bims-imicid 2022-10-30 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–10–30
twenty-two papers selected by
Dylan Ryan, University of Cambridge

Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice.
OPA1 drives macrophage metabolism and functional commitment via p65 signaling.
NKT cells adopt a glutamine-addicted phenotype to regulate their homeostasis and function.
Ornithine decarboxylase supports ILC3 responses in infectious and autoimmune colitis through positive regulation of IL-22 transcription.
Targeting T cell (oxidative) metabolism to improve immunity to viral infection in the context of obesity.
Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism.
Deficiency of IRG1/itaconate aggravates endotoxemia-induced acute lung injury by inhibiting autophagy in mice.
PTEN directs developmental and metabolic signaling for innate-like T cell fate and tissue homeostasis.
GABA signaling enforces intestinal germinal center B cell differentiation.
Lipids for CD8+ TILs: Beneficial or harmful?
Understanding the Crosstalk Between Epigenetics and Immunometabolism to Combat Cancer.
The Efficient Antiviral Response of A549 Cells Is Enhanced When Mitochondrial Respiration Is Promoted.
Role of Glycolysis and Fatty Acid Synthesis in the Activation and T Cell-Modulating Potential of Dendritic Cells Stimulated with a TLR5-Ligand Allergen Fusion Protein.
Metabolic features of innate lymphoid cells.
G9a Modulates Lipid Metabolism in CD4 T cells to Regulate Intestinal Inflammation.
Reconstructed Genome-Scale Metabolic Model Characterizes Adaptive Metabolic Flux Changes in Peripheral Blood Mononuclear Cells in Severe COVID-19 Patients.
Alterations in Primary Carbon Metabolism in Cucumber Infected with Pseudomonas syringae pv lachrymans: Local and Systemic Responses.
FABP5 Deficiency Impaired Macrophage Inflammation by Regulating AMPK/NF-κB Signaling Pathway.
Isoflavone consumption reduces inflammation through modulation of phenylalanine and lipid metabolism.
Chlorinated Polycyclic Aromatic Hydrocarbons Induce Immunosuppression in THP-1 Macrophages Characterized by Disrupted Amino Acid Metabolism.
IDH1 Promotes Foam Cell Formation by Aggravating Macrophage Ferroptosis.
REDD1 promotes obesity-induced metabolic dysfunction via atypical NF-κB activation.

Science. 2022 Oct 28. 378(6618): eabj3510

Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice.

Muna Al-Habsi, Kenji Chamoto, Ken Matsumoto, Norimichi Nomura, Baihao Zhang, Yuki Sugiura, Kazuhiro Sonomura, Aprilia Maharani, Yuka Nakajima, Yibo Wu, Yayoi Nomura, Rosemary Menzies, Masaki Tajima, Koji Kitaoka, Yasuharu Haku, Sara Delghandi, Keiko Yurimoto, Fumihiko Matsuda, So Iwata, Toshihiko Ogura, Sidonia Fagarasan, Tasuku Honjo.

Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8+ T cells. Treatment of naïve CD8+ T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli, SPD bound to the α and β subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell-specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation.

DOI: https://doi.org/10.1126/science.abj3510
Cell Death Differ. 2022 Oct 28.

OPA1 drives macrophage metabolism and functional commitment via p65 signaling.

Ricardo Sánchez-Rodríguez, Caterina Tezze, Andrielly H R Agnellini, Roberta Angioni, Francisca C Venegas, Chiara Cioccarelli, Fabio Munari, Nicole Bertoldi, Marcella Canton, Maria Andrea Desbats, Leonardo Salviati, Rosanna Gissi, Alessandra Castegna, Maria Eugenia Soriano, Marco Sandri, Luca Scorrano, Antonella Viola, Barbara Molon.

Macrophages are essential players for the host response against pathogens, regulation of inflammation and tissue regeneration. The wide range of macrophage functions rely on their heterogeneity and plasticity that enable a dynamic adaptation of their responses according to the surrounding environmental cues. Recent studies suggest that metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the metabolic pathways orchestrating macrophage activation are still under scrutiny. Optic atrophy 1 (OPA1) is a mitochondria-shaping protein controlling mitochondrial fusion, cristae biogenesis and respiration; clear evidence shows that the lack or dysfunctional activity of this protein triggers the accumulation of metabolic intermediates of the TCA cycle. In this study, we show that OPA1 has a crucial role in macrophage activation. Selective Opa1 deletion in myeloid cells impairs M1-macrophage commitment. Mechanistically, Opa1 deletion leads to TCA cycle metabolite accumulation and defective NF-κB signaling activation. In an in vivo model of muscle regeneration upon injury, Opa1 knockout macrophages persist within the damaged tissue, leading to excess collagen deposition and impairment in muscle regeneration. Collectively, our data indicate that OPA1 is a key metabolic driver of macrophage functions.

DOI: https://doi.org/10.1038/s41418-022-01076-y
Cell Rep. 2022 10 25. pii: S2211-1247(22)01366-3. [Epub ahead of print]41(4): 111516

NKT cells adopt a glutamine-addicted phenotype to regulate their homeostasis and function.

