081813
Antioxidants (Basel). 2022 Jul 29. pii: 1488. [Epub ahead of print]11(8):

Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages.

Jonathan R Erlich, Eunice E To, Raymond Luong, Felicia Liong, Stella Liong, Osezua Oseghale, Mark A Miles, Steven Bozinovski, Robert D Brooks, Ross Vlahos, Stanley Chan, John J O'Leary, Doug A Brooks, Stavros Selemidis.

  Macrophages undergo a metabolic switch from oxidative phosphorylation to glycolysis when exposed to gram-negative bacterial lipopolysaccharide (LPS), which modulates antibacterial host defence mechanisms. Here, we show that LPS treatment of macrophages increased the classical oxidative burst response via the NADPH oxidase (NOX) 2 enzyme, which was blocked by 2-deoxyglucose (2-DG) inhibition of glycolysis. The inhibition of the pentose phosphate pathway with 6-aminonicotinamide (6-AN) also suppressed the LPS-induced increase in NOX2 activity and was associated with a significant reduction in the mRNA expression of NOX2 and its organizer protein p47phox. Notably, the LPS-dependent enhancement in NOX2 oxidase activity was independent of both succinate and mitochondrial reactive oxygen species (ROS) production. LPS also increased type I IFN-β expression, which was suppressed by 2-DG and 6-AN and, therefore, is dependent on glycolysis and the pentose phosphate pathway. The type I IFN-β response to LPS was also inhibited by apocynin pre-treatment, suggesting that NOX2-derived ROS promotes the TLR4-induced response to LPS. Moreover, recombinant IFN-β increased NOX2 oxidase-dependent ROS production, as well as NOX2 and p47phox expression. Our findings identify a previously undescribed molecular mechanism where both glycolysis and the pentose phosphate pathway are required to promote LPS-induced inflammation in macrophages.

Keywords:  LPS; NADPH oxidase; NOX2; glycolysis; inflammation; macrophages; pentose phosphate pathway; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox11081488
Commun Biol. 2022 Aug 26. 5(1): 878

mTOR regulation of metabolism limits LPS-induced monocyte inflammatory and procoagulant responses.

Nina C Lund, Yetunde Kayode, Melanie R McReynolds, Deanna C Clemmer, Hannah Hudson, Isabelle Clerc, Hee-Kyung Hong, Jason M Brenchley, Joseph Bass, Richard T D'Aquila, Harry E Taylor.

Translocated lipopolysaccharide (LPS) activates monocytes via TLR4 and is hypothesized to increase cardiovascular disease risk in persons living with HIV. We tested whether mTOR activity supports LPS-stimulated monocyte production of pro-inflammatory cytokines and tissue factor (TF), as it propels the inflammatory response in several immune cell types besides monocytes. However, multi-omics analyses here demonstrate that mTOR activates a metabolic pathway that limits abundance of these gene products in monocytes. Treatment of primary human monocytes with catalytic mTOR inhibitors (mTORi) increased LPS-induced polyfunctional responses, including production of IL-1β, IL-6, and the pro-coagulant, TF. NF-κB-driven transcriptional activity is enhanced with LPS stimulation after mTORi treatment to increase expression of F3 (TF). Moreover, intracellular NAD+ availability is restricted due to decreased salvage pathway synthesis. These results document mTOR-mediated restraint of the LPS-induced transcriptional response in monocytes and a metabolic mechanism informing strategies to reverse enhanced risk of coagulopathy in pro-inflammatory states.

DOI: https://doi.org/10.1038/s42003-022-03804-z
Annu Rev Nutr. 2022 Aug 22. 42 67-89

Obesity Dysregulates the Immune Response to Influenza Infection and Vaccination Through Metabolic and Inflammatory Mechanisms.

Saame Raza Shaikh, Nancie J MacIver, Melinda A Beck.

  The COVID-19 pandemic demonstrates that obesity alone, independent of comorbidities, is a significant risk factor for severe outcomes from infection. This susceptibility mirrors a similar pattern with influenza infection; that is, obesity is a unique risk factor for increased morbidity and mortality. Therefore, it is critical to understand how obesity contributes to a reduced ability to respond to respiratory viral infections. Herein, we discuss human and animal studies with influenza infection and vaccination that show obesity impairs immunity. We cover several key mechanisms for the dysfunction. These mechanisms include systemic and cellular level changes that dysregulate immune cell metabolism and function in addition to how obesity promotes deficiencies in metabolites that control the resolution of inflammation and infection. Finally, we discuss major gaps in knowledge, particularly as they pertain to diet and mechanisms, which will drive future efforts to improve outcomes in response to respiratory viral infections in an increasingly obese population.

Keywords:  immunity; influenza; metabolism; obesity; specialized proresolving mediators

DOI:  https://doi.org/10.1146/annurev-nutr-062320-115937
Physiol Rep. 2022 Aug;10(16): e15439

Postbiotics engage IRF4 in adipocytes to promote sex-dependent changes in blood glucose during obesity.

