bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022–06–19
twenty-six papers selected by
Dylan Ryan, University of Cambridge
  1. Single-Cell Metabolic Profiling of Macrophages Using 3D OrbiSIMS: Correlations with Phenotype.
  2. Fumarate suppresses B-cell activation and function through direct inactivation of LYN.
  3. Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication.
  4. Immune cell metabolism and metabolic reprogramming.
  5. Editorial: Immune Regulation of Metabolic Homeostasis.
  6. Fatty acid metabolism in T-cell function and differentiation.
  7. Monocarboxylate transporter 1 deficiency impacts CD8+ T lymphocytes proliferation and recruitment to adipose tissue during obesity.
  8. Ubiquitinating the way to T cell metabolism.
  9. Metabolism and polarization regulation of macrophages in the tumor microenvironment.
  10. CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.
  11. High-Fat Diet-Induced Obesity Alters Dendritic Cell Homeostasis by Enhancing Mitochondrial Fatty Acid Oxidation.
  12. Metabolic Reprogramming Mediates Delayed Apoptosis of Human Neutrophils Infected With Francisella tularensis.
  13. Vps33B controls Treg cell suppressive function through inhibiting lysosomal nutrient sensing complex-mediated mTORC1 activation.
  14. Urine metabolomics links dysregulation of the tryptophan-kynurenine pathway to inflammation and severity of COVID-19.
  15. ATP citrate lyase links increases in glycolysis to diminished release of vesicular suppressor of cytokine signaling 3 by alveolar macrophages.
  16. Blood-based untargeted metabolomics in relapsing-remitting multiple sclerosis revealed the testable therapeutic target.
  17. Myeloid FoxO1 depletion attenuates hepatic inflammation and prevents nonalcoholic steatohepatitis.
  18. Interleukin-17 governs hypoxic adaptation of injured epithelium.
  19. SARS-CoV-2 couples evasion of inflammatory response to activated nucleotide synthesis.
  20. cDC1 to cDC2: "Everything I do, Ido1 it for you".
  21. Endogenous glutamine is rate-limiting for anti-CD3 and anti-CD28 induced CD4+ T-cell proliferation and glycolytic activity under hypoxia and normoxia.
  22. Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling.
  23. Voltage-gated Ca2+ channel proteins do not function as ion channels in T cells.
  24. Metabolomic Investigation of Ultraviolet Ray-Inactivated White Spot Syndrome Virus-Induced Trained Immunity in Marsupenaeus japonicus.
  25. Macrophage-NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension.
  26. Mitochondrial complex I dysfunction alters the balance of soluble and membrane-bound TNF during chronic experimental colitis.
  1. Anal Chem. 2022 Jun 17.
    Single-Cell Metabolic Profiling of Macrophages Using 3D OrbiSIMS: Correlations with Phenotype.
    Waraporn Suvannapruk, Max K Edney, Dong-Hyun Kim, David J Scurr, Amir M Ghaemmaghami, Morgan R Alexander.
      Macrophages are important immune cells that respond to environmental cues acquiring a range of activation statuses represented by pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes at each end of their spectrum. Characterizing the metabolic signature (metabolic profiling) of different macrophage subsets is a powerful tool to understand the response of the human immune system to different stimuli. Here, the recently developed 3D OrbiSIMS instrument is applied to yield useful insight into the metabolome from individual cells after in vitro differentiation of macrophages into naïve, M1, and M2 phenotypes using different cytokines. This analysis strategy not only requires more than 6 orders of magnitude less sample than traditional mass spectrometry approaches but also allows the study of cell-to-cell variance. Characteristic metabolites in macrophage subsets are identified using a targeted lipid and data-driven multivariate approach highlighting amino acids and other small molecules. The diamino acids alanylasparagine and lipid sphingomyelin SM(d18/16:0) are uniquely found in M1 macrophages, while pyridine and pyrimidine are observed at increased intensity in M2 macrophages, findings which link to known biological pathways. The first demonstration of this capability illustrates the great potential of direct cell analysis for in situ metabolite profiling with the 3D OrbiSIMS to probe functional phenotype at the single-cell level using molecular signatures and to understand the response of the human body to implanted devices and immune diseases.
