bims-inonme Biomed News
on Immunometabolites, oncometabolites and other metabolites in immune signaling and disease
Issue of 2021‒10‒03
thirty-six papers selected by
Jan Van den Bossche
Amsterdam University Medical Centre
  1. Alpha-Ketoglutarate: A Potential Inner Mitochondrial and Cytosolic Protector against Peroxynitrite and Peroxynitrite-Induced Nitration?
  2. Identifying metabolic alterations in newly diagnosed small cell lung cancer patients.
  3. Breaking the cycle: Succinate in aortic diseases.
  4. Tryptophan: From Diet to Cardiovascular Diseases.
  5. Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis.
  6. Metabolic Hormones Modulate Macrophage Inflammatory Responses.
  7. Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism.
  8. LPS Induces Opposing Memory-like Inflammatory Responses in Mouse Bone Marrow Neutrophils.
  9. Adipose Tissue Immunometabolism and Apoptotic Cell Clearance.
  10. The AhR ligand 2, 2'-aminophenyl indole (2AI) regulates microglia homeostasis and reduces pro-inflammatory signaling.
  11. BiG-MAP: an Automated Pipeline To Profile Metabolic Gene Cluster Abundance and Expression in Microbiomes.
  12. Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled.
  13. Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage.
  14. Crosstalk between Metabolic Disorders and Immune Cells.
  15. High mutations in fatty acid metabolism contribute to a better prognosis of small-cell lung cancer patients treated with chemotherapy.
  16. The modified mitochondrial outer membrane carrier MTCH2 links mitochondrial fusion to lipogenesis.
  17. The Role of Tricarboxylic Acid Cycle Metabolites in Viral Infections.
  18. Galectins in Cancer and the Microenvironment: Functional Roles, Therapeutic Developments, and Perspectives.
  19. Transcriptome profiling reveals new insights into the roles of neuronal nitric oxide synthase on macrophage polarization towards classically activated phenotype.
  20. The Role of Interleukin 1β in the Pathogenesis of Lung Cancer.
  21. Glucose availability limits microglial nitric oxide production.
  22. Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines.
  23. Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells.
  24. Loss of mTORC2-induced metabolic reprogramming in monocytes uncouples migration and maturation from production of proinflammatory mediators.
  25. Integrated Metabolomics and Transcriptomics Analyses Reveal Histidine Metabolism Plays an Important Role in Imiquimod-Induced Psoriasis-like Skin Inflammation.
  26. Early-Released Interleukin-10 Significantly Inhibits Lipopolysaccharide-Elicited Neuroinflammation In Vitro.
  27. Mammalian SIRT6 Represses Invasive Cancer Cell Phenotypes through ATP Citrate Lyase (ACLY)-Dependent Histone Acetylation.
  28. Cytokine exposure mediates transcriptional activation of the orphan nuclear receptor Nur77 in hematopoietic cells.
  29. Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma.
  30. Roles of Skeletal Muscle-Derived Exosomes in Organ Metabolic and Immunological Communication.
  31. CAMKK2 regulates mitochondrial function by controlling succinate dehydrogenase expression, post-translational modification, megacomplex assembly, and activity in a cell-type-specific manner.
  32. Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis.
  33. Glyoxal-Lysine Dimer, an Advanced Glycation End Product, Induces Oxidative Damage and Inflammatory Response by Interacting with RAGE.
  34. MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence.
  35. LSD1 Facilitates Pro-Inflammatory Polarization of Macrophages by Repressing Catalase.
  36. Obesity Promotes Tumor Immune Evasion in Ovarian Cancer Through Increased Production of Myeloid-Derived Suppressor Cells via IL-6.
  1. Antioxidants (Basel). 2021 Sep 21. pii: 1501. [Epub ahead of print]10(9):
    Alpha-Ketoglutarate: A Potential Inner Mitochondrial and Cytosolic Protector against Peroxynitrite and Peroxynitrite-Induced Nitration?
    Joachim Greilberger, Michaela Greilberger, Reinhold Wintersteiger, Klaus Zangger, Ralf Herwig.
      The generation of peroxynitrite (ONOO-) is associated with several diseases, including atherosclerosis, hypertension, neurodegeneration, cancer, inflammation, and sepsis. Alpha-ketoglutarate (αKG) is a known potential highly antioxidative agent for radical oxidative species such as peroxides. The question arises as to whether αKG is also a potential scavenger of ONOO- and a potential protector against ONOO--mediated nitration of proteins. NMR studies of 1 mM αKG in 100 mM phosphate-buffered saline at pH 7.4 and pH 6.0 were carried out in the presence or absence of a final concentration of 2 mM ONOO-. An ONOO--luminol-induced chemiluminescence reaction was used to measure the scavenging function of several concentrations of αKG; quantification of αKG was performed via spectrophotometric enzymatic assay of αKG in the absence or presence of 0, 1, or 2 mM ONOO-. The nitration of tyrosine residues on proteins was measured on ONOO--treated bovine serum albumin (BSA) in the presence or absence of 0-24 mM αKG by an ELISA technique using a specific anti-IgG against nitro-tyrosine. The addition of ONOO- to αKG led to the formation of succinic acid and nitrite at pH 7.0, but not at pH 6.0, as αKG was stable against ONOO-. The absorbance of enzymatically estimated αKG at the time point of 30 min was significantly lower in favour of ONOO- (1 mM: 0.21 ± 0.03, 2 mM: 0.12 ± 0.05 vs. 0 mM: 0.32 ± 0.02; p < 0.001). The luminol technique showed an inverse logarithmic correlation of the ONOO- and αKG concentrations (y = -2 × 105 ln(x) + 1 × 106; r2 = 0.99). The usage of 4 mM αKG showed a significant reduction by nearly half in the chemiluminescence signal (284,456 ± 29,293 cps, p < 0.001) compared to the control (474,401 ± 18,259); for 20 and 200 mM αKG, there were further reductions to 163,546 ± 26,196 cps (p < 0.001) and 12,658 ± 1928 cps (p < 0.001). Nitrated tyrosine residues were estimated using the ELISA technique. A negative linear correlation was obtained by estimating nitrated tyrosine residues in the presence of αKG (r2 = 0.94): a reduction by half of nitrated tyrosine was estimated using 12 mM αKG compared to the control (326.1 ± 39.6 nmol vs. 844.5 ± 128.4 nmol; p < 0.001).
    Keywords:  alpha-ketoglutarate (αKG); peroxynitrite (ONOO−); reactive oxygen and nitrogen species (RONS)
    DOI:  https://doi.org/10.3390/antiox10091501
  2. Metabol Open. 2021 Dec;12 100127
    Identifying metabolic alterations in newly diagnosed small cell lung cancer patients.
    Shona Pedersen, Joachim Bavnhøj Hansen, Raluca Georgiana Maltesen, Weronika Maria Szejniuk, Trygve Andreassen, Ursula Falkmer, Søren Risom Kristensen.
      Background: Small cell lung cancer (SCLC) is a malignant disease with poor prognosis. At the time of diagnosis most patients are already in a metastatic stage. Current diagnosis is based on imaging, histopathology, and immunohistochemistry, but no blood-based biomarkers have yet proven to be clinically successful for diagnosis and screening. The precise mechanisms of SCLC are not fully understood, however, several genetic mutations, protein and metabolic aberrations have been described. We aim at identifying metabolite alterations related to SCLC and to expand our knowledge relating to this aggressive cancer.Methods: A total of 30 serum samples of patients with SCLC, collected at the time of diagnosis, and 25 samples of healthy controls were included in this study. The samples were analyzed with nuclear magnetic resonance spectroscopy. Multivariate, univariate and pathways analyses were performed.