Brittany M Duggan, Anita M Singh, Darryl Y Chan, Jonathan D Schertzer.

  Postbiotics are microbial-derived components or metabolites that can influence host immunity and metabolism. Some postbiotics can improve blood glucose control and lower inflammation during bacterial or nutritional stress. Bacterial cell wall-derived muramyl dipeptide (MDP) is a potent insulin-sensitizing postbiotic that engages NOD2, RIPK2, and requires interferon regulatory factor 4 (IRF4) to lower inflammation and improve blood glucose. However, the sex-dependent effects of this postbiotic and the cell type required for IRF4 to cause inflammatory versus glycemic responses to MDP were unknown. Here, we measured how MDP injection altered glucose tolerance and adipose tissue inflammation during low-level endotoxemia and high fat diet (HFD)-induced obesity in male and female adipocyte-specific IRF4 knockout mice (AdipoIRF4fl/fl ) compared to WTfl/fl mice. Adipocyte IRF4 was required for the blood glucose-lowering effects of MDP during endotoxemia and HFD-induced obesity in male mice. However, MDP did not alter blood glucose in female WTfl/fl and AdipoIRF4fl/f mice during endotoxemia. Unexpectedly, female HFD-fed AdipoIRF4fl/f mice had lower blood glucose after MDP treatment compared to WTfl/fl mice. MDP lowered inflammatory gene expression in adipose tissue of HFD-fed WTfl/fl and AdipoIRF4fl/fl mice of both sexes. Therefore, MDP-mediated lowering of adipose inflammation does not require adipocyte IRF4 and was independent of sex. Together, these data show that injection of MDP, an insulin-sensitizing postbiotic, lowers adipose tissue inflammation in male and female mice, but lower adipose inflammation is not always associated with improved blood glucose. The blood glucose-lowering effect of the postbiotic MDP and dependence on adipocyte IRF4 is sex-dependent.

Keywords:  IRF4; adipocyte; glucose; immunometabolism; insulin; postbiotics

DOI:  https://doi.org/10.14814/phy2.15439
Int J Mol Sci. 2022 Aug 17. pii: 9252. [Epub ahead of print]23(16):

Macrophage Polarization Mediated by Mitochondrial Dysfunction Induces Adipose Tissue Inflammation in Obesity.

Long Xu, Xiaoyu Yan, Yuanxin Zhao, Jian Wang, Buhan Liu, Sihang Yu, Jiaying Fu, Yanan Liu, Jing Su.

  Obesity is one of the prominent global health issues, contributing to the growing prevalence of insulin resistance and type 2 diabetes. Chronic inflammation in adipose tissue is considered as a key risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. Macrophages are the most abundant immune cells in adipose tissue and play an important role in adipose tissue inflammation. Mitochondria are critical for regulating macrophage polarization, differentiation, and survival. Changes to mitochondrial metabolism and physiology induced by extracellular signals may underlie the corresponding state of macrophage activation. Macrophage mitochondrial dysfunction is a key mediator of obesity-induced macrophage inflammatory response and subsequent systemic insulin resistance. Mitochondrial dysfunction drives the activation of the NLRP3 inflammasome, which induces the release of IL-1β. IL-1β leads to decreased insulin sensitivity of insulin target cells via paracrine signaling or infiltration into the systemic circulation. In this review, we discuss the new findings on how obesity induces macrophage mitochondrial dysfunction and how mitochondrial dysfunction induces NLRP3 inflammasome activation. We also summarize therapeutic approaches targeting mitochondria for the treatment of diabetes.

Keywords:  NLRP3 inflammasome; adipose tissue inflammation; insulin resistance; mitochondrial dysfunction; obesity

DOI:  https://doi.org/10.3390/ijms23169252
Trends Endocrinol Metab. 2022 Aug 20. pii: S1043-2760(22)00136-9. [Epub ahead of print]

Understanding lactate sensing and signalling.

Michelangelo Certo, Alba Llibre, Wheeseong Lee, Claudio Mauro.

  Metabolites generated from cellular and tissue metabolism have been rediscovered in recent years as signalling molecules. They may act as cofactor of enzymes or be linked to proteins as post-translational modifiers. They also act as ligands for specific receptors, highlighting that their neglected functions have, in fact, a long standing in evolution. Lactate is one such metabolite that has been considered for long time a waste product of metabolism devoid of any biological function. However, in the past 10 years, lactate has gained much attention in several physio-pathological processes. Mechanisms of sensing and signalling have been discovered and implicated in a broad range of diseases, from cancer to inflammation and fibrosis, providing opportunities for novel therapeutic avenues. Here, we review some of the most recently discovered mechanisms of lactate sensing and signalling.

