bims-mepmim 2022-06-12 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2022‒06‒12
39 papers selected by
Erika Mariana Palmieri
NIH/NCI Laboratory of Cancer ImmunoMetabolism

Nanodrug regulates lactic acid metabolism to reprogram the immunosuppressive tumor microenvironment for enhanced cancer immunotherapy.
Cholesterol crystals drive metabolic reprogramming and M1 macrophage polarisation in primary human macrophages.
Empagliflozin modulates CD4+ T-cell differentiation via metabolic reprogramming in immune thrombocytopenia.
LDHB Overexpression Can Partially Overcome T Cell Inhibition by Lactic Acid.
AMPK Modulates the Metabolic Adaptation of C6 Glioma Cells in Glucose-Deprived Conditions without Affecting Glutamate Transport.
Fungal Patterns Induce Cytokine Expression through Fluxes of Metabolic Intermediates That Support Glycolysis and Oxidative Phosphorylation.
SCAP deficiency facilitates obesity and insulin resistance through shifting adipose tissue macrophage polarization.
The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis.
pH sensing controls tissue inflammation by modulating cellular metabolism and endo-lysosomal function of immune cells.
Nitric oxide favours tumour-promoting inflammation through mitochondria-dependent and -independent actions on macrophages.
Immunomodulatory properties of mesenchymal stromal/stem cells: the link with metabolism.
Mammary adipocytes protect triple-negative breast cancer cells from ferroptosis.
13C-Labeled Diethyl Ketoglutarate Derivatives as Hyperpolarized Probes of 2-Ketoglutarate Dehydrogenase Activity.
Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle.
Tracing Lipid Metabolism by Alkyne Lipids and Mass Spectrometry: The State of the Art.
Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
Modulation of Inflammation-Related Lipid Mediator Pathways by Celastrol During Human Macrophage Polarization.
Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation.
The CXCL12/CXCR4/ACKR3 Signaling Axis Regulates PKM2 and Glycolysis.
A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer.
Inhibition of the 3-mercaptopyruvate sulfurtransferase-hydrogen sulfide system promotes cellular lipid accumulation.
Roles of Notch Signaling in the Tumor Microenvironment.
Targeting tumor-associated macrophages for cancer treatment.
Cellular senescence and the tumor microenvironment.
The Role of Indoleamine 2, 3-Dioxygenase 1 in Regulating Tumor Microenvironment.
The polyol pathway is an evolutionarily conserved system for sensing glucose uptake.
WNT links metabolism and cell cycle in postnatal cardiomyocytes.
Reprogramming Mitochondrial Metabolism in Synovial Macrophages of Early Osteoarthritis by A Camouflaged meta-Defensome.
Metabolic and immune-sensitive contacts between lipid droplets and endoplasmic reticulum reconstituted in vitro.
Lipid metabolism and neutrophil function.
High glutamine suppresses osteogenesis through mTORC1-mediated inhibition of the mTORC2/AKT-473/RUNX2 axis.
Human Mesenchymal Stromal Cells Resolve Lipid Load in High Fat Diet-Induced Non-Alcoholic Steatohepatitis in Mice by Mitochondria Donation.
Fructose-mediated NLRP3 activation induces inflammation and lipogenesis in adipose tissue.
LXRα Regulates oxLDL-Induced Trained Immunity in Macrophages.
Integration of metabolomics with genomics: Metabolic gene prioritization using metabolomics data and genomic variant (CADD) scores.
Succinate metabolism in the retinal pigment epithelium uncouples respiration from ATP synthesis.
Hydrogen sulfide regulates macrophage function in cardiovascular diseases.
Extracellular ATP and Imbalance of CD4+ T Cell Compartment in Pediatric COVID-19.
Metabolic Profiling of Mice with Deletion of the Orphan G Protein-Coupled Receptor, GPR37L1.

Biomater Sci. 2022 Jun 10.

Nanodrug regulates lactic acid metabolism to reprogram the immunosuppressive tumor microenvironment for enhanced cancer immunotherapy.

Li-Rong Tian, Min-Zhao Lin, Hui-Hai Zhong, Yu-Jun Cai, Bo Li, Ze-Cong Xiao, Xin-Tao Shuai.

A majority of cancers fail to respond to immunotherapy due to the immunosuppressive tumor microenvironment (TME), and metabolic regulation of the TME has been a promising strategy to improve immunotherapy. Lactate is a key metabolic player in tumor immune response since its excess secretion aggravates tumor immune escape by favoring the polarization of tumor-associated macrophages (TAMs) to an immunosuppressive phenotype meanwhile impeding the tumor infiltration of the cytotoxic T lymphocyte. Here, we proposed a metabolic reprogramming mechanism to ameliorate tumor immunosuppression by using lonidamine and syrosingopine incorporated liposomes (L@S/L) to regulate lactate production and efflux. Concretely, lonidamine reduced lactate production by affecting the glycolytic metabolic pathway while syrosingopine decreased lactate efflux by inhibiting the key protein expression of the lactate transporter MCT-4. Consequently, both the drugs synergistically normalize the pH of the TME to overcome the tumor immunosuppressive microenvironment. In vivo studies demonstrated that the decreased extracellular lactate preferentially polarized TAMs to the M1 phenotype, simultaneously increased the proportion of NK cells and reduced the number of Treg cells. These results validated an efficient tumor immunotherapy in the breast cancer model. This new strategy of lactic acid metabolism regulation is proposed to operate in concert with immune modulation in the TME, which shows great potential for immunotherapy of immunologically "cold" tumors.

DOI: https://doi.org/10.1039/d2bm00650b
Atherosclerosis. 2022 May 25. pii: S0021-9150(22)00251-9. [Epub ahead of print]352 35-45

Cholesterol crystals drive metabolic reprogramming and M1 macrophage polarisation in primary human macrophages.

Sinead A O'Rourke, Nuno G B Neto, Eimear Devilly, Lianne C Shanley, Hannah K Fitzgerald, Michael G Monaghan, Aisling Dunne.

  BACKGROUND AND AIMS: Metabolic reprogramming of innate immune cells is emerging as a key player in the progression of a number of chronic diseases, including atherosclerosis, where high rates of glycolysis correlate with plaque instability. This study aimed to investigate if cholesterol crystals, which are key atherosclerosis-associated DAMPs (damage/danger-associated molecular patterns), alter immune cell metabolism and whether this, in turn, impacts on macrophage phenotype and function.METHODS AND RESULTS: Primary human macrophages were treated with cholesterol crystals and expression of M1 (CXCL9, CXCL10) and M2-associated (MRC1, CCL13) macrophage markers, alarmins, and inflammatory cytokines were assessed either by real-time PCR or ELISA. Cholesterol crystal-induced changes in glycolytic markers were determined using real-time PCR and western blotting, while changes in cellular respiration and mitochondrial dynamics were examined via Seahorse analysis, Fluorescence Lifetime Imaging Microscopy (FLIM) and confocal microscopy. Treatment of macrophages with cholesterol crystals upregulated mRNA levels of CXCL9 and CXCL10, while concomitantly downregulating expression of MRC1 and CCL13. Cholesterol crystal--treated macrophages also exhibited a significant shift in metabolism to favour glycolysis, accompanied by the expression of key glycolytic markers GLUT1, Hexokinase 2, HIF1α, GAPDH and PFKFB3. Furthermore, we show that these effects are mediated upstream by the glycolytic enzyme, PKM2, and that direct inhibition of glycolysis or PKM2 nuclear localisation leads to a significant reduction in cholesterol crystal-induced inflammatory readouts.
CONCLUSIONS: This study not only provides further insight into how atherosclerosis-associated DAMPs impact on immune cell function, but also highlights metabolic reprogramming as a potential therapeutic target for cholesterol crystal-related inflammation.

Keywords:  Atherosclerosis; Cardiovascular disease; Immunometabolism; Inflammation; Innate immunity; Macrophages; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.atherosclerosis.2022.05.015
Br J Haematol. 2022 Jun 08.

Empagliflozin modulates CD4+ T-cell differentiation via metabolic reprogramming in immune thrombocytopenia.

Jing Qin, Qiang Liu, Anli Liu, Shaoqiu Leng, Shuwen Wang, Chaoyang Li, Ji Ma, Jun Peng, Miao Xu.