    Results: Several metabolites were identified to be altered in the pre-treatment serum samples of small-cell lung cancer patients compared to healthy individuals. Metabolites involved in tricarboxylic acid cycle (succinate: fold change (FC) = 2.4, p = 0.068), lipid metabolism (LDL triglyceride: FC = 1.3, p = 0.001; LDL-1 triglyceride: FC = 1.3, p = 0.012; LDL-2 triglyceride: FC = 1.4, p = 0.009; LDL-6 triglyceride: FC = 1.5, p < 0.001; LDL-4 cholesterol: FC = 0.5, p = 0.007; HDL-3 free cholesterol: FC = 0.7, p = 0.002; HDL-4 cholesterol FC = 0.8, p < 0.001; HDL-4 apolipoprotein-A1: FC = 0.8, p = 0.005; HDL-4 apolipoprotein-A2: FC ≥ 0.7, p ≤ 0.001), amino acids (glutamic acid: FC = 1.7, p < 0.001; glutamine: FC = 0.9, p = 0.007, leucine: FC = 0.8, p < 0.001; isoleucine: FC = 0.8, p = 0.016; valine: FC = 0.9, p = 0.032; lysine: FC = 0.8, p = 0.004; methionine: FC = 0.8, p < 0.001; tyrosine: FC = 0.7, p = 0.002; creatine: FC = 0.9, p = 0.030), and ketone body metabolism (3-hydroxybutyric acid FC = 2.5, p < 0.001; acetone FC = 1.6, p < 0.001), among other, were found deranged in SCLC.
    Conclusions: This study provides novel insight into the metabolic disturbances in pre-treatment SCLC patients, expanding our molecular understanding of this malignant disease.
    Keywords:  Diagnostic signatures; Metabolomics; Pathways; Serum metabolites; Small-cell lung cancer
    DOI:  https://doi.org/10.1016/j.metop.2021.100127
  3. Eur Heart J. 2021 Sep 26. pii: ehab514. [Epub ahead of print]
    Breaking the cycle: Succinate in aortic diseases.
    Rohan Bhandari, Scott J Cameron.
      
    DOI:  https://doi.org/10.1093/eurheartj/ehab514
  4. Int J Mol Sci. 2021 Sep 14. pii: 9904. [Epub ahead of print]22(18):
    Tryptophan: From Diet to Cardiovascular Diseases.
    Nada Joe Melhem, Soraya Taleb.
      Cardiovascular disease (CVD) is one of the major causes of mortality worldwide. Inflammation is the underlying common mechanism involved in CVD. It has been recently related to amino acid metabolism, which acts as a critical regulator of innate and adaptive immune responses. Among different metabolites that have emerged as important regulators of immune and inflammatory responses, tryptophan (Trp) metabolites have been shown to play a pivotal role in CVD. Here, we provide an overview of the fundamental aspects of Trp metabolism and the interplay between the dysregulation of the main actors involved in Trp metabolism such as indoleamine 2, 3-dioxygenase 1 (IDO) and CVD, including atherosclerosis and myocardial infarction. IDO has a prominent and complex role. Its activity, impacting on several biological pathways, complicates our understanding of its function, particularly in CVD, where it is still under debate. The discrepancy of the observed IDO effects could be potentially explained by its specific cell and tissue contribution, encouraging further investigations regarding the role of this enzyme. Thus, improving our understanding of the function of Trp as well as its derived metabolites will help to move one step closer towards tailored therapies aiming to treat CVD.
    Keywords:  IDO; atherosclerosis; cardiometabolic diseases; cardiovascular disease; kynurenine; myocardial infarction; tryptophan; tryptophan catabolism
    DOI:  https://doi.org/10.3390/ijms22189904
  5. FASEB J. 2021 Nov;35(11): e21935
    Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis.
    Marianna Lovászi, Zoltán H Németh, William C Gause, Jennet Beesley, Pál Pacher, György Haskó.
      Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular purine metabolism. IMP can also serve as an extracellular signaling molecule, and can regulate diverse processes such as taste sensation, neutrophil function, and ischemia-reperfusion injury. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP suppressed tumor necrosis factor (TNF)-α production and augmented IL-10 production in endotoxemic mice. IMP exerted its effects through metabolism to inosine, as IMP only suppressed TNF-α following its CD73-mediated degradation to inosine in lipopolysaccharide-activated macrophages. Studies with gene targeted mice and pharmacological antagonism indicated that A2A , A2B, and A3 adenosine receptors are not required for the inosine suppression of TNF-α production. The inosine suppression of TNF-α production did not require its metabolism to hypoxanthine through purine nucleoside phosphorylase or its uptake into cells through concentrative nucleoside transporters indicating a role for alternative metabolic/uptake pathways. Inosine augmented IL-β production by macrophages in which inflammasome was activated by lipopolysaccharide and ATP. In contrast to its effects in endotoxemia, IMP failed to affect the inflammatory response to abdominal sepsis and pneumonia. We conclude that extracellular IMP and inosine differentially regulate the inflammatory response.
    Keywords:  endotoxemia; inosine; inosine 5′-monophosphate; sepsis
    DOI:  https://doi.org/10.1096/fj.202100862R
  6. Cancers (Basel). 2021 Sep 17. pii: 4661. [Epub ahead of print]13(18):
    Metabolic Hormones Modulate Macrophage Inflammatory Responses.
    Matthew J Batty, Gwladys Chabrier, Alanah Sheridan, Matthew C Gage.
      Macrophages are phagocytotic leukocytes that play an important role in the innate immune response and have established roles in metabolic diseases and cancer progression. Increased adiposity in obese individuals leads to dysregulation of many hormones including those whose functions are to coordinate metabolism. Recent evidence suggests additional roles of these metabolic hormones in modulating macrophage inflammatory responses. In this review, we highlight key metabolic hormones and summarise their influence on the inflammatory response of macrophages and consider how, in turn, these hormones may influence the development of different cancer types through the modulation of macrophage functions.
    Keywords:  TAMs; cancer; hormones; inflammation; macrophages; metabolism; obesity; polarisation
    DOI:  https://doi.org/10.3390/cancers13184661
  7. Int J Mol Sci. 2021 Sep 13. pii: 9889. [Epub ahead of print]22(18):
    Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism.
    Hidetoshi Nara, Rin Watanabe.
      Interleukin (IL)-6 has been studied since its discovery for its role in health and diseases. It is one of the most important pro-inflammatory cytokines. IL-6 was reported as an exacerbating factor in coronavirus disease. In recent years, it has become clear that the function of muscle-derived IL-6 is different from what has been reported so far. Exercise is accompanied by skeletal muscle contraction, during which, several bioactive substances, collectively named myokines, are secreted from the muscles. Many reports have shown that IL-6 is the most abundant myokine. Interestingly, it was indicated that IL-6 plays opposing roles as a myokine and as a pro-inflammatory cytokine. In this review, we discuss why IL-6 has different functions, the signaling mode of hyper-IL-6 via soluble IL-6 receptor (sIL-6R), and the involvement of soluble glycoprotein 130 in the suppressive effect of hyper-IL-6. Furthermore, the involvement of a disintegrin and metalloprotease family molecules in the secretion of sIL-6R is described. One of the functions of muscle-derived IL-6 is lipid metabolism in the liver. However, the differences between the functions of IL-6 as a pro-inflammatory cytokine and the functions of muscle-derived IL-6 are unclear. Although the involvement of myokines in lipid metabolism in adipocytes was previously discussed, little is known about the direct relationship between nonalcoholic fatty liver disease and muscle-derived IL-6. This review is the first to discuss the relationship between the function of IL-6 in diseases and the function of muscle-derived IL-6, focusing on IL-6 signaling and lipid metabolism in the liver.
    Keywords:  IL-6; NAFLD; exercise; gp130; myokine; soluble IL-6R
    DOI:  https://doi.org/10.3390/ijms22189889
  8. Int J Mol Sci. 2021 Sep 10. pii: 9803. [Epub ahead of print]22(18):
    LPS Induces Opposing Memory-like Inflammatory Responses in Mouse Bone Marrow Neutrophils.
    Trim Lajqi, Maylis Braun, Simon Alexander Kranig, David Frommhold, Johannes Pöschl, Hannes Hudalla.