Keywords:  G protein-coupled receptor; acidity; lactylation; metabolic reprogramming

DOI:  https://doi.org/10.1016/j.tem.2022.07.004
Front Immunol. 2022 ;13 909580

Metabolic rewiring directs melanoma immunology.

Ningyue Sun, Yangzi Tian, Yuhan Chen, Weinan Guo, Chunying Li.

  Melanoma results from the malignant transformation of melanocytes and accounts for the most lethal type of skin cancers. In the pathogenesis of melanoma, disordered metabolism is a hallmark characteristic with multiple metabolic paradigms involved in, e.g., glycolysis, lipid metabolism, amino acid metabolism, oxidative phosphorylation, and autophagy. Under the driving forces of oncogenic mutations, melanoma metabolism is rewired to provide not only building bricks for macromolecule synthesis and sufficient energy for rapid proliferation and metastasis but also various metabolic intermediates for signal pathway transduction. Of note, metabolic alterations in tumor orchestrate tumor immunology by affecting the functions of surrounding immune cells, thereby interfering with their antitumor capacity, in addition to the direct influence on tumor cell intrinsic biological activities. In this review, we first introduced the epidemiology, clinical characteristics, and treatment proceedings of melanoma. Then, the components of the tumor microenvironment, especially different populations of immune cells and their roles in antitumor immunity, were reviewed. Sequentially, how metabolic rewiring contributes to tumor cell malignant behaviors in melanoma pathogenesis was discussed. Following this, the proceedings of metabolism- and metabolic intermediate-regulated tumor immunology were comprehensively dissertated. Finally, we summarized currently available drugs that can be employed to target metabolism to intervene tumor immunology and modulate immunotherapy.

Keywords:  glycolysis; immunology; immunotherapy; melanoma; metabolism

DOI:  https://doi.org/10.3389/fimmu.2022.909580
Int J Mol Sci. 2022 Aug 14. pii: 9069. [Epub ahead of print]23(16):

Influence of Microbial Metabolites and Itaconic Acid Involved in Bacterial Inflammation on the Activity of Mitochondrial Enzymes and the Protective Role of Alkalization.

Nadezhda Fedotcheva, Natalia Beloborodova.

  Human microbiota produces metabolites that may enter the bloodstream and exert systemic influence on various functions including mitochondrial. Mitochondria are not only a target for microbial metabolites, but also themselves, due to the inhibition of several enzymes, produce metabolites involved in infectious processes and immune response. The influence of indolic acids, microbial derivatives of tryptophan, as well as itaconic acid, formed in the tricarboxylic acid cycle under the action of bacterial lipopolysaccharides, on the activity of mitochondrial enzymes was studied by methyl thiazolyl tetrazolium (MTT), dichlorophenolindophenol (DCPIP) and pyridine nucleotide fluorescence assays. Thus, it was found that indolic acids suppressed succinate and glutamate oxidation, shifting the redox potential of pyridine nucleotides to a more oxidized state. Itaconic acid, in addition to the well-known inhibition of succinate oxidation, also decreased NAD reduction in reactions with glutamate as a substrate. Unlike itaconic acid, indolic acids are not direct inhibitors of succinate dehydrogenase and glutamate dehydrogenase as their effects could be partially eliminated by the thiol antioxidant dithiothreitol (DTT) and the scavenger of lipid radicals butyl-hydroxytoluene (BHT). Alkalization turned out to be the most effective means to decrease the action of these metabolites, including itaconic acid, which is due to the protective influence on redox-dependent processes. Thus, among mitochondrial oxidative enzymes, the most accessible targets of these microbial-related metabolites are succinate dehydrogenase and glutamate dehydrogenase. These are important in the context of the shifting of metabolic pathways involved in bacterial inflammation and sepsis as well as the detection of new markers of these pathologies.

Keywords:  acidosis; biomarkers; glutamate; inflammation; itaconic acid; microbial metabolites; mitochondrial dysfunction; succinate

DOI:  https://doi.org/10.3390/ijms23169069
Biochim Biophys Acta Mol Basis Dis. 2022 Aug 22. pii: S0925-4439(22)00198-3. [Epub ahead of print] 166527

Epigenetic perspectives of COVID-19: Virus infection to disease progression and therapeutic control.

Samir Kumar Patra, Moshe Szyf.