  Immune thrombocytopenia (ITP) is an acquired autoimmune disease, in which the imbalance of CD4+ T cell subsets play a key role in the pathogenesis. Since T cells highly depend on metabolism for their function, we hypothesized that T cell dysfunction may be due to intracellular metabolic reprogramming. We found that in ITP, T cell metabolism shifts from oxidative phosphorylation to glycolysis. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown regulatory metabolic effects on proximal tubular epithelial cells and cardiac cells beyond glucose lowering. However, the effects of empagliflozin on T cells remain unknown. To further investigate the metabolic dysfunction of CD4+ T cells in ITP, we explored the effect of empagliflozin on CD4+ T-cell differentiation in ITP. Our results are the first to show that increased glycolysis in CD4+ T cells resulted in an unbalanced CD4+ T-cell population. Furthermore, empagliflozin can affect the differentiation of CD4+ T-cell subsets by inhibiting Th1 and Th17 cell populations while increasing Tregs. Empagliflozin appears to regulate CD4+ T cells through inhibiting the mTOR signal pathway. Considering these results, we propose that empagliflozin could be used as a potential therapeutic option for ITP by modulating metabolic reprogramming in CD4+ T cells.

Keywords:  SGLT2 inhibitor; T subsets; glycolysis; immune thrombocytopenia; oxidative phosphorylation

DOI:  https://doi.org/10.1111/bjh.18293
Int J Mol Sci. 2022 May 26. pii: 5970. [Epub ahead of print]23(11):

LDHB Overexpression Can Partially Overcome T Cell Inhibition by Lactic Acid.

Sonja-Maria Decking, Christina Bruss, Nathalie Babl, Sebastian Bittner, Sebastian Klobuch, Simone Thomas, Markus Feuerer, Petra Hoffmann, Katja Dettmer, Peter J Oefner, Kathrin Renner, Marina Kreutz.

  Accelerated glycolysis leads to secretion and accumulation of lactate and protons in the tumor environment and determines the efficacy of adoptive T cell and checkpoint inhibition therapy. Here, we analyzed effects of lactic acid on different human CD4 T cell subsets and aimed to increase CD4 T cell resistance towards lactic acid. In all CD4 T cell subsets analyzed, lactic acid inhibited metabolic activity (glycolysis and respiration), cytokine secretion, and cell proliferation. Overexpression of the lactate-metabolizing isoenzyme LDHB increased cell respiration and mitigated lactic acid effects on intracellular cytokine production. Strikingly, LDHB-overexpressing cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules. We conclude, that LDHB overexpression might be a promising strategy to increase the efficacy of adoptive T cell transfer therapy.

Keywords:  LDH; T cell metabolism; T cells; adoptive cell transfer; glycolysis; interferon gamma; lactate; lactic acid

DOI:  https://doi.org/10.3390/ijms23115970
Cells. 2022 May 31. pii: 1800. [Epub ahead of print]11(11):

AMPK Modulates the Metabolic Adaptation of C6 Glioma Cells in Glucose-Deprived Conditions without Affecting Glutamate Transport.

Inês Belo do Nascimento, Marie Verfaillie, Gamze Ates, Pauline Beckers, Virginie Joris, Nathalie Desmet, Ann Massie, Emmanuel Hermans.

  Energy homeostasis in the central nervous system largely depends on astrocytes, which provide metabolic support and protection to neurons. Astrocytes also ensure the clearance of extracellular glutamate through high-affinity transporters, which indirectly consume ATP. Considering the role of the AMP-activated protein kinase (AMPK) in the control of cell metabolism, we have examined its implication in the adaptation of astrocyte functions in response to a metabolic stress triggered by glucose deprivation. We genetically modified the astrocyte-like C6 cell line to silence AMPK activity by overexpressing a dominant negative mutant of its catalytic subunit. Upon glucose deprivation, we found that C6 cells maintain stable ATP levels and glutamate uptake capacity, highlighting their resilience during metabolic stress. In the same conditions, cells with silenced AMPK activity showed a reduction in motility, metabolic activity, and ATP levels, indicating that their adaptation to stress is compromised. The rate of ATP production remained, however, unchanged by AMPK silencing, suggesting that AMPK mostly influences energy consumption during stress conditions in these cells. Neither AMPK modulation nor prolonged glucose deprivation impaired glutamate uptake. Together, these results indicate that AMPK contributes to the adaptation of astrocyte metabolism triggered by metabolic stress, but not to the regulation of glutamate transport.

Keywords:  ATP; astrocyte; glucose deprivation; glutamate transporter; metabolic stress

DOI:  https://doi.org/10.3390/cells11111800
J Immunol. 2022 Jun 10. pii: ji2100666. [Epub ahead of print]

Fungal Patterns Induce Cytokine Expression through Fluxes of Metabolic Intermediates That Support Glycolysis and Oxidative Phosphorylation.

Cristina Mancebo, José Javier Fernández, Carmen Herrero-Sánchez, Yolanda Alvarez, Sara Alonso, Tito A Sandoval, Juan R Cubillos-Ruiz, Olimpio Montero, Nieves Fernández, Mariano Sánchez Crespo.

Cytokine expression is fine-tuned by metabolic intermediates, which makes research on immunometabolism suitable to yield drugs with a wider prospect of application than the biological therapies that block proinflammatory cytokines. Switch from oxidative phosphorylation (OXPHOS) to glycolysis has been considered a characteristic feature of activated immune cells. However, some stimuli might enhance both routes concomitantly. The connection between the tricarboxylic acid cycle and cytokine expression was scrutinized in human monocyte-derived dendritic cells stimulated with the fungal surrogate zymosan. Results showed that nucleocytosolic citrate and ATP-citrate lyase activity drove IL1B, IL10, and IL23A expression by yielding acetyl-CoA and oxaloacetate, with the latter one supporting glycolysis and OXPHOS by maintaining cytosolic NAD+ and mitochondrial NADH levels through mitochondrial shuttles. Succinate dehydrogenase showed a subunit-specific ability to modulate IL23A and IL10 expression. Succinate dehydrogenase A subunit activity supported cytokine expression through the control of the 2-oxoglutarate/succinate ratio, whereas C and D subunits underpinned cytokine expression by conveying electron flux from complex II to complex III of the electron transport chain. Fatty acids may also fuel the tricarboxylic acid cycle and influence cytokine expression. Overall, these results show that fungal patterns support cytokine expression through a strong boost of glycolysis and OXPHOS supported by the use of pyruvate, citrate, and succinate, along with the compartmentalized NAD(H) redox state maintained by mitochondrial shuttles.

DOI: https://doi.org/10.4049/jimmunol.2100666
J Adv Res. 2022 May 31. pii: S2090-1232(22)00124-2. [Epub ahead of print]

SCAP deficiency facilitates obesity and insulin resistance through shifting adipose tissue macrophage polarization.

Jae-Ho Lee, Sun Hee Lee, Eun-Ho Lee, Jeong-Yong Cho, Dae-Kyu Song, Young Jae Lee, Taeg Kyu Kwon, Byung-Chul Oh, Kae Won Cho, Timothy F Osborne, Tae-Il Jeon, Seung-Soon Im.

  INTRODUCTION: Sterol regulatory element binding protein (SREBP) cleavage-associating protein (SCAP) is a sterol-regulated escort protein that translocates SREBPs from the endoplasmic reticulum to the Golgi apparatus, thereby activating lipid metabolism and cholesterol synthesis. Although SCAP regulates lipid metabolism in metabolic tissues, such as the liver and muscle, the effect of macrophage-specific SCAP deficiency in adipose tissue macrophages (ATMs) of patients with metabolic diseases is not completely understood.OBJECTIVES: Here, we examined the function of SCAP in high-fat/high-sucrose diet (HFHS)-fed mice and investigated its role in the polarization of classical activated macrophages in adipose tissue.
METHODS: Macrophage-specific SCAP knockout (mKO) mice were generated through crossbreeding lysozyme 2-cre mice with SCAP floxed mice which were then fed HFHS for 12 weeks. Primary macrophages were derived from bone marrow cells and analyzed further.
RESULTS: We found that fat accumulation and the appearance of proinflammatory M1 macrophages were both higher in HFHS-fed SCAP mKO mice relative to floxed control mice. We traced the effect to a defect in the lipopolysaccharide-mediated increase in SREBP-1a that occurs in control but not SCAP mKO mice. Mechanistically, SREBP-1a increased expression of cholesterol 25-hydroxylase transcription, resulting in an increase in the production of 25-hydroxycholesterol (25-HC), an endogenous agonist of liver X receptor alpha (LXRα) which increased expression of cholesterol efflux to limit cholesterol accumulation and M1 polarization. In the absence of SCAP mediated activation of SREBP-1a, increased M1 macrophage polarization resulted in reduced cholesterol efflux downstream from 25-HC-dependent LXRα activation.
CONCLUSION: Overall, the activation of the SCAP-SREBP-1a pathway in macrophages may provide a novel therapeutic strategy that ameliorates obesity by controlling cholesterol homeostasis in ATMs.

Keywords:  Cholesterol 25-hydroxylase; Cholesterol efflux; Macrophages; SCAP; White adipose tissue

DOI:  https://doi.org/10.1016/j.jare.2022.05.013
Front Immunol. 2022 ;13 867260

The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis.

Maurizio Cutolo, Rosanna Campitiello, Emanuele Gotelli, Stefano Soldano.