Ajay Kumar, Emily L Yarosz, Anthony Andren, Li Zhang, Costas A Lyssiotis, Cheong-Hee Chang.

  Natural killer T (NKT) cells operate distinctly different metabolic programming from CD4 T cells, including a strict requirement for glutamine to regulate cell homeostasis. However, the underlying mechanisms remain unknown. Here, we report that at a steady state, NKT cells have higher glutamine levels than CD4 T cells and that NKT cells increase glutaminolysis on activation. Activated NKT cells use glutamine to fuel the tricarboxylic acid cycle and glutathione synthesis. In addition, glutamine-derived nitrogen enables protein glycosylation via the hexosamine biosynthesis pathway (HBP). Each of these branches of glutamine metabolism seems to be critical for NKT cell homeostasis and mitochondrial functions. Glutaminolysis and HBP differentially regulate interleukin-4 (IL-4) and interferon γ (IFNγ) production. Glutamine metabolism appears to be controlled by AMP-activated protein kinase (AMPK)-mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight a distinct metabolic requirement of NKT cells compared with CD4 T cells, which may have therapeutic implications in the treatment of certain nutrient-restricted diseases.

Keywords:  CP: Immunology; HBP; PPP; ROS; glutathione; glycosylation; metabolism

DOI:  https://doi.org/10.1016/j.celrep.2022.111516
Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2214900119

Ornithine decarboxylase supports ILC3 responses in infectious and autoimmune colitis through positive regulation of IL-22 transcription.

Vincent Peng, Siyan Cao, Tihana Trsan, Jennifer K Bando, Julian Avila-Pacheco, John L Cleveland, Clary Clish, Ramnik J Xavier, Marco Colonna.

  Group 3 innate lymphoid cells (ILC3s) are RORγT+ lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17 cells. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against Citrobacter rodentium infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that ILC3-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as exacerbates autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.

Keywords:  IL-22; enteritis; innate lymphoid cells; ornithine decarboxylase; polyamines

DOI:  https://doi.org/10.1073/pnas.2214900119
Front Immunol. 2022 ;13 1025495

Targeting T cell (oxidative) metabolism to improve immunity to viral infection in the context of obesity.

Elizabeth Greene, Nancie J MacIver.

  Disorders of systemic metabolism can influence immunity. Individuals with obesity are known to have increased inflammation, increased risk to select autoimmune diseases, impaired response to several infections, and impaired vaccine response. For example, over the last decade, it has become clear that individuals with obesity have increased risk of morbidity and mortality from influenza infection. Unsurprisingly, this finding is also observed in the current COVID-19 pandemic: individuals with obesity, particularly severe obesity, have increased risk of poor outcomes from SARS-CoV-2 infection, including increased rates of hospitalization, ICU admission, mechanical ventilation, and death. Several studies have now demonstrated a critical role for T cells in the context of obesity-associated immune dysfunction in response to viral infection, and one mechanism for this may be altered T cell metabolism. Indeed, recent studies have shown that activated T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, both in vitro and in vivo following viral infection. For that reason, treatments that target abnormal immune cell metabolism in obesity may improve outcomes to viral infection. To that end, several recent studies have shown that use of the metabolic drug, metformin, can reverse abnormal T cell metabolism and restore T cell immunity, as well as survival, in response to viral infection. These findings will be discussed in detail here.

Keywords:  T cells; coronavirus disease 2019 (COVID-19); influenza; metabolism; metformin; obesity

DOI:  https://doi.org/10.3389/fimmu.2022.1025495
Mucosal Immunol. 2022 Oct 27.

Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism.

Athena Cavounidis, Sumeet Pandey, Melania Capitani, Matthias Friedrich, Amy Cross, Lisa Gartner, Dominik Aschenbrenner, Seunghee Kim-Schulze, Ying Ka Lam, Georgina Berridge, Dermot P B McGovern, Benedikt Kessler, Roman Fischer, Paul Klenerman, Joanna Hester, Fadi Issa, Esther A Torres, Fiona Powrie, Bernadette R Gochuico, William A Gahl, Louis Cohen, Holm H Uhlig.

Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking. The mechanism for Crohn's disease-like inflammation, lung fibrosis, and macrophage lipid accumulation in these patients remains enigmatic. The aim of this study is to understand the cellular basis of inflammation in HPS-1. We performed mass cytometry, proteomic and transcriptomic analyses to investigate peripheral blood cells and serum of HPS-1 patients. Using spatial transcriptomics, granuloma-associated signatures in the tissue of an HPS-1 patient with granulomatous colitis were dissected. In vitro studies were conducted to investigate anti-microbial responses of HPS-1 patient macrophages and cell lines. Monocytes of HPS-1 patients exhibit an inflammatory phenotype associated with dysregulated TNF, IL-1α, OSM in serum, and monocyte-derived macrophages. Inflammatory macrophages accumulate in the intestine and granuloma-associated macrophages in HPS-1 show transcriptional signatures suggestive of a lipid storage and metabolic defect. We show that HPS1 deficiency leads to an altered metabolic program and Rab32-dependent amplified mTOR signaling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic mechanism translates into aberrant bacterial clearance, which can be rescued with mTORC1 inhibition. Rab32-mediated mTOR signaling acts as an immuno-metabolic checkpoint, adding to the evidence that defective bioenergetics can drive hampered anti-microbial activity and contribute to inflammation.