  COVID-19 has caused numerous deaths as well as imposed social isolation and upheaval world-wide. Although, the genome and the composition of the virus, the entry process and replication mechanisms are well investigated from by several laboratories across the world, there are many unknown remaining questions. For example, what are the functions of membrane lipids during entry, packaging and exit of virus particles? Also, the metabolic aspects of the infected tissue cells are poorly understood. In the course of virus replication and formation of virus particles within the host cell, the enhanced metabolic activities of the host is directly proportional to viral loads. The epigenetic landscape of the host cells is also altered, particularly the expression/repression of genes associated with cellular metabolism as well as cellular processes that are antagonistic to the virus. Metabolic pathways are enzyme driven processes and the expression profile and mechanism of regulations of the respective genes encoding those enzymes during the course of pathogen invasion might be highly informative on the course of the disease. Recently, the metabolic profile of the patients' sera have been analysed from few patients. In view of this, and to gain further insights into the roles that epigenetic mechanisms might play in this scenario in regulation of metabolic pathways during the progression of COVID-19 are discussed and summarised in this contribution for ensuring best therapy.

Keywords:  ACE2; Autophagy; COVID-19; Cellular metabolism; Epigenetics; IL-6; Methionine; Ribosome; S-adenosylmethionine; SARS-CoV-2; rDNA

DOI:  https://doi.org/10.1016/j.bbadis.2022.166527
Front Immunol. 2022 ;13 956876

Editorial: T cell metabolism in infection.

Jin-Fu Xu, Ying-Zhou Xie, Duo-Jiao Wu.



Keywords:  T cell; Tfh; infection; metabolism; therapeutics

DOI:  https://doi.org/10.3389/fimmu.2022.956876
PLoS Biol. 2022 Aug 26. 20(8): e3001516

Macrophages take up VLDL-sized emulsion particles through caveolae-mediated endocytosis and excrete part of the internalized triglycerides as fatty acids.

Lei Deng, Frank Vrieling, Rinke Stienstra, Guido J Hooiveld, Anouk L Feitsma, Sander Kersten.

Triglycerides are carried in the bloodstream as part of very low-density lipoproteins (VLDLs) and chylomicrons, which represent the triglyceride-rich lipoproteins. Triglyceride-rich lipoproteins and their remnants contribute to atherosclerosis, possibly by carrying remnant cholesterol and/or by exerting a proinflammatory effect on macrophages. Nevertheless, little is known about how macrophages process triglyceride-rich lipoproteins. Here, using VLDL-sized triglyceride-rich emulsion particles, we aimed to study the mechanism by which VLDL triglycerides are taken up, processed, and stored in macrophages. Our results show that macrophage uptake of VLDL-sized emulsion particles is dependent on lipoprotein lipase (LPL) and requires the lipoprotein-binding C-terminal domain but not the catalytic N-terminal domain of LPL. Subsequent internalization of VLDL-sized emulsion particles by macrophages is carried out by caveolae-mediated endocytosis, followed by triglyceride hydrolysis catalyzed by lysosomal acid lipase. It is shown that STARD3 is required for the transfer of lysosomal fatty acids to the ER for subsequent storage as triglycerides, while NPC1 likely is involved in promoting the extracellular efflux of fatty acids from lysosomes. Our data provide novel insights into how macrophages process VLDL triglycerides and suggest that macrophages have the remarkable capacity to excrete part of the internalized triglycerides as fatty acids.

DOI: https://doi.org/10.1371/journal.pbio.3001516
Virulence. 2022 Dec;13(1): 1407-1422

SLC1A3 facilitates Newcastle disease virus replication by regulating glutamine catabolism.

Panrao Liu, Ning Tang, Chunchun Meng, Yuncong Yin, Xusheng Qiu, Lei Tan, Yingjie Sun, Cuiping Song, Weiwei Liu, Ying Liao, Shu-Hai Lin, Chan Ding.

  As obligate intracellular parasites, viruses rely completely on host metabolic machinery and hijack host nutrients for viral replication. Newcastle disease virus (NDV) causes acute, highly contagious avian disease and functions as an oncolytic agent. NDV efficiently replicates in both chicken and tumour cells. However, how NDV reprograms host cellular metabolism for its efficient replication is still ill-defined. We previously identified a significantly upregulated glutamate transporter gene, solute carrier family 1 member 3 (SLC1A3), during NDV infection via transcriptome analysis. To investigate the potential role of SLC1A3 during NDV infection, we first confirmed the marked upregulation of SLC1A3 in NDV-infected DF-1 or A549 cells through p53 and NF-κB pathways. Knockdown of SLC1A3 inhibited NDV infection. Western blot analysis further confirmed that glutamine, but not glutamate, asparagine, or aspartate, was required for NDV replication. Metabolic flux data showed that NDV promotes the decomposition of glutamine into the tricarboxylic acid cycle. Importantly, the level of glutamate and glutaminolysis were reduced by SLC1A3 knockdown, indicating that SLC1A3 propelled glutaminolysis for glutamate utilization and NDV replication in host cells. Taken together, our data identify that SLC1A3 serves as an important regulator for glutamine metabolism and is hijacked by NDV for its efficient replication during NDV infection. These results improve our understanding of the interaction between NDV and host cellular metabolism and lay the foundation for further investigation of efficient vaccines.