    DOI:  https://doi.org/10.1021/acs.analchem.2c01375
  2. Nat Chem Biol. 2022 Jun 16.
    Fumarate suppresses B-cell activation and function through direct inactivation of LYN.
    Jie Cheng, Ying Liu, Jinxin Yan, Lina Zhao, Yinglin Zhou, Xuyang Shen, Yunan Chen, Yining Chen, Xianbin Meng, Xinxiang Zhang, Peng Jiang.
      Activated B cells increase central carbon metabolism to fulfill their bioenergetic demands, yet the mechanistic basis for this, as well as metabolic regulation in B cells, remains largely unknown. Here, we demonstrate that B-cell activation reprograms the tricarboxylic acid cycle and boosts the expression of fumarate hydratase (FH), leading to decreased cellular fumarate abundance. Fumarate accumulation by FH inhibition or dimethyl-fumarate treatment suppresses B-cell activation, proliferation and antibody production. Mechanistically, fumarate is a covalent inhibitor of tyrosine kinase LYN, a key component of the BCR signaling pathway. Fumarate can directly succinate LYN at C381 and abrogate LYN activity, resulting in a block to B-cell activation and function in vitro and in vivo. Therefore, our findings uncover a previously unappreciated metabolic regulation of B cells, and reveal LYN is a natural sensor of fumarate, connecting cellular metabolism to B-cell antigen receptor signaling.
    DOI:  https://doi.org/10.1038/s41589-022-01052-0
  3. Immunity. 2022 Jun 14. pii: S1074-7613(22)00233-3. [Epub ahead of print]55(6): 1032-1050.e14
    Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication.
    Marco Gargaro, Giulia Scalisi, Giorgia Manni, Carlos G Briseño, Prachi Bagadia, Vivek Durai, Derek J Theisen, Sunkyung Kim, Marilena Castelli, Chenling A Xu, Gerd Meyer Zu Hörste, Giuseppe Servillo, Maria A Della Fazia, Giulia Mencarelli, Doriana Ricciuti, Eleonora Padiglioni, Nicola Giacchè, Carolina Colliva, Roberto Pellicciari, Mario Calvitti, Teresa Zelante, Dietmar Fuchs, Ciriana Orabona, Louis Boon, Alban Bessede, Marco Colonna, Paolo Puccetti, Theresa L Murphy, Kenneth M Murphy, Francesca Fallarino.
      Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity and maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role in different subsets remains unclear. At homeostasis, only mature CCR7+ cDC1 expressed IDO1 that was dependent on IRF8. Lipopolysaccharide treatment induced maturation and IDO1-dependent tolerogenic activity in isolated immature cDC1, but not isolated cDC2. However, both human and mouse cDC2 could induce IDO1 and acquire tolerogenic function when co-cultured with mature cDC1 through the action of cDC1-derived l-kynurenine. Accordingly, cDC1-specific inactivation of IDO1 in vivo exacerbated disease in experimental autoimmune encephalomyelitis. This study identifies a previously unrecognized metabolic communication in which IDO1-expressing cDC1 cells extend their immunoregulatory capacity to the cDC2 subset through their production of tryptophan metabolite l-kynurenine. This metabolic axis represents a potential therapeutic target in treating autoimmune demyelinating diseases.
    Keywords:  AhR; IDO1; IL-6; RelB; dendritic cells; immunotolerance; kynurenine; metabolites; neuroinflammation; tryptophan metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2022.05.013
  4. Mol Biol Rep. 2022 Jun 13.
    Immune cell metabolism and metabolic reprogramming.
    Chenchen Hu, Yuxin Xuan, Xiyang Zhang, Yang Liu, Shuya Yang, Kun Yang.
      Energy metabolism maintains the activation of intracellular and intercellular signal transduction, and plays a crucial role in immune response. Under environmental stimulation, immune cells change from resting to activation and trigger metabolic reprogramming. The immune system cells exhibit different metabolic characteristics when performing functions. The study of immune metabolism provides new insights into the function of immune cells, including how they differentiate, migrate and exert immune responses. Studies of immune cell energy metabolism are beginning to shed light on the metabolic mechanism of disease progression and reveal new ways to target inflammatory diseases such as autoimmune diseases, chronic viral infections, and cancer. Here, we discussed the relationship between immune cells and metabolism, and proposed the possibility of targeted metabolic process for disease treatment.