DOI: https://doi.org/10.1038/s41385-022-00572-1
Exp Anim. 2022 Oct 26.

Deficiency of IRG1/itaconate aggravates endotoxemia-induced acute lung injury by inhibiting autophagy in mice.

Jing-Huan Qiu, Li Zhang, Ke-Xin Li, Qiu-Hong Zhang, Ke-Rui Fan, Kun Chen, Yu Jiang, Gang Liu.

  Itaconate, produced by aconitate decarboxylase 1 (ACOD1) which is encoded by immune-responsive gene 1 (Irg1), is one of the metabolites derived from the tricarboxylic acid cycle. It has been reported that exogenous itaconate plays an anti-inflammatory role in the progression of multiple diseases, including activated macrophage, ischemia-reperfusion Injury, and acute lung injury. However, the role and specific mechanism of endogenous itaconate in endotoxemia-induced acute lung injury (ALI) remain unclear. The animal model of ALI in WT and Irg1-/- mice was constructed by LPS intraperitoneal injection. Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) analysis was performed to measure the quantity of endogenous itaconate. The protective effect of itaconate was investigated by the behavioral assessment and levels of inflammatory cytokines. Acute lung injury was assessed by H&E staining, BALF, and Evans blue leakage. Western blotting was used to detect the IRG1 expression and autophagic protein in the lung. We demonstrated that IRG1 was highly expressed in ALI, and endogenous itaconate was produced simultaneously and up to 100 times. Using Irg1-/- mice, we found that endogenous itaconate was likely to exert an anti-inflammatory effect by activating NRF2 and promoting autophagy. Furthermore, Autophagy was restrained by LPS but enhanced by 4-octyl itaconate (4-OI) pretreatment. Our study illustrated the deficiency of IRG1/Itaconate aggravates ALI and the IRG1/Itaconate pathway protects against ALI. The protective mechanisms could be related to facilitate autophagy. Such findings may provide a theoretical foundation for endotoxemia-induced ALI treatment.

Keywords:  acute lung injury; autophagy; inflammation; itaconate; metabolite

DOI:  https://doi.org/10.1538/expanim.22-0104
Nat Cell Biol. 2022 Oct 27.

PTEN directs developmental and metabolic signaling for innate-like T cell fate and tissue homeostasis.

Daniel Bastardo Blanco, Nicole M Chapman, Jana L Raynor, Chengxian Xu, Wei Su, Anil Kc, Wei Li, Seon Ah Lim, Stefan Schattgen, Hao Shi, Isabel Risch, Yu Sun, Yogesh Dhungana, Yunjung Kim, Jun Wei, Sherri Rankin, Geoffrey Neale, Paul G Thomas, Kai Yang, Hongbo Chi.

Phosphatase and tensin homologue (PTEN) is frequently mutated in human cancer, but its roles in lymphopoiesis and tissue homeostasis remain poorly defined. Here we show that PTEN orchestrates a two-step developmental process linking antigen receptor and IL-23-Stat3 signalling to type-17 innate-like T cell generation. Loss of PTEN leads to pronounced accumulation of mature IL-17-producing innate-like T cells in the thymus. IL-23 is essential for their accumulation, and ablation of IL-23 or IL-17 signalling rectifies the reduced survival of female PTEN-haploinsufficient mice that model human patients with PTEN mutations. Single-cell transcriptome and network analyses revealed the dynamic regulation of PTEN, mTOR and metabolic activities that accompanied type-17 cell programming. Furthermore, deletion of mTORC1 or mTORC2 blocks PTEN loss-driven type-17 cell accumulation, and this is further shaped by the Foxo1 and Stat3 pathways. Collectively, our study establishes developmental and metabolic signalling networks underpinning type-17 cell fate decisions and their functional effects at coordinating PTEN-dependent tissue homeostasis.

DOI: https://doi.org/10.1038/s41556-022-01011-w
Proc Natl Acad Sci U S A. 2022 Nov;119(44): e2215921119

GABA signaling enforces intestinal germinal center B cell differentiation.

Yuexia Liao, Lijuan Fan, Peng Bin, Congrui Zhu, Qingyi Chen, Yepeng Cai, Jielin Duan, Qian Cai, Wei Han, Shizhen Ding, Xiangyu Hu, Yiran Zhang, Yulong Yin, Wenkai Ren.

  Recent compelling results indicate possible links between neurotransmitters, intestinal mucosal IgA+ B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA-mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling-mediated intestinal mucosal immunity as a previously unstudied pathogenesis mechanism of IgAN and challenges the current paradigms of IgAN.

Keywords:  B cells; GABA; IgA; IgAN; germinal center

DOI:  https://doi.org/10.1073/pnas.2215921119
Front Immunol. 2022 ;13 1020422

Lipids for CD8+ TILs: Beneficial or harmful?

Duojiao Wu, Yuwen Chen.