Keywords:  Infection; Newcastle disease virus; SLC1A3; glutaminolysis; host

DOI:  https://doi.org/10.1080/21505594.2022.2112821
Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2116505119

Blocking CHOP-dependent TXNIP shuttling to mitochondria attenuates albuminuria and mitigates kidney injury in nephrotic syndrome.

Sun-Ji Park, Yeawon Kim, Chuang Li, Junwoo Suh, Jothilingam Sivapackiam, Tassia M Goncalves, George Jarad, Guoyan Zhao, Fumihiko Urano, Vijay Sharma, Ying Maggie Chen.

  Albuminuria is a hallmark of glomerular disease of various etiologies. It is not only a symptom of glomerular disease but also a cause leading to glomerulosclerosis, interstitial fibrosis, and eventually, a decline in kidney function. The molecular mechanism underlying albuminuria-induced kidney injury remains poorly defined. In our genetic model of nephrotic syndrome (NS), we have identified CHOP (C/EBP homologous protein)-TXNIP (thioredoxin-interacting protein) as critical molecular linkers between albuminuria-induced ER dysfunction and mitochondria dyshomeostasis. TXNIP is a ubiquitously expressed redox protein that binds to and inhibits antioxidant enzyme, cytosolic thioredoxin 1 (Trx1), and mitochondrial Trx2. However, very little is known about the regulation and function of TXNIP in NS. By utilizing Chop-/- and Txnip-/- mice as well as 68Ga-Galuminox, our molecular imaging probe for detection of mitochondrial reactive oxygen species (ROS) in vivo, we demonstrate that CHOP up-regulation induced by albuminuria drives TXNIP shuttling from nucleus to mitochondria, where it is required for the induction of mitochondrial ROS. The increased ROS accumulation in mitochondria oxidizes Trx2, thus liberating TXNIP to associate with mitochondrial nod-like receptor protein 3 (NLRP3) to activate inflammasome, as well as releasing mitochondrial apoptosis signal-regulating kinase 1 (ASK1) to induce mitochondria-dependent apoptosis. Importantly, inhibition of TXNIP translocation and mitochondrial ROS overproduction by CHOP deletion suppresses NLRP3 inflammasome activation and p-ASK1-dependent mitochondria apoptosis in NS. Thus, targeting TXNIP represents a promising therapeutic strategy for the treatment of NS.

Keywords:  CHOP; ER stress; TXNIP; Trx2; mitochondria

DOI:  https://doi.org/10.1073/pnas.2116505119
Sleep Med Rev. 2022 Aug 11. pii: S1087-0792(22)00081-8. [Epub ahead of print]65 101668

Immunometabolism: An evolutionary perspective in obstructive sleep apnea.

Mohit, Ankit Pateriya, Manendra Singh Tomar, Ashutosh Shrivastava, Pooran Chand.



Keywords:  Immune system; Immunometabolism; Intermittent hypoxia; Metabolic disorders; Obstructive sleep apnea

DOI:  https://doi.org/10.1016/j.smrv.2022.101668
Cell Rep. 2022 Aug 23. pii: S2211-1247(22)01073-7. [Epub ahead of print]40(8): 111255

Macrophages and neutrophils are necessary for ER stress-induced β cell loss.

Bingyuan Yang, Liu Yang, Yueyang Wang, Lisette A Maddison, Zihan Tang, Sander Haigh, Yulong Gong, Yue Zhang, Brittney A Covington, Karin J Bosma, Xin Tong, Patrick Page-McCaw, Maureen Gannon, Qing Deng, Wenbiao Chen.

  Persistent endoplasmic reticulum (ER) stress induces islet inflammation and β cell loss. How islet inflammation contributes to β cell loss remains uncertain. We have reported previously that chronic overnutrition-induced ER stress in β cells causes Ripk3-mediated islet inflammation, macrophage recruitment, and a reduction of β cell numbers in a zebrafish model. We show here that β cell loss results from the intricate communications among β cells, macrophages, and neutrophils. Macrophage-derived Tnfa induces cxcl8a in β cells. Cxcl8a, in turn, attracts neutrophils to macrophage-contacted "hotspots" where β cell loss occurs. We also show potentiation of chemokine expression in stressed mammalian β cells by macrophage-derived TNFA. In Akita and db/db mice, there is an increase in CXCL15-positive β cells and intra-islet neutrophils. Blocking neutrophil recruitment in Akita mice preserves β cell mass and slows diabetes progression. These results reveal an important role of neutrophils in persistent ER stress-induced β cell loss.

Keywords:  CP; ER stress; Metabolism; diabetes; islet inflammation; macrophages; neutrophils; overnutrition; zebrafish; β cell loss

DOI:  https://doi.org/10.1016/j.celrep.2022.111255
Front Immunol. 2022 ;13 918241

DMGV Is a Rheostat of T Cell Survival and a Potential Therapeutic for Inflammatory Diseases and Cancers.