      A growing body of evidence suggests that innate immune cells can respond in a memory-like (adaptive) fashion, which is referred to as trained immunity. Only few in vivo studies have shown training effects in neutrophils; however, no in vitro setup has been established to study the induction of trained immunity or tolerance in neutrophils by microbial agents. In light of their short lifespan (up to 48 h), we suggest to use the term trained sensitivity for neutrophils in an in vitro setting. Here, we firstly describe a feasible two-hit model, using different doses of lipopolysaccharide (LPS) in bone marrow neutrophils. We found that low doses (10 pg/mL) induce pro-inflammatory activation (trained sensitivity), whereas priming with high doses (100 ng/mL) leads to suppression of pro-inflammatory mediators such as TNF-α or IL-6 (tolerance) (p < 0.05). On a functional level, trained neutrophils displayed increased phagocytic activity and LFA-1 expression as well as migrational capacity and CD11a expression, whereas tolerant neutrophils show contrasting effects in vitro. Mechanistically, TLR4/MyD88/PI3Ks regulate the activation of p65, which controls memory-like responses in mouse bone marrow neutrophils (p < 0.05). Our results open a new window for further in vitro studies on memory-like inflammatory responses of short-lived innate immune cells such as neutrophils.
    Keywords:  LPS; migration; neutrophils; phagocytosis; priming; tolerance; trained sensitivity
    DOI:  https://doi.org/10.3390/ijms22189803
  9. Cells. 2021 Sep 02. pii: 2288. [Epub ahead of print]10(9):
    Adipose Tissue Immunometabolism and Apoptotic Cell Clearance.
    Tamás Röszer.
      The safe removal of apoptotic debris by macrophages-often referred to as efferocytosis-is crucial for maintaining tissue integrity and preventing self-immunity or tissue damaging inflammation. Macrophages clear tissues of hazardous materials from dying cells and ultimately adopt a pro-resolving activation state. However, adipocyte apoptosis is an inflammation-generating process, and the removal of apoptotic adipocytes by so-called adipose tissue macrophages triggers a sequence of events that lead to meta-inflammation and obesity-associated metabolic diseases. Signals that allow apoptotic cells to control macrophage immune functions are complex and involve metabolites released by the apoptotic cells and also metabolites produced by the macrophages during the digestion of apoptotic cell contents. This review provides a concise summary of the adipocyte-derived metabolites that potentially control adipose tissue macrophage immune functions and, hence, may induce or alleviate adipose tissue inflammation.
    Keywords:  M2 macrophage; apoptosis; efferocytosis; immunometabolism; macrophage; meta-inflammation; obesity; phagocytosis
    DOI:  https://doi.org/10.3390/cells10092288
  10. Biochem Biophys Res Commun. 2021 Sep 23. pii: S0006-291X(21)01354-1. [Epub ahead of print]579 15-21
    The AhR ligand 2, 2'-aminophenyl indole (2AI) regulates microglia homeostasis and reduces pro-inflammatory signaling.
    Amir Saeed Khan, Anne Wolf, Thomas Langmann.
      Retinal degeneration is a leading cause of visual impairment and blindness worldwide. Microglia reactivity is a hallmark of neurodegenerative diseases and a driving force for retinal cell death and disease progression. Thus, immunomodulation emerges as a potential therapeutic option. AhR deficiency is known to trigger inflammation and previous studies revealed important roles for AhR ligands in neuroprotection without focusing on microglia. Here, we investigate the anti-inflammatory and antioxidant effects of the synthetic aryl hydrocarbon receptor (AhR) ligand 2, 2'-aminophenyl indole (2AI) on microglia reactivity. We showed that 2AI potently reduced pro-inflammatory gene expression and induced antioxidant genes in activated human and murine microglia cells, in LPS-stimulated retinal explants as well as in stressed human ARPE-19 cells. 2AI also diminished LPS-induced nitric oxide (NO) release, their neurotoxic activity on photoreceptor cells, phagocytosis, and migration in murine BV-2 cells as important functional microglia parameters. siRNA-mediated knockdown of AhR partially prevented the previously observed gene regulatory effects in BV-2 cells. Our results show for the first time, that the synthetic AhR agonist 2AI regulates microglia homeostasis, highlighting AhR as a potential drug target for immunomodulatory and antioxidant therapies.
    Keywords:  2AI; Antioxidants; Aryl hydrocarbon receptor; Inflammation; Microglia; Retina
    DOI:  https://doi.org/10.1016/j.bbrc.2021.09.054
  11. mSystems. 2021 Sep 28. e0093721
    BiG-MAP: an Automated Pipeline To Profile Metabolic Gene Cluster Abundance and Expression in Microbiomes.
    Victória Pascal Andreu, Hannah E Augustijn, Koen van den Berg, Justin J J van der Hooft, Michael A Fischbach, Marnix H Medema.
      Microbial gene clusters encoding the biosynthesis of primary and secondary metabolites play key roles in shaping microbial ecosystems and driving microbiome-associated phenotypes. Although effective approaches exist to evaluate the metabolic potential of such bacteria through identification of these metabolic gene clusters in their genomes, no automated pipelines exist to profile the abundance and expression levels of such gene clusters in microbiome samples to generate hypotheses about their functional roles, and to find associations with phenotypes of interest. Here, we describe BiG-MAP, a bioinformatic tool to profile abundance and expression levels of gene clusters across metagenomic and metatranscriptomic data and evaluate their differential abundance and expression under different conditions. To illustrate its usefulness, we analyzed 96 metagenomic samples from healthy and caries-associated human oral microbiome samples and identified 252 gene clusters, including unreported ones, that were significantly more abundant in either phenotype. Among them, we found the muc operon, a gene cluster known to be associated with tooth decay. Additionally, we found a putative reuterin biosynthetic gene cluster from a Streptococcus strain to be enriched but not exclusively found in healthy samples; metabolomic data from the same samples showed masses with fragmentation patterns consistent with (poly)acrolein, which is known to spontaneously form from the products of the reuterin pathway and has been previously shown to inhibit pathogenic Streptococcus mutans strains. Thus, we show how BiG-MAP can be used to generate new hypotheses on potential drivers of microbiome-associated phenotypes and prioritize the experimental characterization of relevant gene clusters that may mediate them. IMPORTANCE Microbes play an increasingly recognized role in determining host-associated phenotypes by producing small molecules that interact with other microorganisms or host cells. The production of these molecules is often encoded in syntenic genomic regions, also known as gene clusters. With the increasing numbers of (multi)omics data sets that can help in understanding complex ecosystems at a much deeper level, there is a need to create tools that can automate the process of analyzing these gene clusters across omics data sets. This report presents a new software tool called BiG-MAP, which allows assessing gene cluster abundance and expression in microbiome samples using metagenomic and metatranscriptomic data. Here, we describe the tool and its functionalities, as well as its validation using a mock community. Finally, using an oral microbiome data set, we show how it can be used to generate hypotheses regarding the functional roles of gene clusters in mediating host phenotypes.
    Keywords:  biosynthesis; metabolic gene cluster; metabolomics; metagenomics; metatranscriptomics; microbiome; microbiome-associated phenotype; specialized metabolism
    DOI:  https://doi.org/10.1128/mSystems.00937-21
  12. Cells. 2021 Sep 20. pii: 2486. [Epub ahead of print]10(9):
    Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled.
    Ronit Vogt Sionov.
      Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil-tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.
    Keywords:  Cathepsin G; NETs; RAGE; TRAIL; cancer; chemokines; chronic inflammation; metastasis; neutrophils; reactive oxygen species
    DOI:  https://doi.org/10.3390/cells10092486
  13. Biomedicines. 2021 Sep 02. pii: 1139. [Epub ahead of print]9(9):
    Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage.
    Carla Iacobini, Martina Vitale, Giuseppe Pugliese, Stefano Menini.
      Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.
    Keywords:  Warburg effect; carnosine; cellular energetics; diabetes; glycolysis; hyperglycemia; inflammation; methylglyoxal; prolyl 4-hydroxylase 2; trans-resveratrol
    DOI:  https://doi.org/10.3390/biomedicines9091139
  14. Int J Mol Sci. 2021 Sep 16. pii: 10017. [Epub ahead of print]22(18):
    Crosstalk between Metabolic Disorders and Immune Cells.
    Shinichi Saitoh, Koen Van Wijk, Osamu Nakajima.