  Lipids and lipid metabolism play crucial roles in regulating T cell function and are tightly related to the establishment of immune memory. It is reported that tumor-infiltrating CD8+T lymphocytes (CD8+TILs) burn fats to restore their impaired effector function due to the lack of glucose. Conversely, fatty acids (FAs) and cholesterol in the tumor microenvironment (TME) drive the CD8+ TILs dysfunction. The origin of dysfunctional CD8+ TILs shares important features with memory T cell's precursor, but whether lipids and/or lipid metabolism reprogramming directly influence the memory plasticity of dysfunctional CD8+ TILs remains elusive. It is necessary to understand the interplay between cellular lipid metabolism and dysfunction of CD8+ TILs in the case of targeting T cell's metabolism to synergize cancer immunotherapy. Therefore, in this review, we summarize the latest research on CD8+ TILs lipid metabolism, evaluate the impacts of lipids in the TME to CD8+ TILs, and highlight the significance of promoting memory phenotype cell formation by targeting CD8+ T cells lipid metabolism to provide longer duration of cancer immunotherapy efficacy.

Keywords:  CD8+ T cell; Exhausted T cell; cholesterol; fatty acid; fatty acid oxidation; metabolism; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2022.1020422
Subcell Biochem. 2022 ;100 581-616

Understanding the Crosstalk Between Epigenetics and Immunometabolism to Combat Cancer.

Anuradha Seth, Susanta Kar.

  The interaction between metabolic and epigenetic events shapes metabolic adaptations of cancer cells and also helps rewire the proliferation and activity of surrounding immune cells in the tumor microenvironment (TME). Recent studies indicate that the TME imposes metabolic constraints on immune cells, inducing them to attain a tolerogenic state, incompetent of mounting effective tumor eradication. Owing to extensive mutations acquired over repeated cell divisions, tumor cells selectively accumulate metabolites that regulate the activity of key epigenetic enzymes to mediate activation/suppression of genes associated with T-cell function and macrophage polarization. Further, multiple modulators connecting epigenetic and metabolic pathways help dictate the preferential induction of cytokines and expression of lineage-specifying genes associated with immunosuppressive T-cell differentiation.In this chapter, we attempt to discuss the mechanisms underpinning the metabolic and epigenetic interplay in immune cells of the TME and how modulating these events can boost the application of existing anticancer immunotherapy.

Keywords:  Cancer immune cell; DNA methylation; Epigenetics; Histone acetylation; Histone methylation; Oncometabolites

DOI:  https://doi.org/10.1007/978-3-031-07634-3_18
Pathogens. 2022 Oct 11. pii: 1168. [Epub ahead of print]11(10):

The Efficient Antiviral Response of A549 Cells Is Enhanced When Mitochondrial Respiration Is Promoted.

Grégorie Lebeau, Daed El Safadi, Aurélie Paulo-Ramos, Mathilde Hoareau, Philippe Desprès, Pascale Krejbich-Trotot, Florian Chouchou, Marjolaine Roche, Wildriss Viranaicken.

  When exposed to a viral infection, the attacked cells promptly set up defense mechanisms. As part of the antiviral responses, the innate immune interferon pathway and associated interferon-stimulated genes notably allow the production of proteins bearing antiviral activity. Numerous viruses are able to evade the interferon response, highlighting the importance of controlling this pathway to ensure their efficient replication. Several viruses are also known to manipulate the metabolism of infected cells to optimize the availability of amino acids, nucleotides, and lipids. They then benefit from a reprogramming of the metabolism that favors glycolysis instead of mitochondrial respiration. Given the increasingly discussed crosstalk between metabolism and innate immunity, we wondered whether this switch from glycolysis to mitochondrial respiration would be beneficial or deleterious for an efficient antiviral response. We used a cell-based model of metabolic reprogramming. Interestingly, we showed that increased mitochondrial respiration was associated with an enhanced interferon response following polyriboinosinic:polyribocytidylic acid (poly:IC) stimulation. This suggests that during viral infection, the metabolic reprogramming towards glycolysis is also part of the virus' strategies to inhibit the antiviral response.

Keywords:  ISGs; OXPHOS; antiviral response; metabolic reprogramming; mitochondrial respiration

DOI:  https://doi.org/10.3390/pathogens11101168
Int J Mol Sci. 2022 Oct 21. pii: 12695. [Epub ahead of print]23(20):

Role of Glycolysis and Fatty Acid Synthesis in the Activation and T Cell-Modulating Potential of Dendritic Cells Stimulated with a TLR5-Ligand Allergen Fusion Protein.

Alexandra Goretzki, Yen-Ju Lin, Jennifer Zimmermann, Hannah Rainer, Ann-Christine Junker, Sonja Wolfheimer, Stefan Vieths, Stephan Scheurer, Stefan Schülke.