  Innate and adaptive immunity represent a harmonic counterbalanced system involved in the induction, progression, and possibly resolution of the inflammatory reaction that characterize autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA). Although the immunopathophysiological mechanisms of the ARDs are not fully clarified, they are often associated with an inappropriate macrophage/T-cell interaction, where classical (M1) or alternative (M2) macrophage activation may influence the occurrence of T-helper (Th)1 or Th2 responses. In RA patients, M1/Th1 activation occurs in an inflammatory environment dominated by Toll-like receptor (TLR) and interferon (IFN) signaling, and it promotes a massive production of pro-inflammatory cytokines [i.e., tumor necrosis factor-α (TNFα), interleukin (IL)-1, IL-12, IL-18, and IFNγ], chemotactic factors, and matrix metalloproteinases resulting in osteoclastogenesis, erosion, and progressive joint destruction. On the other hand, the activation of M2/Th2 response determines the release of growth factors and cytokines [i.e., IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β] involved in the anti-inflammatory process leading to the clinical remission of RA. Several subtypes of macrophages have been described. Five polarization states from M1 to M2 have been confirmed in in vitro studies analyzing morphological characteristics, gene expression of phenotype markers (CD80, CD86, TLR2, TLR4, or CD206, CD204, CD163, MerTK), and functional aspect, including the production of reactive oxygen species (ROS). An M1 and M2 macrophage imbalance may induce pathological consequences and contribute to several diseases, such as asthma or osteoclastogenesis in RA patients. In addition, the macrophage dynamic polarization from M1 to M2 includes the presence of intermediate polarity stages distinguished by the expression of specific surface markers and the production/release of distinct molecules (i.e., nitric oxide, cytokines), which characterize their morphological and functional state. This suggests a "continuum" of macrophage activation states playing an important role during inflammation and its resolution. This review discusses the importance of the delicate M1/M2 imbalance in the different phases of the inflammatory process together with the identification of specific pathways, cytokines, and chemokines involved, and its clinical outcomes in RA. The analysis of these aspects could shed a light on the abnormal inflammatory activation, leading to novel therapeutical approaches which may contribute to restore the M1/M2 balance.

Keywords:  Inflammation; Macrophage polarization; Rheumatoid anhritis; Synovitis; bDMARD therapy

DOI:  https://doi.org/10.3389/fimmu.2022.867260
Nat Immunol. 2022 Jun 06.

pH sensing controls tissue inflammation by modulating cellular metabolism and endo-lysosomal function of immune cells.

Xiangjun Chen, Alok Jaiswal, Zachary Costliow, Paula Herbst, Elizabeth A Creasey, Noriko Oshiro-Rapley, Mark J Daly, Kimberly L Carey, Daniel B Graham, Ramnik J Xavier.

Extracellular acidification occurs in inflamed tissue and the tumor microenvironment; however, a systematic study on how pH sensing contributes to tissue homeostasis is lacking. In the present study, we examine cell type-specific roles of the pH sensor G protein-coupled receptor 65 (GPR65) and its inflammatory disease-associated Ile231Leu-coding variant in inflammation control. GPR65 Ile231Leu knock-in mice are highly susceptible to both bacterial infection-induced and T cell-driven colitis. Mechanistically, GPR65 Ile231Leu elicits a cytokine imbalance through impaired helper type 17 T cell (TH17 cell) and TH22 cell differentiation and interleukin (IL)-22 production in association with altered cellular metabolism controlled through the cAMP-CREB-DGAT1 axis. In dendritic cells, GPR65 Ile231Leu elevates IL-12 and IL-23 release at acidic pH and alters endo-lysosomal fusion and degradation capacity, resulting in enhanced antigen presentation. The present study highlights GPR65 Ile231Leu as a multistep risk factor in intestinal inflammation and illuminates a mechanism by which pH sensing controls inflammatory circuits and tissue homeostasis.

DOI: https://doi.org/10.1038/s41590-022-01231-0
Redox Biol. 2022 May 27. pii: S2213-2317(22)00122-7. [Epub ahead of print]54 102350

Nitric oxide favours tumour-promoting inflammation through mitochondria-dependent and -independent actions on macrophages.

Daiana Drehmer, João Paulo Mesquita Luiz, Cesar Augusto Speck Hernandez, José Carlos Alves-Filho, Tracy Hussell, Paul Andrew Townsend, Salvador Moncada.

Production of nitric oxide (NO) has been demonstrated in several malignancies, however its role remains not fully understood, specifically in relation to the metabolic and functional implications that it may have on immune cells participating in tumorigenesis. Here, we show that inducible NO synthase (iNOS) is expressed in cancers of the colon and the prostate, mainly by tumour cells, and NO generation is evidenced by widespread nitrotyrosine (NT) staining in tumour tissue. Furthermore, presence of NT is observed in the majority of tumour-associated macrophages (TAMs), despite low iNOS expression by these cells, suggesting that NO from the tumour microenvironment affects TAMs. Indeed, using a co-culture model, we demonstrate that NO produced by colon and prostate cancer cells is sufficient to induce NT formation in neighbouring macrophages. Moreover, exposure to exogenous NO promotes mitochondria-dependent and -independent changes in macrophages, which orientate their polarity towards an enhanced pro-inflammatory phenotype, whilst decreasing antigen-presenting function and wound healing capacity. Abrogating endogenous NO generation in murine macrophages, on the other hand, decreases their pro-inflammatory phenotype. These results suggest that the presence of NO in cancer may regulate TAM metabolism and function, favouring the persistence of inflammation, impairing healing and subverting adaptive immunity responses.

DOI: https://doi.org/10.1016/j.redox.2022.102350
J Adv Res. 2022 May 31. pii: S2090-1232(22)00125-4. [Epub ahead of print]

Immunomodulatory properties of mesenchymal stromal/stem cells: the link with metabolism.

Hanyue Li, Hongwei Dai, Jie Li.

  BACKGROUND: Mesenchymal stromal/stem cells (MSCs) are the most promising stem cells for the treatment of multiple inflammatory and immune diseases due to their easy acquisition and potent immuno-regulatory capacities. These immune functions mainly depend on the MSC secretion of soluble factors. Recent studies have shown that the metabolism of MSCs plays critical roles in immunomodulation, which not only provides energy and building blocks for macromolecule synthesis but is also involved in the signaling pathway regulation.AIM OF REVIEW: A thorough understanding of metabolic regulation in MSC immunomodulatory properties can provide new sights to the enhancement of MSC-based therapy.
KEY SCIENTIFIC CONCEPTS OF REVIEW: MSC immune regulation can be affected by cellular metabolism (glucose, fatty acid and amino acid metabolism), which further mediates MSC therapy efficiency in inflammatory and immune diseases. The enhancement of glycolysis of MSCs, such as signaling molecule activation, inflammatory cytokines priming, or environmental control can promote MSC immune functions and therapeutic potential. Besides glucose metabolism, inflammatory stimuli also alter the lipid molecular profile of MSCs, but the direct link with immunomodulatory properties remains to be further explored. Arginine metabolism, glutamine-glutamate metabolism and tryptophan-kynurenine via indoleamine 2,3-dioxygenase (IDO) metabolism all contribute to the immune regulation of MSCs. In addition to the metabolism dictating the MSC immune functions, MSCs also influence the metabolism of immune cells and thus determine their behaviors. However, more direct evidence of the metabolism in MSC immune abilities as well as the underlying mechanism requires to be uncovered.

Keywords:  Immunomodulatory properties; Mesenchymal stromal/stem cells (MSCs); Metabolism; Therapy

DOI:  https://doi.org/10.1016/j.jare.2022.05.012
J Hematol Oncol. 2022 Jun 03. 15(1): 72

Mammary adipocytes protect triple-negative breast cancer cells from ferroptosis.

Yizhao Xie, Biyun Wang, Yannan Zhao, Zhonghua Tao, Ye Wang, Guangliang Chen, Xichun Hu.

  Ferroptosis, a novel non-apoptotic form of cell death, can induce tumor cell death and treatment resistance. Lipid metabolism is closely related to ferroptosis; however, the effect of mammary adipocytes on breast cancer ferroptosis remains to be elucidated. Here, we established the co-culture system of adipocyte-breast cancer cells and revealed the protection of triple-negative breast cancer from ferroptosis by adipocytes. Then, we performed the lipidomics analysis comparing lipid metabolites of co-cultured and normal-cultured cells. Mechanistically, oleic acid secreted from adipocytes inhibited lipid peroxidation and ferroptosis of triple-negative breast cancer cells in the presence of ACSL3. Taken together, mammary adipocytes can protect breast cancer cells from ferroptosis through oleic acid in the presence of ACSL3. These findings could provide new ideas and targets for tumor treatment.