      Metabolic syndrome results from multiple risk factors that arise from insulin resistance induced by abnormal fat deposition. Chronic inflammation owing to obesity primarily results from the recruitment of pro-inflammatory M1 macrophages into the adipose tissue stroma, as the adipocytes within become hypertrophied. During obesity-induced inflammation in adipose tissue, pro-inflammatory cytokines are produced by macrophages and recruit further pro-inflammatory immune cells into the adipose tissue to boost the immune response. Here, we provide an overview of the biology of macrophages in adipose tissue and the relationship between other immune cells, such as CD4+ T cells, natural killer cells, and innate lymphoid cells, and obesity and type 2 diabetes. Finally, we discuss the link between the human pathology and immune response and metabolism and further highlight potential therapeutic targets for the treatment of metabolic disorders.
    Keywords:  5-aminolevulinic acid; CD4+ T cells; M1/M2 macrophages; chronic inflammation; cytokine; innate lymphoid cells; mesenchymal stem cells; natural killer cells; non-obese metabolic disorder; obesity
    DOI:  https://doi.org/10.3390/ijms221810017
  15. Cancer Med. 2021 Sep 26.
    High mutations in fatty acid metabolism contribute to a better prognosis of small-cell lung cancer patients treated with chemotherapy.
    Qiong Lyu, Weiliang Zhu, Ting Wei, Weimin Ding, Manming Cao, Qiongyao Wang, Linlang Guo, Peng Luo, Jian Zhang.
      BACKGROUND: The majority of patients with small-cell lung cancer (SCLC) show a good response in the early stages of treatment, but more than 90% of patients will develop drug resistance. Therefore, biomarkers are urgently needed to identify patients who can benefit from systemic treatment.METHODS: We prospectively enrolled 52 extensive-stage SCLC patients before treatment from a local hospital to identify mutations related to patient prognosis, and verified them in the published Jiang's cohort and George's cohort.
    RESULTS: We found that patients with high mutations (mut-high) in the fatty acid (FA) metabolism pathway had a longer progression-free survival (PFS) in the local hospital cohort (HR = 0.446, 95% CI, 0.207-0.959, p = 0.0387) and a longer overall survival (OS) in Jiang's cohort (HR = 0.549, 95% CI, 0.314-0.960, p = 0.0351) than patients with low mutations (mut-low). Multivariate analysis suggested that mut-high status was an independent prognostic factor in both cohorts. George's cohort verified that mut-high status was associated with a longer OS than mut-low status (HR = 0.730, 95% CI 0.440-1.220, p = 0.2277). The possible mechanisms were as follows: the frequency of mutated FA synthase (FASN) in the mut-high group was greater than that in the mut-low group, and pathways related to the cell cycle, DNA repair, and oxidative phosphorylation were enriched in the mut-high group.
    CONCLUSIONS: The prognosis of SCLC patients treated with chemotherapy was better among patients with more mutations in the FA metabolism pathway, and the underlying mechanisms could be found at the genome and transcriptome levels.
    Keywords:  biomarker; fatty acid metabolic pathway; prognosis; small-cell lung cancer (SCLC); whole exome sequencing (WES)
    DOI:  https://doi.org/10.1002/cam4.4290
  16. J Cell Biol. 2021 Nov 01. pii: e202103122. [Epub ahead of print]220(11):
    The modified mitochondrial outer membrane carrier MTCH2 links mitochondrial fusion to lipogenesis.
    Katherine Labbé, Shona Mookerjee, Maxence Le Vasseur, Eddy Gibbs, Chad Lerner, Jodi Nunnari.
      Mitochondrial function is integrated with cellular status through the regulation of opposing mitochondrial fusion and division events. Here we uncover a link between mitochondrial dynamics and lipid metabolism by examining the cellular role of mitochondrial carrier homologue 2 (MTCH2). MTCH2 is a modified outer mitochondrial membrane carrier protein implicated in intrinsic cell death and in the in vivo regulation of fatty acid metabolism. Our data indicate that MTCH2 is a selective effector of starvation-induced mitochondrial hyperfusion, a cytoprotective response to nutrient deprivation. We find that MTCH2 stimulates mitochondrial fusion in a manner dependent on the bioactive lipogenesis intermediate lysophosphatidic acid. We propose that MTCH2 monitors flux through the lipogenesis pathway and transmits this information to the mitochondrial fusion machinery to promote mitochondrial elongation, enhanced energy production, and cellular survival under homeostatic and starvation conditions. These findings will help resolve the roles of MTCH2 and mitochondria in tissue-specific lipid metabolism in animals.
    DOI:  https://doi.org/10.1083/jcb.202103122
  17. Front Cell Infect Microbiol. 2021 ;11 725043
    The Role of Tricarboxylic Acid Cycle Metabolites in Viral Infections.
    Francisco Javier Sánchez-García, Celia Angélica Pérez-Hernández, Miguel Rodríguez-Murillo, María Maximina Bertha Moreno-Altamirano.
      Host cell metabolism is essential for the viral replication cycle and, therefore, for productive infection. Energy (ATP) is required for the receptor-mediated attachment of viral particles to susceptible cells and for their entry into the cytoplasm. Host cells must synthesize an array of biomolecules and engage in intracellular trafficking processes to enable viruses to complete their replication cycle. The tricarboxylic acid (TCA) cycle has a key role in ATP production as well as in the synthesis of the biomolecules needed for viral replication. The final assembly and budding process of enveloped viruses, for instance, require lipids, and the TCA cycle provides the precursor (citrate) for fatty acid synthesis (FAS). Viral infections may induce host inflammation and TCA cycle metabolic intermediates participate in this process, notably citrate and succinate. On the other hand, viral infections may promote the synthesis of itaconate from TCA cis-aconitate. Itaconate harbors anti-inflammatory, anti-oxidant, and anti-microbial properties. Fumarate is another TCA cycle intermediate with immunoregulatory properties, and its derivatives such as dimethyl fumarate (DMF) are therapeutic candidates for the contention of virus-induced hyper-inflammation and oxidative stress. The TCA cycle is at the core of viral infection and replication as well as viral pathogenesis and anti-viral immunity. This review highlights the role of the TCA cycle in viral infections and explores recent advances in the fast-moving field of virometabolism.
    Keywords:  host cell metabolism; metabolic reprogramming; mitochondria; tricarboxylic acid cycle; viruses
    DOI:  https://doi.org/10.3389/fcimb.2021.725043
  18. Biomedicines. 2021 Sep 04. pii: 1159. [Epub ahead of print]9(9):
    Galectins in Cancer and the Microenvironment: Functional Roles, Therapeutic Developments, and Perspectives.
    Chien-Hsiu Li, Yu-Chan Chang, Ming-Hsien Chan, Yi-Fang Yang, Shu-Mei Liang, Michael Hsiao.
      Changes in cell growth and metabolism are affected by the surrounding environmental factors to adapt to the cell's most appropriate growth model. However, abnormal cell metabolism is correlated with the occurrence of many diseases and is accompanied by changes in galectin (Gal) performance. Gals were found to be some of the master regulators of cell-cell interactions that reconstruct the microenvironment, and disordered expression of Gals is associated with multiple human metabolic-related diseases including cancer development. Cancer cells can interact with surrounding cells through Gals to create more suitable conditions that promote cancer cell aggressiveness. In this review, we organize the current understanding of Gals in a systematic way to dissect Gals' effect on human disease, including how Gals' dysregulated expression affects the tumor microenvironment's metabolism and elucidating the mechanisms involved in Gal-mediated diseases. This information may shed light on a more precise understanding of how Gals regulate cell biology and facilitate the development of more effective therapeutic strategies for cancer treatment by targeting the Gal family.
    Keywords:  cancer; galectin; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines9091159
  19. PLoS One. 2021 ;16(9): e0257908
    Transcriptome profiling reveals new insights into the roles of neuronal nitric oxide synthase on macrophage polarization towards classically activated phenotype.
    Pingan Chang, Hao Gao, Quan Sun, Xiaohong He, Feifei Huang.