  Trained immune responses, based on metabolic and epigenetic changes in innate immune cells, are de facto innate immune memory and, therefore, are of great interest in vaccine development. In previous studies, the recombinant fusion protein rFlaA:Betv1, combining the adjuvant and toll-like receptor (TLR)5-ligand flagellin (FlaA) and the major birch pollen allergen Bet v 1 into a single molecule, significantly suppressed allergic sensitization in vivo while also changing the metabolism of myeloid dendritic cells (mDCs). Within this study, the immune-metabolic effects of rFlaA:Betv1 during mDC activation were elucidated. In line with results for other well-characterized TLR-ligands, rFlaA:Betv1 increased glycolysis while suppressing oxidative phosphorylation to different extents, making rFlaA:Betv1 a suitable model to study the immune-metabolic effects of TLR-adjuvanted vaccines. In vitro pretreatment of mDCs with cerulenin (inhibitor of fatty acid biosynthesis) led to a decrease in both rFlaA:Betv1-induced anti-inflammatory cytokine Interleukin (IL) 10 and T helper cell type (TH) 1-related cytokine IL-12p70, while the pro-inflammatory cytokine IL 1β was unaffected. Interestingly, pretreatment with the glutaminase inhibitor BPTES resulted in an increase in IL-1β, but decreased IL-12p70 secretion while leaving IL-10 unchanged. Inhibition of the glycolytic enzyme hexokinase-2 by 2-deoxyglucose led to a decrease in all investigated cytokines (IL-10, IL-12p70, and IL-1β). Inhibitors of mitochondrial respiration had no effect on rFlaA:Betv1-induced IL-10 level, but either enhanced the secretion of IL-1β (oligomycin) or decreased IL-12p70 (antimycin A). In extracellular flux measurements, mDCs showed a strongly enhanced glycolysis after rFlaA:Betv1 stimulation, which was slightly increased after respiratory shutdown using antimycin A. rFlaA:Betv1-stimulated mDCs secreted directly antimicrobial substances in a mTOR- and fatty acid metabolism-dependent manner. In co-cultures of rFlaA:Betv1-stimulated mDCs with CD4+ T cells, the suppression of Bet v 1-specific TH2 responses was shown to depend on fatty acid synthesis. The effector function of rFlaA:Betv1-activated mDCs mainly relies on glycolysis, with fatty acid synthesis also significantly contributing to rFlaA:Betv1-mediated cytokine secretion, the production of antimicrobial molecules, and the modulation of T cell responses.

Keywords:  Bet v 1; Warburg; allergy; flagellin; fusion protein; immune metabolism

DOI:  https://doi.org/10.3390/ijms232012695
J Exp Med. 2022 Nov 07. pii: e20221140. [Epub ahead of print]219(11):

Metabolic features of innate lymphoid cells.

Huiyang Yu, Nicolas Jacquelot, Gabrielle T Belz.

Innate and adaptive immune cells are found in distinct tissue niches where they orchestrate immune responses. This requires intrinsic and temporal metabolic adaptability to coordinately activate the immune response cascade. Dysregulation of this program is a key feature of immunosuppression. Direct or indirect metabolic immune cell reprogramming may offer new approaches to modulate immune cells behavior for therapy to overcome dysregulation. In this review, we explored how metabolism regulates lymphocytes beyond the classical T cell subsets. We focus on the innate lymphoid cell (ILC) family, highlighting the distinct metabolic characteristics of these cells, the impact of environmental factors, and the receptors that could alter immune cell functions through manipulation of metabolic pathways to potentially prevent or treat various diseases.

DOI: https://doi.org/10.1084/jem.20221140
Gastroenterology. 2022 Oct 19. pii: S0016-5085(22)01185-4. [Epub ahead of print]

G9a Modulates Lipid Metabolism in CD4 T cells to Regulate Intestinal Inflammation.

Guilherme Piovezani Ramos, Adebowale O Bamidele, Emily E Klatt, Mary R Sagstetter, Ahmed T Kurdi, Feda H Hamdan, Robyn Laura Kosinsky, Joseph M Gaballa, Asha Nair, Zhifu Sun, Surendra Dasari, Ian R Lanza, Cody N Rozeveld, Micah B Schott, Guillermo Urrutia, Maria S Westphal, Benjamin D Clarkson, Charles L Howe, Eric V Marietta, David H Luckey, Joseph A Murray, Michelle Gonzalez, Manuel B Braga Neto, Hunter R Gibbons, Thomas C Smyrk, Steven Johnsen, Gwen Lomberk, William A Faubion.

   BACKGROUND: /Aims: Although T cell intrinsic expression of G9a has been associated with murine intestinal inflammation, mechanistic insight into the role of this methyltransferase in human T cell differentiation is ill-defined and manipulation of G9a function for therapeutic use against inflammatory disorders is unexplored.
METHODS: Human naïve T cells were isolated from peripheral blood and differentiated in vitro in the presence of a G9a inhibitor (UNC0642) prior to being characterized via the transcriptome (RNA-seq), chromatin accessibility (ATAC-seq), protein expression (CyTOF, flow cytometry), metabolism (mitochondrial stress test, UPLC-MS/MS) and function (T cell suppression assay). In vivo role of G9a was assessed using three murine models.
RESULTS: We discovered that pharmacologic inhibition of G9a enzymatic function in human CD4 T cells led to spontaneous generation of FOXP3+ T cells (G9ai-Tregs) in vitro that faithfully reproduce human Tregs, functionally and phenotypically. Mechanistically, G9a inhibition altered the transcriptional regulation of genes involved in lipid biosynthesis in T cells resulting in increased intracellular cholesterol. Metabolomic profiling of G9ai-Tregs confirmed elevated lipid pathways that support Treg development through oxidative phosphorylation and enhanced lipid membrane composition. Pharmacologic G9a inhibition promoted Treg expansion in vivo upon antigen (gliadin) stimulation and ameliorated acute TNBS-induced colitis secondary to tissue specific Treg development. Lastly, Tregs lacking G9a expression (G9aKO Tregs) remain functional chronically and can rescue T cell transfer induced colitis.
CONCLUSION: G9a inhibition promotes cholesterol metabolism in T cells favoring a metabolic profile that facilitates Treg development in vitro and in vivo. Our data support the potential use of G9a inhibitors in the treatment of immune-mediated conditions including inflammatory bowel disease.