Fengyuan Mandy Yang, Liya Shen, Dengxia Denise Fan, Kuan-Hung Chen, Jongdae Lee.

  Activated effector T cells (Teff) and/or compromised regulatory T cells (Treg) underlie many chronic inflammatory diseases. We discovered a novel pathway to regulate survival and expansion of Teff without compromising Treg survival and a potential therapeutic to treat these diseases. We found dimethylguanidino valeric acid (DMGV) as a rheostat for Teff survival: while cell-intrinsic DMGV generated by Alanine-Glyoxylate Aminotransferase 2 (AGXT2) is essential for survival and expansion by inducing mitochondrial ROS and regulation of glycolysis, an excessive (or exogenous) DMGV level inhibits activated Teff survival, thereby the AGXT2-DMGV-ROS axis functioning as a switch to turn on and off Teff expansion. DMGV-induced ROS is essential for glycolysis in Teff, and paradoxically DMGV induces ROS only when glycolysis is active. Mechanistically, DMGV rapidly activates mitochondrial calcium uniporter (MCU), causing a surge in mitochondrial Ca2+ without provoking calcium influx to the cytosol. The mitochondrial Ca2+ surge in turn triggers the mitochondrial Na+/Ca2+ exchanger (NCLX) and the subsequent mitochondrial Na+ import induces ROS by uncoupling the Coenzyme Q cycle in Complex III of the electron transport chain. In preclinical studies, DMGV administration significantly diminished the number of inflammatory T cells, effectively suppressing chronic inflammation in mouse models of colitis and rheumatoid arthritis. DMGV also suppressed expansion of cancer cells in vitro and in a mouse T cell leukemic model by the same mechanism. Our data provide a new pathway regulating T cell survival and a novel mode to treat autoimmune diseases and cancers.

Keywords:  ADMA; AGXT2; DMGV; MCU; NLCX ; SDMA

DOI:  https://doi.org/10.3389/fimmu.2022.918241
Mol Cell Biochem. 2022 Aug 27.

Multi-omics analysis identifies potential mechanisms by which high glucose accelerates macrophage foaming.

Jie Qi, Ying Lv, Ni-Er Zhong, Wen-Qi Han, Qi-Ling Gou, Chao-Feng Sun.

  Atherosclerotic morbidity is significantly higher in the diabetic population. Hyperglycemia, a typical feature of diabetes, has been proven to accelerate foam cell formation. However, the molecular mechanisms behind this process remain unclear. In this study, LPS and IFN-γ were used to convert THP-1-derived macrophages into M1 macrophages, which were then activated with ox-LDL in either high glucose or normal condition. We identified lipids within macrophages by Oil red O staining and total cholesterol detection. The genes involved in lipid absorption, efflux, inflammation, and metabolism were analyzed using qRT-PCR. The mechanisms of high glucose-induced foam cell formation were further investigated through metabolomics and transcriptomics analysis. We discovered that high glucose speed up lipid accumulation in macrophages (both lipid droplets and total cholesterol increased), diminished lipid efflux (ABCG1 down-regulation), and aggravated inflammation (IL1B and TNF up-regulation). Following multi-omics analysis, it was determined that glucose altered the metabolic and transcriptional profiles of macrophages, identifying 392 differently expressed metabolites and 293 differentially expressed genes, respectively. Joint pathway analysis suggested that glucose predominantly disrupted the glycerolipid, glycerophospholipid, and arachidonic acid metabolic pathways in macrophages. High glucose in the glyceride metabolic pathway, for instance, suppressed the transcription of triglyceride hydrolase (LIPG and LPL), causing cells to deposit excess triglycerides into lipid droplets and encouraging foam cell formation. More importantly, high glucose triggered the accumulation of pro-atherosclerotic lipids (7-ketocholesterol, lysophosphatidylcholine, and glycerophosphatidylcholine). In conclusion, this work elucidated mechanisms of glucose-induced foam cell formation via a multi-omics approach.

Keywords:  Foam cell formation; High glucose; Lipid metabolism disorders; Sequence analysis

DOI:  https://doi.org/10.1007/s11010-022-04542-w
Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2209729119

Malaria parasite evades mosquito immunity by glutaminyl cyclase-mediated posttranslational protein modification.

Surendra Kumar Kolli, Alvaro Molina-Cruz, Tamasa Araki, Fiona J A Geurten, Jai Ramesar, Severine Chevalley-Maurel, Hans J Kroeze, Sascha Bezemer, Clarize de Korne, Roxanne Withers, Nadia Raytselis, Angela F El Hebieshy, Robbert Q Kim, Matthew A Child, Soichiro Kakuta, Hajime Hisaeda, Hirotaka Kobayashi, Takeshi Annoura, Paul J Hensbergen, Blandine M Franke-Fayard, Carolina Barillas-Mury, Ferenc A Scheeren, Chris J Janse.