      In response to various stimuli, naïve macrophages usually polarize to M1 (classically activated) or M2 (alternatively activated) cells with distinct biological functions. Neuronal nitric oxide synthase (NOS1) is involved in M1 macrophage polarization at an early stage. Here, we show for the first time that NOS1 is dispensable for M2 macrophage polarization for the first time. Further, differentially expressed genes (DEGs) regulated by NOS1 signaling in M1-polarized macrophages stimulated with lipopolysaccharide (LPS) were characterized by transcriptome analysis of wild-type (WT) and NOS1 knockout mouse macrophages. Thousands of affected genes were detected 2 h post LPS challenge, and this wide-ranging effect became greater with a longer stimulation time (8 h post LPS). NOS1 deficiency caused dysregulated expression of hundreds of LPS-responsive genes. Most DEGs were enriched in biological processes related to transcription and regulation of the immune and inflammatory response. At 2 h post-LPS, the toll-like receptor (TLR) signaling pathway, cytokine-cytokine receptor interaction, and NOD-like receptor signaling pathway were the major pathways affected, whereas the main pathways affected at 8 h post-LPS were Th1 and Th2 cell differentiation, FoxO, and AMPK signaling pathway. Identified DEGs were validated by real-time quantitative PCR and interacted in a complicated signaling pathway network. Collectively, our data show that NOS1 is dispensable for M2 macrophage polarization and reveal novel insights in the role of NOS1 signaling at different stages of M1 macrophage polarization through distinct TLR4 plasma membrane-localized and endosome-internalized signaling pathways.
    DOI:  https://doi.org/10.1371/journal.pone.0257908
  20. JTO Clin Res Rep. 2020 Mar;1(1): 100001
    The Role of Interleukin 1β in the Pathogenesis of Lung Cancer.
    Edward B Garon, James Chih-Hsin Yang, Steven M Dubinett.
      Introduction: Chronic inflammation is associated with an increased risk of several diseases, including cancer. A complex tumor microenvironment created and maintained by a range of cell types promotes tumor growth, angiogenesis, and metastasis. Inflammasomes, multicomplex cytosolic proteins, generate much of this inflammation, including the activation of the cytokine interleukin (IL)-1β. Inflammation generated by IL-1β is present in several disease states, including atherosclerosis, diabetes, and arthritis. IL-1β is activated when a specific inflammasome, nucleotide-binding domain-like receptor protein 3, induces cleavage of pro-IL-1β into its active form. Nucleotide-binding domain-like receptor protein 3 is up-regulated in lung cancer; IL-1β binds to its receptor and activates signaling pathways, including the MAPK, cyclooxygenase, and nuclear factor-κB pathways, leading to macrophage activation, intratumoral accumulation of immunosuppressive myeloid cells, and tumor growth, invasiveness, metastasis, and angiogenesis. Evidence suggests a role for IL-1β and some of its downstream effectors (e.g., IL-6, IL-8, C-reactive protein, cyclooxygenase-2) as prognostic markers in many malignancies, including lung cancer.Methods: A phase III cardiovascular study of canakinumab, a human immunoglobulin Gk monoclonal antibody with high affinity and specificity for IL-1β, was conducted in patients who had a myocardial infarction.
    Results: A subanalysis of this study found that treatment with canakinumab substantially reduced incident lung cancer and lung cancer mortality in a dose-dependent manner.
    Conclusions: A phase III trial is currently recruiting participants to evaluate canakinumab as adjuvant treatment versus placebo in patients with lung cancer. Other studies are investigating combinations of established antineoplastic agents and canakinumab in both early- and advanced-stage NSCLC.
    Keywords:  Canakinumab; IL-1β; Inflammasome; Lung cancer
    DOI:  https://doi.org/10.1016/j.jtocrr.2020.100001
  21. J Neurochem. 2021 Sep 29.
    Glucose availability limits microglial nitric oxide production.
    Erika Castillo, Ebony Mocanu, Gӧkhan Uruk, Raymond A Swanson.
      Metabolic intermediates influence inflammation not only through signaling effects, but also by fueling production of pro-inflammatory molecules. Microglial production of nitric oxide (NO) requires consumption of NADPH. NADPH consumed in this process is regenerated from NADP+ primarily through the hexose monophosphate shunt, which can utilize only glucose as a substrate. These factors predict that glucose availability can be rate-limiting for glial NO production. To test this prediction, cultured astrocytes and microglia were incubated with lipopolysaccharide and interferon-γ to promote expression of inducible nitric oxide synthase, and the rate of NO production was assessed at defined glucose concentrations. Increased NO production was detected only in cultures containing microglia. The NO production was markedly slowed at glucose concentrations below 0.5 mM, and comparably reduced by inhibition of the hexose monophosphate shunt with 6-aminonicotinamide. Reduced NO production caused by glucose deprivation was partly reversed by malate, which fuels NADPH production by malate dehydrogenase, and by NADPH itself. These findings highlight the role of the hexose monophosphate shunt in fueling NO synthesis and suggest that microglial NO production in brain may be limited at sites of low glucose availability, such as abscesses or other compartmentalized infections.
    Keywords:  NADPH; abscess; hyperglycemia; iNOS; pentose phosphate pathway
    DOI:  https://doi.org/10.1111/jnc.15522
  22. Cells. 2021 Sep 07. pii: 2340. [Epub ahead of print]10(9):
    Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines.
    Mykyta I Malkov, Chee Teik Lee, Cormac T Taylor.
      Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.
    Keywords:  HIF; HIF-1α; IL-1β; TNF-α; hypoxia; inflammation
    DOI:  https://doi.org/10.3390/cells10092340
  23. Cells. 2021 Sep 12. pii: 2398. [Epub ahead of print]10(9):
    Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells.
    Friederike Steifensand, Julia Gallwas, Gerd Bauerschmitz, Carsten Gründker.
      Cancer cells have an increased need for glucose and, despite aerobic conditions, obtain their energy through aerobic oxidation and lactate fermentation, instead of aerobic oxidation alone. Glutamine is an essential amino acid in the human body. Glutaminolysis and glycolysis are crucial for cancer cell survival. In the therapy of estrogen receptor α (ERα)-positive breast cancer (BC), the focus lies on hormone sensitivity targeting therapy with selective estrogen receptor modulators (SERMs) such as 4-hydroxytamoxifen (4-OHT), although this therapy is partially limited by the development of resistance. Therefore, further targets for therapy improvement of ERα-positive BC with secondary 4-OHT resistance are needed. Hence, increased glucose requirement and upregulated glutaminolysis in BC cells could be used. We have established sublines of ERα-positive MCF7 and T47D BC cells, which were developed to be resistant to 4-OHT. Further, glycolysis inhibitor 2-Deoxy-D-Glucose (2-DG) and glutaminase inhibitor CB-839 were analyzed. Co-treatments using 4-OHT and CB-839, 2-DG and CB-839, or 4-OHT, 2-DG and CB-839, respectively, showed significantly stronger inhibitory effects on viability compared to single treatments. It could be shown that tamoxifen-resistant BC cell lines, compared to the non-resistant cell lines, exhibited a stronger reducing effect on cell viability under co-treatments. In addition, the tamoxifen-resistant BC cell lines showed increased expression of proto-oncogene c-Myc compared to the parental cell lines. This could be reduced depending on the treatment. Suppression of c-Myc expression using specific siRNA completely abolished resistance to 4OH-tamoxifen. In summary, our data suggest that combined treatments affecting the metabolism of BC are suitable depending on the cellularity and resistance status. In addition, the anti-metabolic treatments affected the expression of the proto-oncogene c-Myc, a key player in the regulation of cancer cell metabolism.
    Keywords:  breast cancer; estrogen receptor α; glutaminolysis; glycolysis; tamoxifen resistance
    DOI:  https://doi.org/10.3390/cells10092398
  24. J Leukoc Biol. 2021 Sep 29.
    Loss of mTORC2-induced metabolic reprogramming in monocytes uncouples migration and maturation from production of proinflammatory mediators.
    Maryam Jangani, Juho Vuononvirta, Lamya Yamani, Eleanor Ward, Melania Capasso, Suchita Nadkarni, Frances Balkwill, Federica Marelli-Berg.