Keywords:  Cholesterol; Inflammatory Bowel Disease; Lipid Metabolism; Regulatory T cells

DOI:  https://doi.org/10.1053/j.gastro.2022.10.011
Int J Mol Sci. 2022 Oct 17. pii: 12400. [Epub ahead of print]23(20):

Reconstructed Genome-Scale Metabolic Model Characterizes Adaptive Metabolic Flux Changes in Peripheral Blood Mononuclear Cells in Severe COVID-19 Patients.

Hao Tang, Yanguang Liu, Yao Ruan, Lingqiao Ge, Qingye Zhang.

  Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a mortal threat to human health. The elucidation of the relationship between peripheral immune cells and the development of inflammation is essential for revealing the pathogenic mechanism of COVID-19 and developing related antiviral drugs. The immune cell metabolism-targeting therapies exhibit a desirable anti-inflammatory effect in some treatment cases. In this study, based on differentially expressed gene (DEG) analysis, a genome-scale metabolic model (GSMM) was reconstructed by integrating transcriptome data to characterize the adaptive metabolic changes in peripheral blood mononuclear cells (PBMCs) in severe COVID-19 patients. Differential flux analysis revealed that metabolic changes such as enhanced aerobic glycolysis, impaired oxidative phosphorylation, fluctuating biogenesis of lipids, vitamins (folate and retinol), and nucleotides played important roles in the inflammation adaptation of PBMCs. Moreover, the main metabolic enzymes such as the solute carrier (SLC) family 2 member 3 (SLC2A3) and fatty acid synthase (FASN), responsible for the reactions with large differential fluxes, were identified as potential therapeutic targets. Our results revealed the inflammation regulation potentials of partial metabolic reactions with differential fluxes and their metabolites. This study provides a reference for developing potential PBMC metabolism-targeting therapy strategies against COVID-19.

Keywords:  COVID-19; PBMCs; inflammatory; metabolic model; metabolism; metabolism-directed therapy

DOI:  https://doi.org/10.3390/ijms232012400
Int J Mol Sci. 2022 Oct 17. pii: 12418. [Epub ahead of print]23(20):

Alterations in Primary Carbon Metabolism in Cucumber Infected with Pseudomonas syringae pv lachrymans: Local and Systemic Responses.

Tomasz Kopczewski, Elżbieta Kuźniak, Iwona Ciereszko, Andrzej Kornaś.

  The reconfiguration of the primary metabolism is essential in plant-pathogen interactions. We compared the local metabolic responses of cucumber leaves inoculated with Pseudomonas syringae pv lachrymans (Psl) with those in non-inoculated systemic leaves, by examining the changes in the nicotinamide adenine dinucleotides pools, the concentration of soluble carbohydrates and activities/gene expression of carbohydrate metabolism-related enzymes, the expression of photosynthesis-related genes, and the tricarboxylic acid cycle-linked metabolite contents and enzyme activities. In the infected leaves, Psl induced a metabolic signature with an altered [NAD(P)H]/[NAD(P)+] ratio; decreased glucose and sucrose contents, along with a changed invertase gene expression; and increased glucose turnover and accumulation of raffinose, trehalose, and myo-inositol. The accumulation of oxaloacetic and malic acids, enhanced activities, and gene expression of fumarase and l-malate dehydrogenase, as well as the increased respiration rate in the infected leaves, indicated that Psl induced the tricarboxylic acid cycle. The changes in gene expression of ribulose-l,5-bis-phosphate carboxylase/oxygenase large unit, phosphoenolpyruvate carboxylase and chloroplast glyceraldehyde-3-phosphate dehydrogenase were compatible with a net photosynthesis decline described earlier. Psl triggered metabolic changes common to the infected and non-infected leaves, the dynamics of which differed quantitatively (e.g., malic acid content and metabolism, glucose-6-phosphate accumulation, and glucose-6-phosphate dehydrogenase activity) and those specifically related to the local or systemic response (e.g., changes in the sugar content and turnover). Therefore, metabolic changes in the systemic leaves may be part of the global effects of local infection on the whole-plant metabolism and also represent a specific acclimation response contributing to balancing growth and defense.

Keywords:  TCA cycle; angular leaf spot disease; malic acid; plant–pathogen interaction; pyridine nucleotides; raffinose; soluble sugars

DOI:  https://doi.org/10.3390/ijms232012418
J Immunol. 2022 Oct 24. pii: ji2200182. [Epub ahead of print]

FABP5 Deficiency Impaired Macrophage Inflammation by Regulating AMPK/NF-κB Signaling Pathway.