    Keywords:  Immune cells; Immune metabolism; Metabolic reprogramming; Targeted therapy
    DOI:  https://doi.org/10.1007/s11033-022-07474-2
  5. Front Endocrinol (Lausanne). 2022 ;13 929460
    Editorial: Immune Regulation of Metabolic Homeostasis.
    Bruno Guigas, Tony Jourdan, Rinke Stienstra.
      
    Keywords:  NASH; T cells; dendritic cells; immunometabolism; macrophages; metaflammation; obesity; type 2 diabetes
    DOI:  https://doi.org/10.3389/fendo.2022.929460
  6. Int Immunol. 2022 Jun 14. pii: dxac025. [Epub ahead of print]
    Fatty acid metabolism in T-cell function and differentiation.
    Yusuke Endo, Toshio Kanno, Takahiro Nakajima.
      Immunometabolism has recently emerged as a field of study examining the intersection between immunology and metabolism. Studies in this area have yielded new findings on the roles of a diverse range of metabolic pathways and metabolites, which have been found to control many aspects of T-cell biology, including cell differentiation, function, and fate. A particularly important finding has been the discovery that to meet the energy requirements associated with their proliferation, activation, and specific functions, T cells switch their metabolic signatures during differentiation. For example, whereas the induction of de novo fatty acid biosynthesis and fatty acid uptake programs are required for antigen-stimulation-induced proliferation and differentiation of effector T cells, fatty acid catabolism via β-oxidation is essential for the generation of memory T cells and the differentiation of regulatory T cells. In this review, we discuss recent advances in our understanding of the metabolism in different stages of T cells and how fatty acid metabolism in these cells controls their specific functions.
    Keywords:  ACC1; fatty acid biosynthesis; immunological memory
    DOI:  https://doi.org/10.1093/intimm/dxac025
  7. iScience. 2022 Jun 17. 25(6): 104435
    Monocarboxylate transporter 1 deficiency impacts CD8+ T lymphocytes proliferation and recruitment to adipose tissue during obesity.
    C Macchi, A Moregola, M F Greco, M Svecla, F Bonacina, S Dhup, R K Dadhich, M Audano, P Sonveaux, C Mauro, N Mitro, M Ruscica, G D Norata.
      Lactate sits at the crossroad of metabolism, immunity, and inflammation. The expression of cellular lactate transporter MCT1 (known as Slc16a1) increases during immune cell activation to cope with the metabolic reprogramming. We investigated the impact of MCT1 deficiency on CD8+ T cell function during obesity-related inflammatory conditions. The absence of MCT1 impaired CD8+ T cell proliferation with a shift of ATP production to mitochondrial oxidative phosphorylation. In Slc16a1 f/f Tcell cre mice fed a high-fat diet, a reduction in the number of CD8+ T cells, which infiltrated epididymal visceral adipose tissue (epiWAT) or subcutaneous adipose tissue, was observed. Adipose tissue weight and adipocyte area were significantly reduced together with downregulation of adipogenic genes only in the epiWAT. Our findings highlight a distinct effect of MCT1 deficiency in CD8+ T cells in the crosstalk with adipocytes and reinforce the concept that targeting immunometabolic reprogramming in lymphocyte could impact the immune-adipose tissue axis in obesity.
    Keywords:  Biological sciences; Immunology; Metabolomics; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2022.104435
  8. J Cell Biol. 2022 Jul 04. pii: e202206006. [Epub ahead of print]221(7):
    Ubiquitinating the way to T cell metabolism.
    Sarah McPhedran, Julian J Lum.
      In this issue, Harris et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202203095) show that phosphofructokinase is a substrate for ubiquitination by Fbxo7, a key protein in the ubiquitination pathway. Their findings point to a new interplay between metabolic enzyme degradation in the regulation of T cells.
    DOI:  https://doi.org/10.1083/jcb.202206006
  9. Cancer Lett. 2022 Jun 08. pii: S0304-3835(22)00250-6. [Epub ahead of print]543 215766
    Metabolism and polarization regulation of macrophages in the tumor microenvironment.
    Jia Wang, Shichao Mi, Muyao Ding, Xue Li, Shengtao Yuan.