Keywords:  Adipocytes; Breast cancer; Cell death; Ferroptosis; Lipid metabolism

DOI:  https://doi.org/10.1186/s13045-022-01297-1
Anal Sens. 2021 Nov;1(4): 156-160

13C-Labeled Diethyl Ketoglutarate Derivatives as Hyperpolarized Probes of 2-Ketoglutarate Dehydrogenase Activity.

Jaspal Singh, Eul Hyun Suh, Gaurav Sharma, Jun Chen, Edward P Hackett, Xiaodong Wen, A Dean Sherry, Chalermchai Khemtong, Craig R Malloy, Jae Mo Park, Zoltan Kovacs.

  The TCA cycle is a central metabolic pathway for energy production and biosynthesis. A major control point of metabolic flux through the cycle is the decarboxylation of 2-ketoglutarate by the TCA cycle enzyme 2-ketoglutarate dehydrogenase (2-KGDH). In this project, we developed 13C labeled 2-ketoglutarate derivatives to monitor 2-KGDH activity in vivo. 13C NMR analysis of liver extracts revealed that uniformly 13C labeled 2-ketogutarate, in its cell permeable ester form, was rapidly taken up and hydrolyzed in liver and underwent extensive metabolism to produce labeled glutamate, succinate, lactate and other metabolites. Diethyl [1,2-13C2]-2-ketoglutarate was successfully polarized by dynamic nuclear polarization and within seconds after injection into rats, the probe produced hyperpolarized [13C]bicarbonate in the liver reflecting flux through the TCA cycle. These experiments demonstrate that this tracer offers the possibility of directly monitoring flux through 2-KGDH in vivo.

Keywords:  NMR spectroscopy; TCA cycle; hyperpolarization; isotopic labeling; ketoglutarates

DOI:  https://doi.org/10.1002/anse.202100021
Cell Rep. 2022 Jun 07. pii: S2211-1247(22)00689-1. [Epub ahead of print]39(10): 110912

Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle.

Sophia Urbanczyk, Olivier R Baris, Jörg Hofmann, R Verena Taudte, Naïg Guegen, Florian Golombek, Kathrin Castiglione, Xianyi Meng, Aline Bozec, Jana Thomas, Leonie Weckwerth, Dimitrios Mougiakakos, Sebastian R Schulz, Wolfgang Schuh, Ursula Schlötzer-Schrehardt, Tobit D Steinmetz, Susanne Brodesser, Rudolf J Wiesner, Dirk Mielenz.

  To elucidate the function of oxidative phosphorylation (OxPhos) during B cell differentiation, we employ CD23Cre-driven expression of the dominant-negative K320E mutant of the mitochondrial helicase Twinkle (DNT). DNT-expression depletes mitochondrial DNA during B cell maturation, reduces the abundance of respiratory chain protein subunits encoded by mitochondrial DNA, and, consequently, respiratory chain super-complexes in activated B cells. Whereas B cell development in DNT mice is normal, B cell proliferation, germinal centers, class switch to IgG, plasma cell maturation, and T cell-dependent as well as T cell-independent humoral immunity are diminished. DNT expression dampens OxPhos but increases glycolysis in lipopolysaccharide and B cell receptor-activated cells. Lipopolysaccharide-activated DNT-B cells exhibit altered metabolites of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle and a lower amount of phosphatidic acid. Consequently, mTORC1 activity and BLIMP1 induction are curtailed, whereas HIF1α is stabilized. Hence, mitochondrial DNA controls the metabolism of activated B cells via OxPhos to foster humoral immunity.

Keywords:  B lymphocyte; CP: Immunology; HIF1; TCA cycle; class switch recombination; germinal center; hypoxia inducible factor 1; mTOR; mammalian target of Rapamycin; mitochondrial DNA; mitochondrial respiration; oxidative phosphorylation; phosphatidic acid; plasma cell

DOI:  https://doi.org/10.1016/j.celrep.2022.110912
Front Mol Biosci. 2022 ;9 880559

Tracing Lipid Metabolism by Alkyne Lipids and Mass Spectrometry: The State of the Art.

Lars Kuerschner, Christoph Thiele.

  Lipid tracing studies are a key method to gain a better understanding of the complex metabolic network lipids are involved in. In recent years, alkyne lipid tracers and mass spectrometry have been developed as powerful tools for such studies. This study aims to review the present standing of the underlying technique, highlight major findings the strategy allowed for, summarize its advantages, and discuss some limitations. In addition, an outlook on future developments is given.

Keywords:  analog; click; fatty acid; lipidomics; metabolism; probe; tracer; β-oxidation

DOI:  https://doi.org/10.3389/fmolb.2022.880559
Nat Cancer. 2022 Jun 09.

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.

Ali Vaziri-Gohar, Joel Cassel, Farheen S Mohammed, Mehrdad Zarei, Jonathan J Hue, Omid Hajihassani, Hallie J Graor, Yellamelli V V Srikanth, Saadia A Karim, Ata Abbas, Erin Prendergast, Vanessa Chen, Erryk S Katayama, Katerina Dukleska, Imran Khokhar, Anthony Andren, Li Zhang, Chunying Wu, Bernadette Erokwu, Chris A Flask, Mahsa Zarei, Rui Wang, Luke D Rothermel, Andrea M P Romani, Jessica Bowers, Robert Getts, Curtis Tatsuoka, Jennifer P Morton, Ilya Bederman, Henri Brunengraber, Costas A Lyssiotis, Joseph M Salvino, Jonathan R Brody, Jordan M Winter.

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

DOI: https://doi.org/10.1038/s43018-022-00393-y
J Inflamm Res. 2022 ;15 3285-3304

Modulation of Inflammation-Related Lipid Mediator Pathways by Celastrol During Human Macrophage Polarization.

Kehong Zhang, Paul Mike Jordan, Simona Pace, Robert K Hofstetter, Markus Werner, Xinchun Chen, Oliver Werz.

  Background and Purpose: Celastrol (CS) is a major active ingredient of the Chinese/Asian herb Tripterygium wilfordii that is frequently used as phytomedicine to treat inflammation and autoimmune diseases. We showed before that short-term exposure to CS (1 µM) favorably impacts the biosynthesis of inflammation-related lipid mediators (LM) in human polarized macrophages by modulating the activities of different lipoxygenases (LOXs). However, whether CS regulates the expression of LOXs and other related LM-biosynthetic enzymes during macrophage polarization is unknown. Here, we investigated how CS affects LM-biosynthetic enzyme expression on the protein level and studied concomitant LM signature profiles during polarization of human monocyte-derived macrophages (MDM) towards M1- and M2-like phenotypes.Methods and Results: We used LM metabololipidomics to study the long-term effects of CS on LM profile signatures after manipulation of human monocyte-derived macrophages (MDM) during polarization. Exposure of MDM to low concentrations of CS (ie, 0.2 µM) during polarization to an inflammatory M1 phenotype potently suppressed the formation of pro-inflammatory cyclooxygenase (COX)- and 5-LOX-derived LM, especially prostaglandin (PG)E2. Notably, gene and enzyme expression of COX-2 and microsomal PGE2 synthase (mPGES)-1 as well as M1 markers were strongly decreased by CS during M1-MDM polarization, along with impaired activation of nuclear factor-κB and p38 mitogen-activated protein kinase. During IL-4-induced M2 polarization, CS decreased the capacity of the resulting M2-MDM to generate pro-inflammatory COX and 5-LOX products as well but it also reduced the formation of 12/15-LOX products and specialized pro-resolving mediators, without affecting the levels of liberated fatty acid substrates.
Conclusion: Depending on the timing and concentration, CS not only favorably affects LOX activities in macrophages but also the expression of LM-biosynthetic enzymes during macrophage polarization connected to changes of inflammation-related LM which might be of relevance for potential application of CS to treat inflammatory disorders.

Keywords:  celastrol; cyclooxygenase; inflammation; lipid mediators; lipoxygenase; macrophages; specialized pro-resolving mediators

DOI:  https://doi.org/10.2147/JIR.S356964
Front Immunol. 2022 ;13 880262

Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation.

Qiang Yu, Honghu Tu, Xueyi Yin, Chang Peng, Chuanyun Dou, Wenhua Yang, Wenbiao Wu, Xiaotong Guan, Jia Li, Hexin Yan, Yi Zang, Haowen Jiang, Qiang Xia.