Yangxiao Hou, Dong Wei, Elhusseny A Bossila, Zhaoqi Zhang, Sihong Li, Jiaming Bao, Huawen Xu, Lianfeng Zhang, Yong Zhao.

Fatty acid binding protein 5 (FABP5) is mainly involved in the uptake, transport, and metabolism of fatty acid in the cytoplasm, and its role in immune cells has been recognized in recent years. However, the role of FABP5 in macrophage inflammation and its underlying mechanisms were not fully addressed. In our study, the acute liver injury and sepsis mouse models were induced by i.p. injection of LPS and cecal contents, respectively. Oleic acid (0.6 g/kg) was injected four times by intragastric administration every week, and this lasted for 1 wk before the LPS or cecal content challenge. We found that myeloid-specific deletion of FABP5 mitigated LPS-induced acute liver injury with reduced mortality of mice, histological liver damage, alanine aminotransferase, and proinflammatory factor levels. Metabolic analysis showed that FABP5 deletion increased the intracellular unsaturated fatty acids, especially oleic acid, in LPS-induced macrophages. The addition of oleic acid also decreased LPS-stimulated macrophage inflammation in vitro and reduced acute liver injury in LPS-induced or cecal content-induced sepsis mice. RNA-sequencing and molecular mechanism studies showed that FABP5 deletion or oleic acid supplementation increased the AMP/ATP ratio and AMP-activated protein kinase (AMPK) activation and inhibited the NF-κB pathway during the inflammatory response to LPS stimulation of macrophages. Inhibiting AMPK activation or expression by chemical or genetic approaches significantly rescued the decreased NF-κB signaling pathway and inflammatory response in LPS-treated FABP5-knockout macrophages. Our present study indicated that inhibiting FABP5 or supplementation of oleic acid might be used for the treatment of sepsis-caused acute liver injury.

DOI: https://doi.org/10.4049/jimmunol.2200182
Metabolomics. 2022 Oct 26. 18(11): 84

Isoflavone consumption reduces inflammation through modulation of phenylalanine and lipid metabolism.

Rachel L Shrode, Nicole Cady, Samantha N Jensen, Nicholas Borcherding, Ashutosh K Mangalam.

   INTRODUCTION: Phytoestrogens found in soy, fruits, peanuts, and other legumes, have been identified as metabolites capable of providing beneficial effects in multiple pathological conditions due to their ability to mimic endogenous estrogen. Interestingly, the health-promoting effects of some phytoestrogens, such as isoflavones, are dependent on the presence of specific gut bacteria. Specifically, gut bacteria can metabolize isoflavones into equol, which has a higher affinity for endogenous estrogen receptors compared to dietary isoflavones. We have previously shown that patients with multiple sclerosis (MS), a neuroinflammatory disease, lack gut bacteria that are able to metabolize phytoestrogen. Further, we have validated the importance of both isoflavones and phytoestrogen-metabolizing gut bacteria in disease protection utilizing an animal model of MS. Specifically, we have shown that an isoflavone-rich diet can protect from neuroinflammatory diseases, and that protection was dependent on the ability of gut bacteria to metabolize isoflavones into equol. Additionally, mice on a diet with isoflavones showed an anti-inflammatory response compared to the mice on a diet lacking isoflavones. However, it is unknown how isoflavones and/or equol mediates their protective effects, especially their effects on host metabolite levels.
OBJECTIVES: In this study, we utilized untargeted metabolomics to identify metabolites found in plasma that were modulated by the presence of dietary isoflavones.
RESULTS: We found that the consumption of isoflavones increased anti-inflammatory monounsaturated fatty acids and beneficial polyunsaturated fatty acids while reducing pro-inflammatory glycerophospholipids, sphingolipids, phenylalanine metabolism, and arachidonic acid derivatives.
CONCLUSION: Isoflavone consumption alters the systemic metabolic landscape through concurrent increases in monounsaturated fatty acids and beneficial polyunsaturated fatty acids plus reduction in pro-inflammatory metabolites and pathways. This highlights a potential mechanism by which an isoflavone diet may modulate immune-mediated disease.

Keywords:  Inflammation; Isoflavone; Metabolites; Multiple sclerosis; Phytoestrogen; Untargeted metabolomics

DOI:  https://doi.org/10.1007/s11306-022-01944-1
Environ Sci Technol. 2022 Oct 25.

Chlorinated Polycyclic Aromatic Hydrocarbons Induce Immunosuppression in THP-1 Macrophages Characterized by Disrupted Amino Acid Metabolism.

Xinyan Li, Mei Ma, Bilin Zhao, Na Li, Ling Fang, Donghong Wang, Tiangang Luan.