      The occurrence and development of tumors depend on the tumor microenvironment (TME), which consists of various types of cellular and acellular components. Tumor-associated macrophages (TAMs) are the most abundant stromal cell types in the TME. The competition for nutrients between tumor cells and macrophages leads to a limited supply of nutrients, such as glucose, lipids, and amino acids, to immune cells, which affects the differentiation and function of macrophages. Other factors in the TME, such as cytokines, chemokines, and immune checkpoints, also affect the polarization and function of macrophages. Remodeling the tumor microenvironment induces changes in macrophage nutrient uptake and polarization status, which enhance anti-tumor immunity and oxidative stress resistance and suppress immune escape. This review summarizes the influence factors on tumor progression and immune function under different conditions of macrophages. It also demonstrates the metabolic heterogeneity and phenotypic plasticity of macrophages, which provides novel strategies for anti-tumor treatment.
    Keywords:  Immune checkpoints; Phenotypic plasticity; Tumor immunotherapy; Tumor microenvironment; Tumor-associated macrophages metabolism
    DOI:  https://doi.org/10.1016/j.canlet.2022.215766
  10. Sci Adv. 2022 Jun 17. 8(24): eabo4271
    CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.
    Ping-Min Chen, Eri Katsuyama, Abhigyan Satyam, Hao Li, Jose Rubio, Sungwook Jung, Sylvia Andrzejewski, J David Becherer, Maria G Tsokos, Reza Abdi, George C Tsokos.
      Infection is one of the major causes of mortality in patients with systemic lupus erythematosus (SLE). We previously found that CD38, an ectoenzyme that regulates the production of NAD+, is up-regulated in CD8+ T cells of SLE patients and correlates with the risk of infection. Here, we report that CD38 reduces CD8+ T cell function by negatively affecting mitochondrial fitness through the inhibition of multiple steps of mitophagy, a process that is critical for mitochondria quality control. Using a murine lupus model, we found that administration of a CD38 inhibitor in a CD8+ T cell-targeted manner reinvigorated their effector function, reversed the defects in autophagy and mitochondria, and improved viral clearance. We conclude that CD38 represents a target to mitigate infection rates in people with SLE.
    DOI:  https://doi.org/10.1126/sciadv.abo4271
  11. J Immunol. 2022 Jun 13. pii: ji2100567. [Epub ahead of print]
    High-Fat Diet-Induced Obesity Alters Dendritic Cell Homeostasis by Enhancing Mitochondrial Fatty Acid Oxidation.
    I-Chun Chen, Deepika Awasthi, Chia-Lang Hsu, Minkyung Song, Chang-Suk Chae, Andrew J Dannenberg, Juan R Cubillos-Ruiz.
      Obesity is associated with increased cancer risk and weak responses to vaccination and sepsis treatment. Although dendritic cells (DCs) are fundamental for the initiation and maintenance of competent immune responses against pathogens and tumors, how obesity alters the normal physiology of these myeloid cells remains largely unexplored. In this study, we report that obesity caused by prolonged high-fat diet feeding disrupts the metabolic and functional status of mouse splenic DCs (SpDCs). High-fat diet-induced obesity drastically altered the global transcriptional profile of SpDCs, causing severe changes in the expression of gene programs implicated in lipid metabolism and mitochondrial function. SpDCs isolated from obese mice demonstrated enhanced mitochondrial respiration provoked by increased fatty acid oxidation (FAO), which drove the intracellular accumulation of reactive oxygen species that impaired Ag presentation to T cells. Accordingly, treatment with the FAO inhibitor etomoxir, or antioxidants such as vitamin E or N-acetyl-l-cysteine, restored the Ag-presenting capacity of SpDCs isolated from obese mice. Our findings reveal a major detrimental effect of obesity in DC physiology and suggest that controlling mitochondrial FAO or reactive oxygen species overproduction may help improve DC function in obese individuals.
    DOI:  https://doi.org/10.4049/jimmunol.2100567
  12. Front Immunol. 2022 ;13 836754
    Metabolic Reprogramming Mediates Delayed Apoptosis of Human Neutrophils Infected With Francisella tularensis.
    Samantha J Krysa, Lee-Ann H Allen.