  Background: Autoimmune hepatitis (AIH) is mediated by a cascade of T cell-mediated events directed at liver cells and persistent inflammation within the liver can eventually result in liver cirrhosis. Targeting glutamine metabolism has an impact on T cell activation and differentiation. However, the effect of glutamine metabolism blocking upon AIH remains unknown. We use glutaminase antagonist 6-diazo-5-oxo-L-norleucine (DON) for in vitro assays and its prodrug 2-(2-amino-4-methylpentanamido)-DON (JHU083) for in vivo assays to investigate the potential therapeutic effect and molecular mechanism of glutamine metabolism blocking in an AIH murine model.Methods: AIH mice were treated with JHU083 or vehicle before concanavalin A (ConA) administration, and disease severity was examined. Then activation and differentiation [including Th1/Th17 cells and cytotoxic T lymphocytes (CTL)] of T cells from Vehicle-WT, JHU083-AIH and Vehicle-AIH mice were tested. Furthermore, in vitro T cell activation and differentiation were measured using separated splenocytes stimulated with ConA with or without DON. The activation and differentiation of T cells were tested using flow cytometry, qRT-PCR and ELISA. Phosphorylation level of mammalian target of rapamycin (mTOR) and 70 kDa ribosomal protein S6 kinase (P70S6K) were examined by western blotting.
Results: JHU083 and DON significantly suppressed the activation of T cells and inhibited the differentiation of Th1/Th17 cells and CTL in vivo and in vitro. Besides, we demonstrated that glutamine metabolism blocking inhibited T cells activation and differentiation through decreasing the mRNA expression of amino acid transporter solute carrier family 7 member 5 (SLC7A5) and mitigating the activation of mTOR signaling.
Conclusions: We proved that targeting glutamine metabolism represents a potential new treatment strategy for patients with AIH and other T cell-mediated disease. Mechanistically, we demonstrated that glutamine metabolism blocking inhibits T cells activation and suppresses the differentiation of Th1/Th17 cells and CTL.

Keywords:  SLC7A5; T cells activation and differentiation; autoimmune hepatitis (AIH); glutamine metabolism; mTOR signaling

DOI:  https://doi.org/10.3389/fimmu.2022.880262
Cells. 2022 May 28. pii: 1775. [Epub ahead of print]11(11):

The CXCL12/CXCR4/ACKR3 Signaling Axis Regulates PKM2 and Glycolysis.

Kathryn E Luker, Gary D Luker.

  In response to CXCL12, CXCR4 and ACKR3 both recruit β-arrestin 2, regulating the assembly of interacting proteins that drive signaling and contribute to the functions of both receptors in cancer and multiple other diseases. A prior proteomics study revealed that β-arrestin 2 scaffolds pyruvate kinase M2 (PKM2), an enzyme implicated in shifting cells to glycolytic metabolism and poor prognosis in cancer. We hypothesized that CXCL12 signaling regulates PKM2 protein interactions, oligomerization, and glucose metabolism. We used luciferase complementation in cell-based assays and a tumor xenograft model of breast cancer in NSG mice to quantify how CXCR4 and ACKR3 change protein interactions in the β-arrestin-ERK-PKM2 pathway. We also used mass spectrometry to analyze the effects of CXCL12 on glucose metabolism. CXCL12 signaling through CXCR4 and ACKR3 stimulated protein interactions among β-arrestin 2, PKM2, ERK2, and each receptor, leading to the dissociation of PKM2 from β-arrestin 2. The activation of both receptors reduced the oligomerization of PKM2, reflecting a shift from tetramers to dimers or monomers with low enzymatic activity. Mass spectrometry with isotopically labeled glucose showed that CXCL12 signaling increased intermediate metabolites in glycolysis and the pentose phosphate pathway, with ACKR3 mediating greater effects. These data establish how CXCL12 signaling regulates PKM2 and reprograms cellular metabolism.

Keywords:  bioluminescence imaging; cancer metabolism; chemokines; luciferase complementation

DOI:  https://doi.org/10.3390/cells11111775
Redox Biol. 2022 Jun 02. pii: S2213-2317(22)00130-6. [Epub ahead of print]54 102358

A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer.

Chang Jiang, Nathan P Ward, Nicolas Prieto-Farigua, Yun Pyo Kang, Anish Thalakola, Mingxiang Teng, Gina M DeNicola.

  The redox regulator NRF2 is hyperactivated in a large percentage of non-small cell lung cancer (NSCLC) cases, which is associated with chemotherapy and radiation resistance. To identify redox vulnerabilities for KEAP1/NRF2 mutant NSCLC, we conducted a CRISPR-Cas9-based negative selection screen for antioxidant enzyme genes whose loss sensitized cells to sub-lethal concentrations of the superoxide (O2•-) -generating drug β-Lapachone. While our screen identified expected hits in the pentose phosphate pathway, the thioredoxin-dependent antioxidant system, and glutathione reductase, we also identified the mitochondrial superoxide dismutase 2 (SOD2) as one of the top hits. Surprisingly, β-Lapachone did not generate mitochondrial O2•- but rather SOD2 loss enhanced the efficacy of β-Lapachone due to loss of iron-sulfur protein function, loss of mitochondrial ATP maintenance and deficient NADPH production. Importantly, inhibition of mitochondrial electron transport activity sensitized cells to β-Lapachone, demonstrating that these effects may be translated to increase ROS sensitivity therapeutically.

Keywords:  KEAP1; NADPH; NFE2L2; NSCLC; ROS; SOD2; β-Lapachone

DOI:  https://doi.org/10.1016/j.redox.2022.102358
Geroscience. 2022 Jun 10.

Inhibition of the 3-mercaptopyruvate sulfurtransferase-hydrogen sulfide system promotes cellular lipid accumulation.

Giovanna Casili, Elisa Randi, Theodora Panagaki, Karim Zuhra, Maria Petrosino, Csaba Szabo.

  H2S is generated in the adipose tissue by cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase (3-MST). H2S plays multiple roles in the regulation of various metabolic processes, including insulin resistance. H2S biosynthesis also occurs in adipocytes. Aging is known to be associated with a decline in H2S. Therefore, the question arises whether endogenous H2S deficiency may affect the process of adipocyte maturation and lipid accumulation. Among the three H2S-generating enzymes, the role of 3-MST is the least understood in adipocytes. Here we tested the effect of the 3-MST inhibitor 2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one (HMPSNE) and the H2S donor (GYY4137) on the differentiation and adipogenesis of the adipocyte-like cells 3T3-L1 in vitro. 3T3-L1 cells were differentiated into mature adipocytes in the presence of GYY4137 or HMPSNE. HMPSNE significantly enhanced lipid accumulation into the maturing adipocytes. On the other hand, suppressed lipid accumulation was observed in cells treated with the H2S donor. 3-MST inhibition increased, while H2S donation suppressed the expression of various H2S-producing enzymes during adipocyte differentiation. 3-MST knockdown also facilitated adipocytic differentiation and lipid uptake. The underlying mechanisms may involve impairment of oxidative phosphorylation and fatty acid oxidation as well as the activation of various differentiation-associated transcription factors. Thus, the 3-MST/H2S system plays a tonic role in suppressing lipid accumulation and limiting the differentiation of adipocytes. Stimulation of 3-MST activity or supplementation of H2S-which has been recently linked to various experimental therapeutic approaches during aging-may be a potential experimental approach to counteract adipogenesis.

Keywords:  3-Mercaptopyruvate sulfurtransferase; Adipocytes; Hydrogen sulfide; Obesity

DOI:  https://doi.org/10.1007/s11357-022-00600-9
Int J Mol Sci. 2022 Jun 02. pii: 6241. [Epub ahead of print]23(11):

Roles of Notch Signaling in the Tumor Microenvironment.

Antonino B D'Assoro, Roberto Leon-Ferre, Eike-Benjamin Braune, Urban Lendahl.

  The Notch signaling pathway is an architecturally simple signaling mechanism, well known for its role in cell fate regulation during organ development and in tissue homeostasis. In keeping with its importance for normal development, dysregulation of Notch signaling is increasingly associated with different types of tumors, and proteins in the Notch signaling pathway can act as oncogenes or tumor suppressors, depending on the cellular context and tumor type. In addition to a role as a driver of tumor initiation and progression in the tumor cells carrying oncogenic mutations, it is an emerging realization that Notch signaling also plays a role in non-mutated cells in the tumor microenvironment. In this review, we discuss how aberrant Notch signaling can affect three types of cells in the tumor stroma-cancer-associated fibroblasts, immune cells and vascular cells-and how this influences their interactions with the tumor cells. Insights into the roles of Notch in cells of the tumor environment and the impact on tumor-stroma interactions will lead to a deeper understanding of Notch signaling in cancer and inspire new strategies for Notch-based tumor therapy.

Keywords:  Notch signaling; cancer; oncogene; tumor; tumor microenvironment; tumor suppressor gene

DOI:  https://doi.org/10.3390/ijms23116241
Cell Biosci. 2022 Jun 07. 12(1): 85

Targeting tumor-associated macrophages for cancer treatment.

Mengjun Li, Linye He, Jing Zhu, Peng Zhang, Shufang Liang.