  Frequent chlorinated polycyclic aromatic hydrocarbon (Cl-PAH) occurrence in environmental samples and emerging detection in human serum have warned of their underestimated risks. Studies showed that some Cl-PAHs exhibit dioxin-like properties, implying immunotoxic potential but lacking direct evidence and specific mechanisms. Here, we integrated a high-content screening (HCS) system and high-resolution mass spectrometry to investigate the immune dysfunction and metabolic disruption induced by Cl-PAHs and their parent PAHs (PPAHs) in THP-1 macrophages. Both 9-chloroanthracene and 2,7-dichlorofluorene exerted clear immunosuppression on THP-1 mφs, while their PPAHs exhibited different immune disturbances. Interestingly, Cl-PAH/PPAHs induced complex alterations in the multicytokine/chemokine network, including biphasic alterations with initial inhibition and later enhancement. Furthermore, the protein-protein interaction results revealed that inflammatory cytokines are the core of this complicated network regulation. Connecting immune phenotypes and metabolomics, amino acid metabolism reprogramming was identified as a potential cause of Cl-PAH/PAH-induced immunotoxicity. Phytosphingosine and l-kynurenine were proposed as candidate immunosuppression biomarkers upon Cl-PAH exposure. This article provides direct immunotoxicity evidence of Cl-PAHs without activating AhR for the first time and discusses the contribution of metabolites to Cl-PAH/PPAH-induced immune responses in macrophages, highlighting the potential of developing new methods based on immunometabolism mechanisms for toxic risk evaluation of environmental chemicals.

Keywords:  Cl-PAHs; PAHs; high-content screening; immunotoxicity; metabolomics

DOI:  https://doi.org/10.1021/acs.est.2c06471
Biology (Basel). 2022 Sep 23. pii: 1392. [Epub ahead of print]11(10):

IDH1 Promotes Foam Cell Formation by Aggravating Macrophage Ferroptosis.

Ben Li, Chufan Wang, Peng Lu, Yumeng Ji, Xufeng Wang, Chaoyang Liu, Xiaohu Lu, Xiaohan Xu, Xiaowei Wang.

  A distinctive feature of ferroptosis is intracellular iron accumulation and the impairment of antioxidant capacity, resulting in a lethal accumulation of lipid peroxides leading to cell death. This study was conducted to determine whether inhibiting isocitrate dehydrogenase 1 (IDH1) may help to prevent foam cell formation by reducing oxidized low-density lipoprotein (ox-LDL)-induced ferroptosis in macrophages and activating nuclear factor erythroid 2-related factor 2 (NRF2). Gene expression profiling (GSE70126 and GSE70619) revealed 21 significantly different genes, and subsequent bioinformatics research revealed that ferroptosis and IDH1 play essential roles in foam cell production. We also confirmed that ox-LDL elevates macrophage ferroptosis and IDH1 protein levels considerably as compared with controls. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, reduced ox-LDL-induced elevated Fe2+ levels, lipid peroxidation (LPO) buildup, lactate dehydrogenase (LDH) buildup, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4), ferritin heavy polypeptide 1 (FTH1), and solute carrier family 7 member 11 (SLC7A11) protein downregulation. More crucially, inhibiting IDH1 reduced Fe2+ overload, lipid peroxidation, LDH, and glutathione depletion, and elevated GPX4, FTH1, and SLC7A11 protein expression, resulting in a reduction in ox-LDL-induced macrophage ferroptosis. IDH1 inhibition suppressed ox-LDL-induced macrophage damage and apoptosis while raising NRF2 protein levels. We have demonstrated that inhibiting IDH1 reduces ox-LDL-induced ferroptosis and foam cell formation in macrophages, implying that IDH1 may be an important molecule regulating foam cell formation and may be a promising molecular target for the treatment of atherosclerosis.

Keywords:  IDH1; NRF2; ferroptosis; foam cell; macrophage

DOI:  https://doi.org/10.3390/biology11101392
Nat Commun. 2022 Oct 22. 13(1): 6303

REDD1 promotes obesity-induced metabolic dysfunction via atypical NF-κB activation.

Dong-Keon Lee, Taesam Kim, Junyoung Byeon, Minsik Park, Suji Kim, Joohwan Kim, Seunghwan Choi, Gihwan Lee, Chanin Park, Keun Woo Lee, Yong Jung Kwon, Jeong-Hyung Lee, Young-Guen Kwon, Young-Myeong Kim.

Regulated in development and DNA damage response 1 (REDD1) expression is upregulated in response to metabolic imbalance and obesity. However, its role in obesity-associated complications is unclear. Here, we demonstrate that the REDD1-NF-κB axis is crucial for metabolic inflammation and dysregulation. Mice lacking Redd1 in the whole body or adipocytes exhibited restrained diet-induced obesity, inflammation, insulin resistance, and hepatic steatosis. Myeloid Redd1-deficient mice showed similar results, without restrained obesity and hepatic steatosis. Redd1-deficient adipose-derived stem cells lost their potential to differentiate into adipocytes; however, REDD1 overexpression stimulated preadipocyte differentiation and proinflammatory cytokine expression through atypical IKK-independent NF-κB activation by sequestering IκBα from the NF-κB/IκBα complex. REDD1 with mutated Lys219/220Ala, key amino acid residues for IκBα binding, could not stimulate NF-κB activation, adipogenesis, and inflammation in vitro and prevented obesity-related phenotypes in knock-in mice. The REDD1-atypical NF-κB activation axis is a therapeutic target for obesity, meta-inflammation, and metabolic complications.

DOI: https://doi.org/10.1038/s41467-022-34110-1