      Neutrophils (polymorphonuclear leukocytes, PMNs) have a distinctively short lifespan, and tight regulation of cell survival and death is imperative for their normal function. We demonstrated previously that Francisella tularensis extends human neutrophil lifespan, which elicits an impaired immune response characterized by neutrophil dysfunction. Herein, we extended these studies, including our transcriptional profiling data, and employed Seahorse extracellular flux analysis, gas chromatography-mass spectrometry metabolite analysis, flow cytometry and several other biochemical approaches to demonstrate that the delayed apoptosis observed in F. tularensis-infected neutrophils is mediated, in part, by metabolic reprogramming. Specifically, we show that F. tularensis-infected neutrophils exhibited a unique metabolic signature characterized by increased glycolysis, glycolytic flux and glucose uptake, downregulation of the pentose phosphate pathway, and complex glycogen dynamics. Glucose uptake and glycolysis were essential for cell longevity, although glucose-6-phosphate translocation into the endoplasmic reticulum was not, and we identify depletion of glycogen as a potential trigger of apoptosis onset. In keeping with this, we also demonstrate that ablation of apoptosis with the pan-caspase inhibitor Q-VD-OPh was sufficient to profoundly increase glycolysis and glycogen stores in the absence of infection. Taken together, our data significantly advance understanding of neutrophil immunometabolism and its capacity to regulate cell lifespan.
    Keywords:  Francisella tularensis; apoptosis; glycogen; glycolysis; immunometabolism; neutrophils (PMNs)
    DOI:  https://doi.org/10.3389/fimmu.2022.836754
  13. Cell Rep. 2022 Jun 14. pii: S2211-1247(22)00725-2. [Epub ahead of print]39(11): 110943
    Vps33B controls Treg cell suppressive function through inhibiting lysosomal nutrient sensing complex-mediated mTORC1 activation.
    Hongrui Xiang, Yuexiao Tao, Zhenyan Jiang, Xian Huang, Huizi Wang, Wei Cao, Jia Li, Rui Ding, Mingyi Shen, Ru Feng, Linsen Li, Chenyang Guan, Jiamin Liu, Jun Ni, Lei Chen, Zhengting Wang, Youqiong Ye, Qing Zhong, Junling Liu, Qiang Zou, Xuefeng Wu.
      The suppressive function of regulatory T (Treg) cells is tightly controlled by nutrient-fueled mechanistic target of rapamycin complex 1 (mTORC1) activation, yet its dynamics and negative regulation remain unclear. Here we show that Treg-specific depletion of vacuolar protein sorting 33B (Vps33B) in mice results in defective Treg cell suppressive function and acquisition of effector phenotype, which in turn leads to disturbed T cell homeostasis and boosted antitumor immunity. Mechanistically, Vps33B binds with lysosomal nutrient-sensing complex (LYNUS) and promotes late endosome and lysosome fusion and clearance of the LYNUS-containing late endosome/lysosome, and therefore suppresses mTORC1 activation. Vps33B deficiency in Treg cells results in disordered endosome lysosome fusion, which leads to accumulation of LYNUS that causes elevated mTORC1 activation and hyper-glycolytic metabolism. Taken together, our study reveals that Vps33B maintains Treg cell suppressive function through sustaining endolysosomal homeostasis and therefore restricting amino acid-licensed mTORC1 activation and metabolism.
    Keywords:  CP: Immunology; CP: Metabolism; Foxp3; Treg; Vps33B; endolysosomal system; mTORC1
    DOI:  https://doi.org/10.1016/j.celrep.2022.110943
  14. Sci Rep. 2022 Jun 15. 12(1): 9959
    Urine metabolomics links dysregulation of the tryptophan-kynurenine pathway to inflammation and severity of COVID-19.
    Joseph P Dewulf, Manon Martin, Sandrine Marie, Fabie Oguz, Leila Belkhir, Julien De Greef, Jean Cyr Yombi, Xavier Wittebole, Pierre-François Laterre, Michel Jadoul, Laurent Gatto, Guido T Bommer, Johann Morelle.