  Tumor-associated macrophages (TAMs) are abundant, nearly accounting for 30-50% of stromal cells in the tumor microenvironment. TAMs exhibit an immunosuppressive M2-like phenotype in advanced cancer, which plays a crucial role in tumor growth, invasion and migration, angiogenesis and immunosuppression. Consequently, the TAM-targeting therapies are particularly of significance in anti-cancer strategies. The application of TAMs as anti-cancer targets is expected to break through traditional tumor-associated therapies and achieves favorable clinical effect. However, the heterogeneity of TAMs makes the strategy of targeting TAMs variable and uncertain. Discovering the subset specificity of TAMs might be a future option for targeting TAMs therapy. Herein, the review focuses on highlighting the different modalities to modulate TAM's functions, including promoting the phagocytosis of TAMs, TAMs depletion, blocking TAMs recruitment, TAMs reprogramming and suppressing immunosuppressive tumor microenvironment. We also discuss about several ways to improve the efficacy of TAM-targeting therapy from the perspective of combination therapy and specificity of TAMs subgroups.

Keywords:  Anticancer therapies; Immunotherapy; TAM-targeting therapy; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s13578-022-00823-5
Mol Oncol. 2022 Jun 08.

Cellular senescence and the tumor microenvironment.

Masaki Takasugi, Yuya Yoshida, Naoko Ohtani.

  The senescence-associated secretory phenotype (SASP), where senescent cells produce a variety of secreted proteins including inflammatory cytokines, chemokines, matrix remodeling factors, growth factors, and so on, plays pivotal but varying roles in the tumor microenvironment. The effects of SASP on the surrounding microenvironment depend on the cell type and process of cellular senescence induction, which is often associated with innate immunity. Via SASP-mediated paracrine effects, senescent cells can remodel the surrounding tissues by modulating the character of adjacent cells, such as stromal, immune cells, as well as cancer cells. The SASP is associated with both tumor-suppressive and tumor-promoting effects, as observed in senescence surveillance effects (tumor-suppressive) and suppression of anti-tumor immunity in most senescent cancer-associated fibroblasts (CAFs) and senescent T cells (tumor-promoting). In this review, we discuss the features and roles of senescent cells in tumor microenvironment with emphasis on their context-dependency that determines whether they promote or suppress cancer development. Potential usage of recently developed drugs that suppress the SASP (senomorphics) or selectively kill senescence cells (senolytics) in cancer therapy are also discussed.

Keywords:  SASP(senescence-associated secretory phenotype); cellular senescence; tumor microenvironment; anti-tumor immunity; senolysis; senomorphics

DOI:  https://doi.org/10.1002/1878-0261.13268
Cancers (Basel). 2022 Jun 01. pii: 2756. [Epub ahead of print]14(11):

The Role of Indoleamine 2, 3-Dioxygenase 1 in Regulating Tumor Microenvironment.

Xinting Huang, Feng Zhang, Xiaobo Wang, Ke Liu.

  Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that metabolizes an essential amino acid tryptophan (Trp) into kynurenine (Kyn), and it promotes the occurrence of immunosuppressive effects by regulating the consumption of Trp and the accumulation of Kyn in the tumor microenvironment (TME). Recent studies have shown that the main cellular components of TME interact with each other through this pathway to promote the formation of tumor immunosuppressive microenvironment. Here, we review the role of the immunosuppression mechanisms mediated by the IDO1 pathway in tumor growth. We discuss obstacles encountered in using IDO1 as a new tumor immunotherapy target, as well as the current clinical research progress.

Keywords:  dendritic cell; indoleamine 2,3-dioxygenase 1; interferon-γ; myeloid-derived suppressor cell; regulatory T cell; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14112756
PLoS Biol. 2022 Jun 10. 20(6): e3001678

The polyol pathway is an evolutionarily conserved system for sensing glucose uptake.

Hiroko Sano, Akira Nakamura, Mariko Yamane, Hitoshi Niwa, Takashi Nishimura, Kimi Araki, Kazumasa Takemoto, Kei-Ichiro Ishiguro, Hiroki Aoki, Yuzuru Kato, Masayasu Kojima.

Cells must adjust the expression levels of metabolic enzymes in response to fluctuating nutrient supply. For glucose, such metabolic remodeling is highly dependent on a master transcription factor ChREBP/MondoA. However, it remains elusive how glucose fluctuations are sensed by ChREBP/MondoA despite the stability of major glycolytic pathways. Here, we show that in both flies and mice, ChREBP/MondoA activation in response to glucose ingestion involves an evolutionarily conserved glucose-metabolizing pathway: the polyol pathway. The polyol pathway converts glucose to fructose via sorbitol. It has been believed that this pathway is almost silent, and its activation in hyperglycemic conditions has deleterious effects on human health. We show that the polyol pathway regulates the glucose-responsive nuclear translocation of Mondo, a Drosophila homologue of ChREBP/MondoA, which directs gene expression for organismal growth and metabolism. Likewise, inhibition of the polyol pathway in mice impairs ChREBP's nuclear localization and reduces glucose tolerance. We propose that the polyol pathway is an evolutionarily conserved sensing system for glucose uptake that allows metabolic remodeling.

DOI: https://doi.org/10.1371/journal.pbio.3001678
J Cardiovasc Aging. 2022 ;pii: 27. [Epub ahead of print]2(2):

WNT links metabolism and cell cycle in postnatal cardiomyocytes.

Ivan Menendez-Montes, Hesham A Sadek.



Keywords:  WNT; cardiomyocytes; cell cycle; metabolism

DOI:  https://doi.org/10.20517/jca.2022.18
Adv Mater. 2022 Jun 07. e2202715

Reprogramming Mitochondrial Metabolism in Synovial Macrophages of Early Osteoarthritis by A Camouflaged meta-Defensome.

Lei Zhang, Xiang Chen, Pingqiang Cai, Han Sun, Siyu Shen, Baosheng Guo, Qing Jiang.

  Osteoarthritis (OA) is a low-grade inflammatory and progressive joint disease, and its progression is closely associated with an imbalance in M1/M2 synovial macrophages. Repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype is emerging as a strategy to alleviate OA progression but is compromised by unsatisfactory efficiency. In this study, we pioneer the reprogramming of mitochondrial dysfunction with a camouflaged meta-Defensome, which can transform M1 synovial macrophages into the M2 phenotype with a high efficiency of 82.3%. The meta-Defensome recognizes activated macrophages via receptor-ligand interactions and accumulates in mitochondria through electrostatic attraction. These meta-Defensomes are macrophage membrane-coated polymeric nanoparticles decorated with dual ligands and co-loaded with S-methylisothiourea and MnO2 . In vitro results indicate that the meta-Defensomes successfully reprogram mitochondrial metabolism of RAW 246.7-differentiated M1 macrophages by restoring aerobic respiration by scavenging mtROS and inhibiting mtNOS, thereby increasing TFAM expression. Furthermore, meta-Defensomes are intravenously injected into CIOA mice and effectively suppress synovial inflammation and progression of early OA, as evident from the Osteoarthritis Research Society International (OARSI) score. Therefore, reprogramming mitochondrial metabolism can serve as a novel and practical approach to repolarize M1 synovial macrophages. The camouflaged meta-Defensomes are a promising therapeutic agent for impeding OA progression in clinical practice. This article is protected by copyright. All rights reserved.

Keywords:  denfensome; mitochondrial dysfunction; mitochondrial targeting; nanoenzyme; osteoarthritis; synovial macrophages

DOI:  https://doi.org/10.1002/adma.202202715
Proc Natl Acad Sci U S A. 2022 Jun 14. 119(24): e2200513119

Metabolic and immune-sensitive contacts between lipid droplets and endoplasmic reticulum reconstituted in vitro.

Sukrut Kamerkar, Jagjeet Singh, Subham Tripathy, Hemangi Bhonsle, Mukesh Kumar, Roop Mallik.

  Coordinated cell function requires a variety of subcellular organelles to exchange proteins and lipids across physical contacts that are also referred to as membrane contact sites. Such organelle-to-organelle contacts also evoke interest because they can appear in response to metabolic changes, immune activation, and possibly other stimuli. The microscopic size and complex, crowded geometry of these contacts, however, makes them difficult to visualize, manipulate, and understand inside cells. To address this shortcoming, we deposited endoplasmic reticulum (ER)-enriched microsomes purified from rat liver or from cultured cells on a coverslip in the form of a proteinaceous planar membrane. We visualized real-time lipid and protein exchange across contacts that form between this ER-mimicking membrane and lipid droplets (LDs) purified from the liver of rat. The high-throughput imaging possible in this geometry reveals that in vitro LD-ER contacts increase dramatically when the metabolic state is changed by feeding the animal and also when the immune system is activated. Contact formation in both cases requires Rab18 GTPase and phosphatidic acid, thus revealing common molecular targets operative in two very different biological pathways. An optical trap is used to demonstrate physical tethering of individual LDs to the ER-mimicking membrane and to estimate the strength of this tether. These methodologies can potentially be adapted to understand and target abnormal contact formation between different cellular organelles in the context of neurological and metabolic disorders or pathogen infection.