  Glutaminyl cyclase (QC) modifies N-terminal glutamine or glutamic acid residues of target proteins into cyclic pyroglutamic acid (pGlu). Here, we report the biochemical and functional analysis of Plasmodium QC. We show that sporozoites of QC-null mutants of rodent and human malaria parasites are recognized by the mosquito immune system and melanized when they reach the hemocoel. Detailed analyses of rodent malaria QC-null mutants showed that sporozoite numbers in salivary glands are reduced in mosquitoes infected with QC-null or QC catalytically dead mutants. This phenotype can be rescued by genetic complementation or by disrupting mosquito melanization or phagocytosis by hemocytes. Mutation of a single QC-target glutamine of the major sporozoite surface protein (circumsporozoite protein; CSP) of the rodent parasite Plasmodium berghei also results in melanization of sporozoites. These findings indicate that QC-mediated posttranslational modification of surface proteins underlies evasion of killing of sporozoites by the mosquito immune system.

Keywords:  glutaminyl cyclase; immune evasion; melanization; pyroglutamic acid; sporozoite

DOI:  https://doi.org/10.1073/pnas.2209729119
Methods Enzymol. 2022 ;pii: S0076-6879(22)00167-7. [Epub ahead of print]674 363-389

Development and validation of a method to deliver vitamin A to macrophages.

Pooja Acharya, Molly Black, Glenn Bressner, Jaume Amengual.

  Macrophages are critical players in the development of atherosclerotic lesions, where they promote local and systemic inflammation. Macrophages engulf lipoproteins and cell debris upon entry into the arterial wall, becoming lipid-laden foam cells. While most lipids found in foam cells are triglyceride and cholesterol, these cells accumulate several other lipids with bioactive properties, such as vitamin A and carotenoids. Vitamin A has strong immunomodulatory actions in macrophages and other immune cells. For example, macrophages release vitamin A as retinoic acid to modulate T cell differentiation, but the implication of intracellular vitamin A stores in this process remains elusive due to the lack of an adequate experimental model to load vitamin A into macrophages. The purpose of this study was to develop a reliable method to deliver vitamin A to cultured murine macrophages. Our results show that thioglycolate-elicited peritoneal macrophages fail to take up significant levels of vitamin A when provided as free retinol. Cultured macrophages and macrophages in the peritoneal cavity can take up retinyl esters, either as retinyl ester-loaded serum or retinyl esters infused directly into the peritoneal cavity. HPLC analyses in macrophage lysates revealed that the intraperitoneal injection method results in a fourfold greater vitamin A loading efficiency than retinyl ester-loaded serum added to cultured cells. These two alternative methods provide an efficient and reliable methodology to load macrophages with vitamin A for downstream applications such as studies of gene regulation trafficking of intracellular vitamin A, and vitamin A release from macrophages.

Keywords:  Atherosclerosis; Cardiovascular disease; Chylomicrons; Retinoic acid; Retinoids

DOI:  https://doi.org/10.1016/bs.mie.2022.04.008
Int J Mol Sci. 2022 Aug 14. pii: 9114. [Epub ahead of print]23(16):

Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release.

Rafael I Jaén, Adrián Povo-Retana, César Rosales-Mendoza, Patricia Capillas-Herrero, Sergio Sánchez-García, Paloma Martín-Sanz, Marina Mojena, Patricia Prieto, Lisardo Boscá.

  Atherosclerosis is a cardiovascular disease caused mainly by dyslipidemia and is characterized by the formation of an atheroma plaque and chronic inflammation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that induces the degradation of the LDL receptor (LDLR), which contributes to increased levels of LDL cholesterol and the progress of atherosclerosis. Given that macrophages are relevant components of the lipidic and inflammatory environment of atherosclerosis, we studied the effects of PCSK9 treatment on human macrophages. Our data show that human macrophages do not express PCSK9 but rapidly incorporate the circulating protein through the LDLR and also activate the pro-inflammatory TLR4 pathway. Both LDLR and TLR4 are internalized after incubation of macrophages with exogenous PCSK9. PCSK9 uptake increases the production of reactive oxygen species and reduces the expression of genes involved in lipid metabolism and cholesterol efflux, while enhancing the production of pro-inflammatory cytokines through a TLR4-dependent mechanism. Under these conditions, the viability of macrophages is compromised, leading to increased cell death. These results provide novel insights into the role of PCSK9 in the crosstalk of lipids and cholesterol metabolism through the LDLR and on the pro-inflammatory activation of macrophages through TLR4 signaling. These pathways are relevant in the outcome of atherosclerosis and highlight the relevance of PCSK9 as a therapeutic target for the treatment of cardiovascular diseases.