      SARS-CoV-2 causes major disturbances in serum metabolite levels, associated with severity of the immune response. Despite the numerous advantages of urine for biomarker discovery, the potential association between urine metabolites and disease severity has not been investigated in coronavirus disease 2019 (COVID-19). In a proof-of-concept study, we performed quantitative urine metabolomics in patients hospitalized with COVID-19 and controls using LC-MS/MS. We assessed whether metabolites alterations were associated with COVID-19, disease severity, and inflammation. The study included 56 patients hospitalized with COVID-19 (26 non-critical and 30 critical disease); 16 healthy controls; and 3 controls with proximal tubule dysfunction unrelated to SARS-CoV-2. Metabolomic profiling revealed a major urinary increase of tryptophan metabolites kynurenine (P < 0.001), 3-hydroxykynurenine (P < 0.001) and 3-hydroxyanthranilate (P < 0.001) in SARS-CoV-2 infected patients. Urine levels of kynurenines were associated with disease severity and systemic inflammation (kynurenine, r 0.43, P = 0.001; 3-hydroxykynurenine, r 0.44, P < 0.001). Increased urinary levels of neutral amino acids and imino acid proline were also common in COVID-19, suggesting specific transport defects. Urine metabolomics identified major alterations in the tryptophan-kynurenine pathway, consistent with changes in host metabolism during SARS-CoV-2 infection. The association between increased urinary levels of kynurenines, inflammation and COVID-19 severity supports further evaluation of these easily available biomarkers.
    DOI:  https://doi.org/10.1038/s41598-022-14292-w
  15. Biochim Biophys Acta Mol Basis Dis. 2022 Jun 11. pii: S0925-4439(22)00129-6. [Epub ahead of print]1868(10): 166458
    ATP citrate lyase links increases in glycolysis to diminished release of vesicular suppressor of cytokine signaling 3 by alveolar macrophages.
    Mikel D Haggadone, Jennifer Speth, Hanna S Hong, Loka R Penke, Eric Zhang, Costas A Lyssiotis, Marc Peters-Golden.
      Extracellular vesicles (EVs) are important vectors for intercellular communication. Lung-resident alveolar macrophages (AMs) tonically secrete EVs containing suppressor of cytokine signaling 3 (SOCS3), a cytosolic protein that promotes homeostasis in the distal lung via its actions in recipient neighboring epithelial cells. AMs are metabolically distinct and exhibit low levels of glycolysis at steady state. To our knowledge, whether cellular metabolism influences the packaging and release of an EV cargo molecule has never been explored in any cellular context. Here, we report that increases in glycolysis following in vitro exposure of AMs to the growth and activating factor granulocyte-macrophage colony-stimulating factor inhibit the release of vesicular SOCS3 by primary AMs. Glycolytically diminished SOCS3 secretion requires export of citrate from the mitochondria to the cytosol and its subsequent conversion to acetyl-CoA by ATP citrate lyase. Our data for the first time implicate perturbations in intracellular metabolites in the regulation of vesicular cargo packaging and secretion.
    Keywords:  ATP citrate lyase; Alveolar macrophage; Extracellular vesicle; Glycolysis; Granulocyte-macrophage colony-stimulating factor; Suppressor of cytokine signaling 3
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166458
  16. Proc Natl Acad Sci U S A. 2022 Jun 21. 119(25): e2123265119
    Blood-based untargeted metabolomics in relapsing-remitting multiple sclerosis revealed the testable therapeutic target.
    Insha Zahoor, Hamid Suhail, Indrani Datta, Mohammad Ejaz Ahmed, Laila M Poisson, Jeffrey Waters, Faraz Rashid, Rui Bin, Jaspreet Singh, Mirela Cerghet, Ashok Kumar, Md Nasrul Hoda, Ramandeep Rattan, Ashutosh K Mangalam, Shailendra Giri.
      Metabolic aberrations impact the pathogenesis of multiple sclerosis (MS) and possibly can provide clues for new treatment strategies. Using untargeted metabolomics, we measured serum metabolites from 35 patients with relapsing-remitting multiple sclerosis (RRMS) and 14 healthy age-matched controls. Of 632 known metabolites detected, 60 were significantly altered in RRMS. Bioinformatics analysis identified an altered metabotype in patients with RRMS, represented by four changed metabolic pathways of glycerophospholipid, citrate cycle, sphingolipid, and pyruvate metabolism. Interestingly, the common upstream metabolic pathway feeding these four pathways is the glycolysis pathway. Real-time bioenergetic analysis of the patient-derived peripheral blood mononuclear cells showed enhanced glycolysis, supporting the altered metabolic state of immune cells. Experimental autoimmune encephalomyelitis mice treated with the glycolytic inhibitor 2-deoxy-D-glucose ameliorated the disease progression and inhibited the disease pathology significantly by promoting the antiinflammatory phenotype of monocytes/macrophage in the central nervous system. Our study provided a proof of principle for how a blood-based metabolomic approach using patient samples could lead to the identification of a therapeutic target for developing potential therapy.