      Monocyte migration to the sites of inflammation and maturation into macrophages are key steps for their immune effector function. Here, we show that mechanistic target of rapamycin complex 2 (mTORC2)-dependent Akt activation is instrumental for metabolic reprogramming at the early stages of macrophage-mediated immunity. Despite an increased production of proinflammatory mediators, monocytes lacking expression of the mTORC2 component Rictor fail to efficiently migrate to inflammatory sites and fully mature into macrophages, resulting in reduced inflammatory responses in vivo. The mTORC2-dependent phosphorylation of Akt is instrumental for the enhancement of glycolysis and mitochondrial respiration, required to sustain monocyte maturation and motility. These observations are discussed in the context of therapeutic strategies aimed at selective inhibition of mTORC2 activity.
    Keywords:  cell metabolism; mTORC2; macrophage; metabolism; monocyte
    DOI:  https://doi.org/10.1002/JLB.1A0920-588R
  25. DNA Cell Biol. 2021 Sep 28.
    Integrated Metabolomics and Transcriptomics Analyses Reveal Histidine Metabolism Plays an Important Role in Imiquimod-Induced Psoriasis-like Skin Inflammation.
    Xia Wu, Jiang Zhu, Siji Chen, Yaohan Xu, Chunting Hua, Lihua Lai, Hao Cheng, Yinjing Song, Xianzhen Chen.
      Psoriasis is a chronic inflammatory skin disease characterized by massive keratinocyte proliferation and immune cell infiltration into the epidermis. However, the specific mechanisms underlying the development of psoriasis remain unclear. Untargeted metabolomics and transcriptomics have been used separately to profile biomarkers and risk genes in the serum of psoriasis patients. However, the integration of metabolomics and transcriptomics to identify dysregulated metabolites and genes in the psoriatic skin is lacking. In this study, we performed an untargeted metabolomics analysis of imiquimod (IMQ)-induced psoriasis-like mice and healthy controls, and found that levels of a total of 4,188 metabolites differed in IMQ-induced psoriasis-like mice compared with those in control mice. Metabolomic data analysis using MetaboAnalyst showed that the metabolic pathways of primary metabolites, such as folate biosynthesis and galactose metabolism, were significantly altered in the skin of mice after treatment with IMQ. Furthermore, IMQ treatment also significantly altered metabolic pathways of secondary metabolites, including histidine metabolism, in mouse skin tissues. The metabolomic results were verified by transcriptomics analysis. RNA-seq results showed that histamine decarboxylase (HDC) mRNA levels were significantly upregulated after IMQ treatment. Targeted inhibition of histamine biosynthesis process using HDC-specific inhibitor, pinocembrin (PINO), significantly alleviated epidermal thickness, downregulated the expression of interleukin (IL)-17A and IL-23, and inhibited the infiltration of immune cells during IMQ-induced psoriasis-like skin inflammation. In conclusion, our study offers a validated and comprehensive understanding of metabolism during the development of psoriasis and demonstrated that PINO could protect against IMQ-induced psoriasis-like skin inflammation.
    Keywords:  histidine metabolism; metabolomics; pinocembrin; psoriasis; transcriptomics
    DOI:  https://doi.org/10.1089/dna.2021.0465
  26. Cells. 2021 Aug 24. pii: 2173. [Epub ahead of print]10(9):
    Early-Released Interleukin-10 Significantly Inhibits Lipopolysaccharide-Elicited Neuroinflammation In Vitro.
    Yubao Wang, Pei Yu, Yi Li, Zhan Zhao, Xiaomei Wu, Lu Zhang, Jing Feng, Jau-Shyong Hong.
      Anti-inflammatory cytokine interleukin (IL)-10 is pivotal for limiting excessive inflammation in the central nervous system. Reports show that lipopolysaccharide (LPS)-induced microglial IL-10 emerges in a delayed manner in vitro and in vivo, lagging behind proinflammatory cytokines to facilitate the resolution of neuroinflammation. We hypothesized that IL-10 releases quite quickly based on our pilot investigation. Here, we uncovered a bimodal expression of microglial IL-10 gene transcription induced by LPS in mouse primary mixed glial cultures. This pattern consisted of a short brief early-phase and a long-lived late-phase, enabling the production of IL-10 protein in a rapid manner. The removal and addition of IL-10 protein assays indicated that early-released IL-10 exerted potent modulatory effects on neuroinflammation at picomolar levels, and IL-10 released at the onset of neuroinflammation is tightly controlled. We further showed that the early-released, but not the late-released, IL-10 was crucial for mediating and potentiating the anti-inflammatory function of a β2-adrenergic receptor agonist salmeterol. This study in vitro highlights the essential role of early-released IL-10 in regulating the appropriate degree of neuroinflammation, overturning the previous notion that microglial IL-10 produces and functions in a delayed manner and providing new insights into anti-inflammatory mechanisms-mediated neuroimmune homeostasis.
    Keywords:  Arg-1; interleukin-10; interleukin-1β; lipopolysaccharide; microglia; neuroinflammation; tumor necrosis factor alpha; β2-adrenergic receptor
    DOI:  https://doi.org/10.3390/cells10092173
  27. Genes (Basel). 2021 Sep 21. pii: 1460. [Epub ahead of print]12(9):
    Mammalian SIRT6 Represses Invasive Cancer Cell Phenotypes through ATP Citrate Lyase (ACLY)-Dependent Histone Acetylation.
    Wei Zheng, Luisa Tasselli, Tie-Mei Li, Katrin F Chua.
      The modulation of dynamic histone acetylation states is key for organizing chromatin structure and modulating gene expression and is regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. The mammalian SIRT6 protein, a member of the Class III HDAC Sirtuin family of NAD+-dependent enzymes, plays pivotal roles in aging, metabolism, and cancer biology. Through its site-specific histone deacetylation activity, SIRT6 promotes chromatin silencing and transcriptional regulation of aging-associated, metabolic, and tumor suppressive gene expression programs. ATP citrate lyase (ACLY) is a nucleo-cytoplasmic enzyme that produces acetyl coenzyme A (acetyl-CoA), which is the required acetyl donor for lysine acetylation by HATs. In addition to playing a central role in generating cytosolic acetyl-CoA for de novo lipogenesis, a growing body of work indicates that ACLY also functions in the nucleus where it contributes to the nutrient-sensitive regulation of nuclear acetyl-CoA availability for histone acetylation in cancer cells. In this study, we have identified a novel function of SIRT6 in controlling nuclear levels of ACLY and ACLY-dependent tumor suppressive gene regulation. The inactivation of SIRT6 in cancer cells leads to the accumulation of nuclear ACLY protein and increases nuclear acetyl-CoA pools, which in turn drive locus-specific histone acetylation and the expression of cancer cell adhesion and migration genes that promote tumor invasiveness. Our findings uncover a novel mechanism of SIRT6 in suppressing invasive cancer cell phenotypes and identify acetyl-CoA responsive cell migration and adhesion genes as downstream targets of SIRT6.
    Keywords:  ACLY; SIRT6; Sirtuin; acetyl-CoA; cancer; chromatin; gene expression; histone acetylation
    DOI:  https://doi.org/10.3390/genes12091460
  28. J Biol Chem. 2021 Sep 24. pii: S0021-9258(21)01043-7. [Epub ahead of print] 101240
    Cytokine exposure mediates transcriptional activation of the orphan nuclear receptor Nur77 in hematopoietic cells.
    Orsola di Martino, Haixia Niu, Gayla Hadwiger, Margaret A Ferris, John S Welch.
      The orphan nuclear receptor Nur77 is an immediate-early response gene that based on tissue and cell context is implicated in a plethora of cellular processes, including proliferation, differentiation, apoptosis, metabolism, and inflammation. Nur77 has a ligand-binding pocket that is obstructed by hydrophobic side-groups. Naturally-occurring, cell-endogenous ligands have not been identified and Nur77 transcriptional activity is thought to be regulated through post-translational modification and modulation of protein levels. To determine whether Nur77 is transcriptionally active in hematopoietic cells in vivo, we used an upstream activating sequence (UAS)-GFP transgenic reporter. We found that Nur77 is transcriptionally inactive in vivo in hematopoietic cells under basal conditions, but that activation occurs following cytokine exposure by G-CSF or IL-3. We also identified a series of serine residues required for cytokine-dependent transactivation of Nur77. Moreover, a kinase inhibitor library screen and proximity labeling-based mass spectrometry identified overlapping kinase pathways that physically interacted with Nur77 and whose inhibition abrogated cytokine-induced activation of Nur77. We determined that transcriptional activation of Nur77 by G-CSF or IL-3 requires functional JAK and mTor signaling since their inhibition leads to Nur77 transcriptional inactivation. Thus, intracellular cytokine signaling networks appear to regulate Nur77 transcriptional activity in mouse hematopoietic cells.