Keywords:  Rab18; lipid droplets; membrane contact sites; optical trap; supported lipid bilayer

DOI:  https://doi.org/10.1073/pnas.2200513119
Cell Immunol. 2022 May 25. pii: S0008-8749(22)00070-3. [Epub ahead of print]377 104546

Lipid metabolism and neutrophil function.

Junjie Jiang, Haiyue Tu, Peishan Li.

  Neutrophils are an essential part of the innate immune system, playing a critical role in the control of infectious diseases, maintenance of tissue homeostasis and regulation of tumorigenesis. However, their functional importance has often been overlooked due to the conception that they are short-lived and unable to proliferate. Recent studies indicate that the functions of neutrophils are diverse and can be influenced by cellular metabolisms, including that governing lipid homeostasis. Here, we review how lipids, especially lipid droplets, in neutrophils are dynamically regulated in different pathophysiological contexts, with a specific focus on the key regulators involved in lipid metabolism. We also describe how alterations in lipid metabolism are intertwined with different signaling pathways orchestrating neutrophil functions during pathogen defense, tissue repair and tumor metastasis.

Keywords:  Immunometabolism; Lipid droplets; Neutrophil extracellular traps (NETs); Neutrophils; Tumor metastasis

DOI:  https://doi.org/10.1016/j.cellimm.2022.104546
Cell Death Discov. 2022 Jun 07. 8(1): 277

High glutamine suppresses osteogenesis through mTORC1-mediated inhibition of the mTORC2/AKT-473/RUNX2 axis.

Meher Bolisetti Gayatri, Navya Naidu Gajula, Suresh Chava, Aramati B M Reddy.

Activation of the key nutrient cellular sensors mTORC1 and mTORC2 directs the fate of mesenchymal stromal cells (MSCs). Here, we report that glutamine regulates crosstalk between mTOR complexes and lineage commitment of MSCs independent of glucose concentration. High glutamine-induced mTORC1 hyperactivation resulted in the suppression of mTORC2, which otherwise stabilizes RUNX2 via GSK3β inhibition through pAKT-473. Activation of GSK3β resulted in the ubiquitination of RUNX2, a key transcription factor for the osteogenic commitment of MSCs. However, low glutamine conditions inhibit mTORC1 hyperactivation followed by increased mTORC2 activation and RUNX2 stabilization. Under diabetic/high-glucose conditions, glutamine-triggered hyperactivation of mTORC1 resulted in mTORC2 suppression, and active GSK3β led to suppression of RUNX2. Activation of p-AMPK by metformin inhibits high glutamine-induced mTORC1 hyperactivation and rescues RUNX2 through the mTORC2/AKT-473 axis. Collectively, our study indicates the role of glutamine in modulating MSC fate through cross-talk between mTOR complexes by identifying a critical switch in signaling. It also shows the importance of glutamine in modulating molecular cues (mTORC1/p-70S6K/mTORC2/RUNX2) that are involved in driving diabetes-induced bone adipogenesis and other secondary complications.

DOI: https://doi.org/10.1038/s41420-022-01077-3
Cells. 2022 Jun 02. pii: 1829. [Epub ahead of print]11(11):

Human Mesenchymal Stromal Cells Resolve Lipid Load in High Fat Diet-Induced Non-Alcoholic Steatohepatitis in Mice by Mitochondria Donation.

Sandra Nickel, Madlen Christ, Sandra Schmidt, Joanna Kosacka, Hagen Kühne, Martin Roderfeld, Thomas Longerich, Lysann Tietze, Ina Bosse, Mei-Ju Hsu, Peggy Stock, Elke Roeb, Bruno Christ.

  Mesenchymal stromal cells (MSC) increasingly emerge as an option to ameliorate non-alcoholic steatohepatitis (NASH), a serious disease, which untreated may progress to liver cirrhosis and cancer. Before clinical translation, the mode of action of MSC needs to be established. Here, we established NASH in an immune-deficient mouse model by feeding a high fat diet. Human bone-marrow-derived MSC were delivered to the liver via intrasplenic transplantation. As verified by biochemical and image analyses, human mesenchymal stromal cells improved high-fat-diet-induced NASH in the mouse liver by decreasing hepatic lipid content and inflammation, as well as by restoring tissue homeostasis. MSC-mediated changes in gene expression indicated the switch from lipid storage to lipid utilization. It was obvious that host mouse hepatocytes harbored human mitochondria. Thus, it is feasible that resolution of NASH in mouse livers involved the donation of human mitochondria to the mouse hepatocytes. Therefore, human MSC might provide oxidative capacity for lipid breakdown followed by restoration of metabolic and tissue homeostasis.

Keywords:  cell transplantation; mesenchymal stromal cells; mitochondria transfer; non-alcoholic steatohepatitis

DOI:  https://doi.org/10.3390/cells11111829
J Nutr Biochem. 2022 Jun 02. pii: S0955-2863(22)00151-6. [Epub ahead of print] 109080

Fructose-mediated NLRP3 activation induces inflammation and lipogenesis in adipose tissue.

Sushmita Singh, Aditya Sharma, Bhavimani Guru, Shadab Ahmad, Farah Gulzar, Pawan Kumar, Ishbal Ahmad, Akhilesh K Tamrakar.

  Adipose tissue plays a crucial role in energy intake and regulation of metabolic homeostasis. Fructose consumption implicates in development and progression of metabolic dysfunctions. Fructose is a lipogenic sugar known to induce inflammatory response. However, the role of specific inflammatory signal such as nucleotide-binding and oligomerization domain-like receptor, leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) in fructose-induced inflammatory response and its relevance to lipogenesis in adipose tissue are elusive. We assessed NLRP3 activation and its significance in inflammatory response and lipogenesis in epididymal adipose tissue of 60% fructose diet (HFrD)-fed rats. The long term consumption of HFrD led to impairment of glucose metabolism, development of visceral adiposity, insulin resistance, and elevation of serum triglycerides level, accompanied by activation of NLRP3 in adipose tissue. NLRP3 inflammasome activation in adipose tissue was associated with up-regulated expression of Nlrp3, Asc, and Caspase-1, and raised caspase-1 activity, which resulted in increased expression of IL-1β and IL-18 and secretion of IL-1β. Moreover, lipid accumulation and expression of transcription factors exacerbating accumulation of lipids were augmented in adipose tissue of HFrD-fed rats. Treatment with glyburide, quercetin or allopurinol corrected HFrD-induced dyslipidemia or hyperuricemia, and blocked NLRP3 activation, leading to mitigated inflammatory signalling and lipid accumulation in adipose tissue, improved glucose tolerance and insulin sensitivity in HFrD-fed rats. These data suggest the role of NLRP3 inflammasome to establish linkage among inflammation, lipid accumulation and insulin resistance in adipose tissue, and targeting NLRP3 inflammasome may be a plausible approach for prevention and management for fructose-induced metabolic impairments.

Keywords:  NLRP3 inflammasome; adipose tissue; fructose; insulin resistance; lipogenesis

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109080
Int J Mol Sci. 2022 May 31. pii: 6166. [Epub ahead of print]23(11):

LXRα Regulates oxLDL-Induced Trained Immunity in Macrophages.

Hannes M Findeisen, Vivienne C Voges, Laura C Braun, Jannik Sonnenberg, Dennis Schwarz, Helena Körner, Holger Reinecke, Yahya Sohrabi.

  Reprogramming of metabolic pathways in monocytes and macrophages can induce a proatherosclerotic inflammatory memory called trained innate immunity. Here, we have analyzed the role of the Liver X receptor (LXR), a crucial regulator of metabolism and inflammation, in oxidized low-density lipoprotein (oxLDL)-induced trained innate immunity. Human monocytes were incubated with LXR agonists, antagonists, and oxLDL for 24 h. After five days of resting time, cells were restimulated with the TLR-2 agonist Pam3cys. OxLDL priming induced the expression of LXRα but not LXRβ. Pharmacologic LXR activation was enhanced, while LXR inhibition prevented the oxLDL-induced inflammatory response. Furthermore, LXR inhibition blocked the metabolic changes necessary for epigenetic reprogramming associated with trained immunity. In fact, enrichment of activating histone marks at the IL-6 and TNFα promotor was reduced following LXR inhibition. Based on the differential expression of the LXR isoforms, we inhibited LXRα and LXRβ genes using siRNA in THP1 cells. As expected, siRNA-mediated knock-down of LXRα blocked the oxLDL-induced inflammatory response, while knock-down of LXRβ had no effect. We demonstrate a specific and novel role of the LXRα isoform in the regulation of oxLDL-induced trained immunity. Our data reveal important aspects of LXR signaling in innate immunity with relevance to atherosclerosis formation.