Keywords:  LDL; PCSK9; ROS; TLR4; atherosclerosis; cholesterol; macrophage

DOI:  https://doi.org/10.3390/ijms23169114
Hypertension. 2022 Aug 22. 101161HYPERTENSIONAHA12219244

Trophoblast-Derived Extracellular Vesicles Promote Preeclampsia by Regulating Macrophage Polarization.

Xiu Liu, Haiyi Fei, Cuiyu Yang, Jianmin Wang, Xiaohong Zhu, Anran Yang, Zhan Shi, Xiaoying Jin, Fei Yang, Dan Wu, Lingling Jiang, Songying Zhang.

   BACKGROUND: Systemic inflammation caused by dysfunctional macrophages is a crucial pathogenetic event in preeclampsia (PE). Trophoblast-derived extracellular vesicles (T-EVs) are potent immune cell signaling modulators in pregnancy. Herein, we aimed to investigate T-EVs' effect and mechanism on macrophage polarization and its role in PE pathogenesis, which remain unclear.
METHODS AND RESULTS: Using flow cytometry and immunochemistry, we confirmed that macrophages shift from the M2 to M1 phenotype in preeclamptic placenta. Also, we immuno-isolated placental T-EVs via placental alkaline phosphatase antibody and observed that PLAP+EVs from women with PE (PE-EVs) significantly upregulated M1 gene markers, such as IL (interleukin)-1β, IL-6, and TNF (tumor necrosis factor) α, and significantly downregulated CD163 expression in macrophages compared with those in women with normal pregnancies (NP-EVs).To explore how T-EVs modulate macrophages, correlation analysis with T-EVs lipidome and the transcriptome of macrophages treated with PE-EVs or normal pregnancies-EVs were performed, which indicated that 37 lipids altered in PE-EVs considerably affected classical inflammatory biological pathways, such as TNF and NF-kB signaling pathways in macrophages. Subsequently, by establishing animal models with PE-EVs with or without macrophage depletion, we found that PE-EVs triggered PE-like symptoms in pregnant mice, but this effect was alleviated after macrophage depletion.
CONCLUSIONS: Our data demonstrated that T-EVs from women with PE could promote preeclampsia by inducing macrophage imbalance polarization, signifying a potential novel interventional target for the prevention and management of PE.

Keywords:  extracellular vesicles; lipidomic analysis; macrophage polarization; placenta/trophoblast-derived; preeclampsia

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.122.19244
Cell Signal. 2022 Aug 20. pii: S0898-6568(22)00203-0. [Epub ahead of print]99 110441

Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl) homoserine lactone induces calcium signaling-dependent crosstalk between autophagy and apoptosis in human macrophages.

Ankit Kushwaha, Rama Shanker Verma, Vishnu Agarwal.

  N-(3-oxododecanoyl) homoserine lactone (3oc) is a Pseudomonas aeruginosa secreted quorum-sensing signal molecule playing a crucial role in regulating quorum-sensing (QS) dependent biofilm formation and secretion of virulence factors. In addition to regulating quorum sensing, 3oc also plays an immunomodulatory role in the host by triggering regulated cell death in immune cells. The molecular mechanisms of 3oc in modulating macrophage pathologies are still unclear. In this study, we hypothesized the novel 3oc mediated crosstalk between autophagy and apoptosis at the interphase of calcium signaling in human macrophages. The study showed that 3oc induces mitochondrial dysfunction and apoptosis in macrophages through elevating cytosolic Ca+2 ([Ca+2]cyt) levels. Pre-treatment with the calcium-specific chelator BAPTA-AM effectively abrogated 3oc-induced apoptotic events, like mitochondrial ROS generation (mROS), mitochondrial membrane potential (MMP) drop, and phosphatidylserine (PS) exposure. The study also showed that 3oc induces autophagy, as assessed by the accumulation of autophagic vacuoles, induction of lysosomal biogenesis, upregulation of autophagy genes (LC3, BECLIN 1, STX17, PINK1, and TFEB), autophagosomes formation, and LC3 lipidation. Mechanistically, our study proved that 3oc-induced autophagy was [Ca+2]cyt dependent as BAPTA-AM pre-treatment reduced autophagosome formation. Furthermore, inhibiting autophagy with chloroquine attenuated 3oc-induced apoptosis, while autophagy induction with rapamycin aggravated cell death, suggesting autophagy plays a role in cell death in 3oc-treated macrophages. In conclusion, our findings indicate that 3oc activates a multifaceted death signaling by activating autophagy and apoptosis through Ca+2 signaling, and we propose pharmacological modulation of Ca+2 signaling may act as a combinatorial therapeutic intervention in patients with Pseudomonas aeruginosa-associated infections.

Keywords:  Apoptosis; Autophagy; Calcium signaling; N-(3-oxododecanoyl) homoserine lactone; Pseudomonas aeruginosa

DOI:  https://doi.org/10.1016/j.cellsig.2022.110441