    Keywords:  G-SCF; IL-3; NR4A1; Nur77 mutants; kinases screening; mass spectrometry (MS); nuclear receptor; phosphorylation; proximity labeling; signal transduction; transcription regulation
    DOI:  https://doi.org/10.1016/j.jbc.2021.101240
  29. Front Immunol. 2021 ;12 680955
    Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma.
    Huimei Huang, Shisheng Li, Qinglai Tang, Gangcai Zhu.
      Nasopharyngeal carcinoma (NPC) is a malignant tumor of the nasopharynx mainly characterized by geographic distribution and EBV infection. Metabolic reprogramming, one of the cancer hallmarks, has been frequently reported in NPCs to adapt to internal energy demands and external environmental pressures. Inevitably, the metabolic reprogramming within the tumor cell will lead to a decreased pH value and diverse nutritional supplements in the tumor-infiltrating micro-environment incorporating immune cells, fibroblasts, and endothelial cells. Accumulated evidence indicates that metabolic reprogramming derived from NPC cells may facilitate cancer progression and immunosuppression by cell-cell communications with their surrounding immune cells. This review presents the dysregulated metabolism processes, including glucose, fatty acid, amino acid, nucleotide metabolism, and their mutual interactions in NPC. Moreover, the potential connections between reprogrammed metabolism, tumor immunity, and associated therapy would be discussed in this review. Accordingly, the development of targets on the interactions between metabolic reprogramming and immune cells may provide assistances to overcome the current treatment resistance in NPC patients.
    Keywords:  immune cell; immunotherapy; metabolism; nasopharyngeal carcinoma; pH
    DOI:  https://doi.org/10.3389/fimmu.2021.680955
  30. Front Endocrinol (Lausanne). 2021 ;12 697204
    Roles of Skeletal Muscle-Derived Exosomes in Organ Metabolic and Immunological Communication.
    Wataru Aoi, Yuko Tanimura.
      Skeletal muscles secrete various factors, such as proteins/peptides, nucleotides, and metabolites, which are referred to as myokines. Many of these factors are transported into extracellular bodily fluids in a free or protein-bound form. Furthermore, several secretory factors have been shown to be wrapped up by small vesicles, particularly exosomes, secreted into circulation, and subsequently regulate recipient cells. Thus, exosome contents can be recognized as myokines. In recipient cells, proteins, microRNAs, and metabolites in exosomes can regulate the expression and activity of target proteins associated with nutrient metabolism and immune function. The levels of circulating exosomes and their contents are altered in muscle disorders and metabolic-related states, such as metabolic dysfunction, sarcopenia, and physical fitness. Therefore, such circulating factors could mediate various interactions between skeletal muscle and other organs and may be useful as biomarkers reflecting physiological and pathological states associated with muscular function. Here, this review summarizes secretory regulation of muscle-derived exosomes. Their metabolic and immunological roles and the significance of their circulating levels are also discussed.
    Keywords:  exosome; metabolism; microRNA; myokine; skeletal muscle
    DOI:  https://doi.org/10.3389/fendo.2021.697204
  31. Cell Commun Signal. 2021 Sep 25. 19(1): 98
    CAMKK2 regulates mitochondrial function by controlling succinate dehydrogenase expression, post-translational modification, megacomplex assembly, and activity in a cell-type-specific manner.
    Mohammad Golam Sabbir, Carla G Taylor, Peter Zahradka.
      BACKGROUND: The calcium (Ca2+)/calmodulin (CAM)-activated kinase kinase 2 (CAMKK2)-signaling regulates several physiological processes, for example, glucose metabolism and energy homeostasis, underlying the pathogenesis of metabolic diseases. CAMKK2 exerts its biological function through several downstream kinases, therefore, it is expected that depending on the cell-type-specific kinome profile, the metabolic effects of CAMKK2 and its underlying mechanism may differ. Identification of the cell-type-specific differences in CAMKK2-mediated glucose metabolism will lead to unravelling the organ/tissue-specific role of CAMKK2 in energy metabolism. Therefore, the objective of this study was to understand the cell-type-specific regulation of glucose metabolism, specifically, respiration under CAMKK2 deleted conditions in transformed human embryonic kidney-derived HEK293 and hepatoma-derived HepG2 cells.METHODS: Cellular respiration was measured in terms of oxygen consumption rate (OCR). OCR and succinate dehydrogenase (SDH) enzyme activity were measured following the addition of substrates. In addition, transcription and proteomic and analyses of the electron transport system (ETS)-associated proteins, including mitochondrial SDH protein complex (complex-II: CII) subunits, specifically SDH subunit B (SDHB), were performed using standard molecular biology techniques. The metabolic effect of the altered SDHB protein content in the mitochondria was further evaluated by cell-type-specific knockdown or overexpression of SDHB.
    RESULTS: CAMKK2 deletion suppressed cellular respiration in both cell types, shifting metabolic phenotype to aerobic glycolysis causing the Warburg effect. However, isolated mitochondria exhibited a cell-type-specific enhancement or dampening of the respiratory kinetics under CAMKK2 deletion conditions. This was mediated in part by the cell-type-specific effect of CAMKK2 loss-of-function on transcription, translation, post-translational modification (PTM), and megacomplex assembly of nuclear-encoded mitochondrial SDH enzyme complex subunits, specifically SDHB. The cell-type-specific increase or decrease in SDHs protein levels, specifically SDHB, under CAMKK2 deletion condition resulted in an increased or decreased enzymatic activity and CII-mediated respiration. This metabolic phenotype was reversed by cell-type-specific knockdown or overexpression of SDHB in respective CAMKK2 deleted cell types. CAMKK2 loss-of-function also affected the overall assembly of mitochondrial supercomplex involving ETS-associated proteins in a cell-type-specific manner, which correlated with differences in mitochondrial bioenergetics.
    CONCLUSION: This study provided novel insight into CAMKK2-mediated cell-type-specific differential regulation of mitochondrial function, facilitated by the differential expression, PTMs, and assembly of SDHs into megacomplex structures. Video Abstract.
    Keywords:  CAMKK2; Oxidative phosphorylation; Respiration; Respiratory supercomplex; Succinate dehydrogenase
    DOI:  https://doi.org/10.1186/s12964-021-00778-z
  32. Genes (Basel). 2021 Aug 25. pii: 1305. [Epub ahead of print]12(9):
    Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis.
    Jingwen Zou, Kunpeng Du, Shaohua Li, Lianghe Lu, Jie Mei, Wenping Lin, Min Deng, Wei Wei, Rongping Guo.
      BACKGROUND: In recent years, metabolic reprogramming has been identified as a hallmark of cancer. Accumulating evidence suggests that glutamine metabolism plays a crucial role in oncogenesis and the tumor microenvironment. In this study, we aimed to perform a systematic and comprehensive analysis of six key metabolic node genes involved in the dynamic regulation of glutamine metabolism (referred to as GLNM regulators) across 33 types of cancer.METHODS: We analyzed the gene expression, epigenetic regulation, and genomic alterations of six key GLNM regulators, including SLC1A5, SLC7A5, SLC3A2, SLC7A11, GLS, and GLS2, in pan-cancer using several open-source platforms and databases. Additionally, we investigated the impacts of these gene expression changes on clinical outcomes, drug sensitivity, and the tumor microenvironment. We also attempted to investigate the upstream microRNA-mRNA molecular networks and the downstream signaling pathways involved in order to uncover the potential molecular mechanisms behind metabolic reprogramming.
    RESULTS: We found that the expression levels of GLNM regulators varied across cancer types and were related to several genomic and immunological characteristics. While the immune scores were generally lower in the tumors with higher gene expression, the types of immune cell infiltration showed significantly different correlations among cancer types, dividing them into two clusters. Furthermore, we showed that elevated GLNM regulators expression was associated with poor overall survival in the majority of cancer types. Lastly, the expression of GLNM regulators was significantly associated with PD-L1 expression and drug sensitivity.