Keywords:  LXR; immunometabolism; inflammation; oxLDL; trained innate immunity

DOI:  https://doi.org/10.3390/ijms23116166
Mol Genet Metab. 2022 May 25. pii: S1096-7192(22)00321-3. [Epub ahead of print]

Integration of metabolomics with genomics: Metabolic gene prioritization using metabolomics data and genomic variant (CADD) scores.

Michiel Bongaerts, Ramon Bonte, Serwet Demirdas, Hidde H Huidekoper, Janneke Langendonk, Martina Wilke, Walter de Valk, Henk J Blom, Marcel J T Reinders, George J G Ruijter.

  The integration of metabolomics data with sequencing data is a key step towards improving the diagnostic process for finding the disease-causing genetic variant(s) in patients suspected of having an inborn error of metabolism (IEM). The measured metabolite levels could provide additional phenotypical evidence to elucidate the degree of pathogenicity for variants found in genes associated with metabolic processes. We present a computational approach, called Reafect, that calculates for each reaction in a metabolic pathway a score indicating whether that reaction is deficient or not. When calculating this score, Reafect takes multiple factors into account: the magnitude and sign of alterations in the metabolite levels, the reaction distances between metabolites and reactions in the pathway, and the biochemical directionality of the reactions. We applied Reafect to untargeted metabolomics data of 72 patient samples with a known IEM and found that in 81% of the cases the correct deficient enzyme was ranked within the top 5% of all considered enzyme deficiencies. Next, we integrated Reafect with Combined Annotation Dependent Depletion (CADD) scores (a measure for gene variant deleteriousness) and ranked the metabolic genes of 27 IEM patients. We observed that this integrated approach significantly improved the prioritization of the genes containing the disease-causing variant when compared with the two approaches individually. For 15/27 IEM patients the correct affected gene was ranked within the top 0.25% of the set of potentially affected genes. Together, our findings suggest that metabolomics data improves the identification of affected genes in patients suffering from IEM.

Keywords:  CADD scores; Data integration; ES; Inborn errors of metabolism; Metabolic pathways; Untargeted metabolomics

DOI:  https://doi.org/10.1016/j.ymgme.2022.05.002
Cell Rep. 2022 Jun 07. pii: S2211-1247(22)00694-5. [Epub ahead of print]39(10): 110917

Succinate metabolism in the retinal pigment epithelium uncouples respiration from ATP synthesis.

Daniel T Hass, Celia M Bisbach, Brian M Robbings, Martin Sadilek, Ian R Sweet, James B Hurley.

  Fumarate can be a surrogate for O2 as a terminal electron acceptor in the electron transport chain. Reduction of fumarate produces succinate, which can be exported. It is debated whether intact tissues can import and oxidize succinate produced by other tissues. In a previous report, we showed that mitochondria in retinal pigment epithelium (RPE)-choroid preparations can use succinate to reduce O2 to H2O. However, cells in that preparation could have been disrupted during tissue isolation. We now use multiple strategies to quantify intactness of the isolated RPE-choroid tissue. We find that exogenous 13C4-succinate is oxidized by intact cells then exported as fumarate or malate. Unexpectedly, we also find that oxidation of succinate is different from oxidation of other substrates because it uncouples electron transport from ATP synthesis. Retinas produce and export succinate. Our findings imply that retina succinate may substantially increase O2 consumption by uncoupling adjacent RPE mitochondria.

Keywords:  CP: metabolism; anion transport; cell metabolism; energy metabolism; mitochondrial respiratory chain; retinal metabolism; retinal pigment epithelium; succinate; uncoupling

DOI:  https://doi.org/10.1016/j.celrep.2022.110917
Antioxid Redox Signal. 2022 Jun 04.

Hydrogen sulfide regulates macrophage function in cardiovascular diseases.

Han Zhang, Junbao Du, Yaqian Huang, Chaoshu Tang, Hongfang Jin.

SIGNIFICANCE: Hydrogen sulfide (H2S) is an endogenous gasotransmitter that plays a vital role in immune system regulation. Recently, the regulation of macrophage function by H2S has been extensively and actively recognized.RECENT ADVANCES: The mechanisms by which endogenous H2S controls macrophage function have attracted increasing attention. The generation of endogenous H2S from macrophages is mainly catalyzed by cystathionine-γ-lyase (CSE). After its generation, H2S exerts immunomodulatory effects. H2S is associated with macrophage activation and inflammasome formation, which contributes to macrophage apoptosis, adhesion, chemotaxis and polarization. In addition, H2S has redox ability and interacts with reactive oxygen species (ROS) to prevent oxidative stress. Additionally, H2S epigenetically regulates gene expression.
CRITICAL ISSUES: In this manuscript, the generation of endogenous H2S in macrophages and its regulatory effect on macrophage function are reviewed. In addition, the signal transduction targeting macrophages by H2S is also addressed. Finally, the potential therapeutic effect of H2S on macrophages is discussed.
FUTURE DIRECTIONS: Further experiments are required to explore the involvement of endogenous H2S in the regulation of macrophage function in various physiological and pathophysiological processes and elucidate the mechanisms involved. Regarding the clinical translation of H2S, further exploration of the application of H2S in inflammatory diseases is needed.

DOI: https://doi.org/10.1089/ars.2022.0075
Front Cell Infect Microbiol. 2022 ;12 893044

Extracellular ATP and Imbalance of CD4+ T Cell Compartment in Pediatric COVID-19.

Constanza Russo, Silvina Raiden, Silvia Algieri, Norberto De Carli, Carolina Davenport, Mariam Sarli, María José Bruera, Vanesa Seery, Inés Sananez, Nancy Simaz, Carola Bayle, Valeria Nivela, Fernando Ferrero, Jorge Geffner, Lourdes Arruvito.

  Severe COVID-19 in children is rare, but the reasons underlying are unclear. Profound alterations in T cell responses have been well characterized in the course of adult severe COVID-19, but little is known about the T cell function in children with COVID-19. Here, we made three major observations in a cohort of symptomatic children with acute COVID-19: 1) a reduced frequency of circulating FoxP3+ regulatory T cells, 2) the prevalence of a TH17 polarizing microenvironment characterized by high plasma levels of IL-6, IL-23, and IL17A, and an increased frequency of CD4+ T cells expressing ROR-γt, the master regulator of TH17 development, and 3) high plasma levels of ATP together with an increased expression of the P2X7 receptor. Moreover, that plasma levels of ATP displayed an inverse correlation with the frequency of regulatory T cells but a positive correlation with the frequency of CD4+ T cells positive for the expression of ROR-γt. Collectively, our data indicate an imbalance in CD4+ T cell profiles during pediatric COVID-19 that might favor the course of inflammatory processes. This finding also suggests a possible role for the extracellular ATP in the acquisition of an inflammatory signature by the T cell compartment offering a novel understanding of the involved mechanisms.

Keywords:  COVID-19; TH17 cells; Tregs (regulatory T cells); children; extracellular ATP

DOI:  https://doi.org/10.3389/fcimb.2022.893044
Cells. 2022 Jun 01. pii: 1814. [Epub ahead of print]11(11):

Metabolic Profiling of Mice with Deletion of the Orphan G Protein-Coupled Receptor, GPR37L1.

Margaret A Mouat, Brendan P Wilkins, Eileen Ding, Hemna Govindaraju, James L J Coleman, Robert M Graham, Nigel Turner, Nicola J Smith.

  Understanding the neurogenic causes of obesity may reveal novel drug targets to counter the obesity crisis and associated sequelae. Here, we investigate whether the deletion of GPR37L1, an astrocyte-specific orphan G protein-coupled receptor, affects whole-body energy homeostasis in mice. We subjected male Gpr37l1-/- mice and littermate wildtype (Gpr37l1+/+, C57BL/6J background) controls to either 12 weeks of high-fat diet (HFD) or chow feeding, or to 1 year of chow diet, with body composition quantified by EchoMRI, glucose handling by glucose tolerance test and metabolic rate by indirect calorimetry. Following an HFD, Gpr37l1-/- mice had similar glucose handling, body weight and fat mass compared with wildtype controls. Interestingly, we observed a significantly elevated respiratory exchange ratio in HFD- and chow-fed Gpr37l1-/- mice during daylight hours. After 1 year of chow feeding, we again saw no differences in glucose and insulin tolerance or body weight between genotypes, nor in energy expenditure or respiratory exchange ratio. However, there was significantly lower fat mass accumulation, and higher ambulatory activity in the Gpr37l1-/- mice during night hours. Overall, these results indicate that while GPR37L1 may play a minor role in whole-body metabolism, it is not a viable clinical target for the treatment of obesity.

Keywords:  G protein-coupled receptor; GPR37L1; metabolism; orphan GPCR; phenotype

DOI:  https://doi.org/10.3390/cells11111814