    CONCLUSIONS: The elevated expression of GLNM regulators was associated with poorer cancer prognoses and a cold tumor microenvironment, providing novel insights into cancer treatment and possibly offering alternative options for the treatment of clinically refractory cancers.
    Keywords:  PD-L1; glutamine; immune; metabolism; multi-omics; pan-cancer
    DOI:  https://doi.org/10.3390/genes12091305
  33. Antioxidants (Basel). 2021 Sep 17. pii: 1486. [Epub ahead of print]10(9):
    Glyoxal-Lysine Dimer, an Advanced Glycation End Product, Induces Oxidative Damage and Inflammatory Response by Interacting with RAGE.
    Hee-Weon Lee, Min Ji Gu, Yoonsook Kim, Jee-Young Lee, Seungju Lee, In-Wook Choi, Sang Keun Ha.
      The glyoxal-lysine dimer (GOLD), which is a glyoxal (GO)-derived advanced glycation end product (AGE), is produced by the glycation reaction. In this study, we evaluated the effect of GOLD on the oxidative damage and inflammatory response in SV40 MES 13 mesangial cells. GOLD significantly increased the linkage with the V-type immunoglobulin domain of RAGE, a specific receptor of AGE. We found that GOLD treatment increased RAGE expression and reactive oxygen species (ROS) production in mesangial cells. GOLD remarkably regulated the protein and mRNA expression of nuclear factor erythroid 2-related factor 2 (NRF2) and glyoxalase 1 (GLO1). In addition, mitochondrial deterioration and inflammation occurred via GOLD-induced oxidative stress in mesangial cells. GOLD regulated the mitogen-activated protein kinase (MAPK) and the release of proinflammatory cytokines associated with the inflammatory mechanism of mesangial cells. Furthermore, oxidative stress and inflammatory responses triggered by GOLD were suppressed through RAGE inhibition using RAGE siRNA. These results demonstrate that the interaction of GOLD and RAGE plays an important role in the function of mesangial cells.
    Keywords:  NRF2/GLO-1; advanced glycation end product; glyoxal-lysine dimer; mitochondrial function; oxidative stress; receptor of advanced glycation end product
    DOI:  https://doi.org/10.3390/antiox10091486
  34. Front Physiol. 2021 ;12 734976
    MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence.
    Chiara Giordani, Andrea Silvestrini, Angelica Giuliani, Fabiola Olivieri, Maria Rita Rippo.
      Mitochondria are essential organelles that generate most of the chemical energy to power the cell through ATP production, thus regulating cell homeostasis. Although mitochondria have their own independent genome, most of the mitochondrial proteins are encoded by nuclear genes. An extensive bidirectional communication network between mitochondria and the nucleus has been discovered, thus making them semi-autonomous organelles. The nucleus-to-mitochondria signaling pathway, called Anterograde Signaling Pathway can be deduced, since the majority of mitochondrial proteins are encoded in the nucleus, less is known about the opposite pathway, the so-called mitochondria-to-nucleus retrograde signaling pathway. Several studies have demonstrated that non-coding RNAs are essential "messengers" of this communication between the nucleus and the mitochondria and that they might have a central role in the coordination of important mitochondrial biological processes. In particular, the finding of numerous miRNAs in mitochondria, also known as mitomiRs, enabled insights into their role in mitochondrial gene transcription. MitomiRs could act as important mediators of this complex crosstalk between the nucleus and the mitochondria. Mitochondrial homeostasis is critical for the physiological processes of the cell. Disruption at any stage in their metabolism, dynamics and bioenergetics could lead to the production of considerable amounts of reactive oxygen species and increased mitochondrial permeability, which are among the hallmarks of cellular senescence. Extensive changes in mitomiR expression and distribution have been demonstrated in senescent cells, those could possibly lead to an alteration in mitochondrial homeostasis. Here, we discuss the emerging putative roles of mitomiRs in the bidirectional communication pathways between mitochondria and the nucleus, with a focus on the senescence-associated mitomiRs.
    Keywords:  microRNA; mitochondria; mitomiRs; mitonuclear communication; senescence
    DOI:  https://doi.org/10.3389/fphys.2021.734976
  35. Cells. 2021 Sep 18. pii: 2465. [Epub ahead of print]10(9):
    LSD1 Facilitates Pro-Inflammatory Polarization of Macrophages by Repressing Catalase.
    Maciej Sobczak, Magdalena Strachowska, Karolina Gronkowska, Iwona Karwaciak, Łukasz Pułaski, Agnieszka Robaszkiewicz.
      The increased level of hydrogen peroxide accompanies some modes of macrophage specification and is linked to ROS-based antimicrobial activity of these phagocytes. In this study, we show that activation of toll-like receptors with bacterial components such as LPS is accompanied by the decline in transcription of hydrogen peroxide decomposing enzyme-catalase, suppression of which facilitates the polarization of human macrophages towards the pro-inflammatory phenotype. The chromatin remodeling at the CAT promoter involves LSD1 and HDAC1, but activity of the first enzyme defines abundance of the two proteins on chromatin, histone acetylation status and the CAT transcription. LSD1 inhibition prior to macrophage activation with LPS prevents CAT repression by enhancing the LSD1 and interfering with the HDAC1 recruitment to the gene promoter. The maintenance of catalase level with LSD1 inhibitors during M1 polarization considerably limits LPS-triggered expression of some pro-inflammatory cytokines and markers such as IL1β, TNFα, COX2, CD14, TLR2, and IFNAR, but the effect of LSD1 inhibitors is lost upon catalase deficiency. Summarizing, activity of LSD1 allows for the CAT repression in LPS stimulated macrophages, which negatively controls expression of some key pro-inflammatory markers. LSD1 inhibitors can be considered as possible immunosuppressive drugs capable of limiting macrophage M1 specialization.
    Keywords:  LSD1; catalase; gene transcription; macrophages; pro-inflammatory markers
    DOI:  https://doi.org/10.3390/cells10092465
  36. Cancer Manag Res. 2021 ;13 7355-7363
    Obesity Promotes Tumor Immune Evasion in Ovarian Cancer Through Increased Production of Myeloid-Derived Suppressor Cells via IL-6.
    Qiannan Yang, Bojun Yu, Jiuhong Kang, Ang Li, Jing Sun.
      Background: Obesity is defined as a chronic, low-grade inflammatory disease that can cause obesity-associated disorders, such as cancer. Obesity has traditionally been thought to be a risk factor for ovarian cancer. Few reports have focused on the specific pathogenesis of obesity-related ovarian cancer. When considering the correlation between obesity and the relative risk of death from ovarian cancer, we investigated whether obesity promotes tumor immune escape in ovarian cancer.Results: In the present study, obese mice were found to have higher rates of tumor growth and tumor infiltration than mice of normal weight. Obesity increased the proportion of myeloid-derived suppressor cells (MDSCs) in peripheral blood compared with mice of normal weight. In addition, the levels of CCL25, CD40L, GM-CSF, IL-5, IGFBP2, IL-6, MMP3, and MMP9 in the peripheral blood, bone marrow, and ovarian tissue of obese mice were higher than in mice of normal weight. Moreover, IL-5 and IL-6 significantly enhanced the expression levels of S100A8 and S100A9 in MDSCs. When compared with the levels in mice of normal weight, the expression levels of S100A8 and S100A9 in the MDSCs of OB/OB mice were also higher within the tumor microenvironment. The infiltration of MDSCs in ovarian cancer was found to be positively correlated with the expression levels of IL-6. The IL-6 expression levels in ovarian cancer tissue are positively correlated with the expression levels of S100A8 and S100A9, which is consistent with the results of previous animal experiments. Finally, we found that LMT28 can suppress the tumor growth by inhibiting IL-6.
    Conclusion: Obesity promotes the expression of the MDSC-related immunosuppressive genes S100A8 and S100A9 by upregulating IL-6, thus promoting tumor immune evasion and metastasis in ovarian cancer.
    Keywords:  IL-6; MDSCs; obesity; ovarian cancer
    DOI:  https://doi.org/10.2147/CMAR.S303707
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