    Keywords:  EAE; glycolysis; metabolomics; multiple sclerosis
    DOI:  https://doi.org/10.1073/pnas.2123265119
  17. J Clin Invest. 2022 Jun 14. pii: e154333. [Epub ahead of print]
    Myeloid FoxO1 depletion attenuates hepatic inflammation and prevents nonalcoholic steatohepatitis.
    Sojin Lee, Taofeek O Usman, Jun Yamauchi, Goma Chhetri, Xingchun Wang, Gina M Coudriet, Cuiling Zhu, Jingyang Gao, Riley McConnell, Kyler Krantz, Dhivyaa Rajasundaram, Sucha Singh, Jon Piganelli, Alina Ostrowska, Alejandro Soto-Gutierrez, Satdarshan P Monga, Aatur D Singhi, Radhika H Muzumdar, Allan Tsung, H Henry Dong.
      Hepatic inflammation is culpable for the evolution of asymptomatic steatosis to nonalcoholic steatohepatitis (NASH). Hepatic inflammation results from abnormal macrophage activation. We found that FoxO1 links overnutrition to hepatic inflammation by regulating macrophage polarization and activation. FoxO1 was upregulated in hepatic macrophages, correlating with hepatic inflammation, steatosis and fibrosis in mice and patients with NASH. Myeloid cell-conditional FoxO1 knockout skewed macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, accompanied by the reduction of macrophage infiltration in liver. These effects mitigated overnutrition-induced hepatic inflammation and insulin resistance, contributing to improved hepatic metabolism and increased energy expenditure in myeloid cell FoxO1 knockout mice on HFD. When fed a NASH-inducing diet, myeloid cell FoxO1 knockout mice were protected from developing NASH, culminating in the reduction of hepatic inflammation, steatosis and fibrosis. Mechanistically, FoxO1 counteracts Stat6 to skew macrophage polarization from M2 toward M1 signatures to perpetuate hepatic inflammation in NASH. FoxO1 appears as a pivotal mediator of macrophage activation in response to overnutrition and a therapeutic target for ameliorating hepatic inflammation to stem the disease progression from benign steatosis to NASH.
    Keywords:  Carbohydrate metabolism; Endocrinology; Macrophages; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI154333
  18. Science. 2022 Jun 16. eabg9302
    Interleukin-17 governs hypoxic adaptation of injured epithelium.
    Piotr Konieczny, Yue Xing, Ikjot Sidhu, Ipsita Subudhi, Kody P Mansfield, Brandon Hsieh, Douglas E Biancur, Samantha B Larsen, Michael Cammer, Dongqing Li, Ning Xu Landén, Cynthia Loomis, Adriana Heguy, Anastasia N Tikhonova, Aristotelis Tsirigos, Shruti Naik.
      Mammalian cells autonomously activate hypoxia-inducible transcription factors to ensure survival in low-oxygen environments. We report that injury-induced hypoxia is insufficient to trigger hypoxia-inducible factor 1 alpha (HIF1α) in damaged epithelium. Instead, multimodal single-cell and spatial transcriptomics analyses and functional studies reveal that RORγt+ γδ T cell-derived interleukin (IL)-17A, is necessary and sufficient to activate HIF1α. Protein kinase B (AKT) and ERK1/2 signaling proximal of IL-17RC activates mammalian target of rapamycin (mTOR) and consequently HIF1α. The IL-17A-HIF1α drives glycolysis in wound front epithelia. Epithelial-specific loss of IL-17RC, HIF1α, or blockade of glycolysis derails repair. Our findings underscore the coupling of inflammatory, metabolic, and migratory programs to expedite epithelial healing and illuminate the immune cell-derived inputs in cellular adaptation to hypoxic stress during repair.
    DOI:  https://doi.org/10.1126/science.abg9302
  19. Proc Natl Acad Sci U S A. 2022 Jun 28. 119(26): e2122897119
    SARS-CoV-2 couples evasion of inflammatory response to activated nucleotide synthesis.
    Chao Qin, Youliang Rao, Hao Yuan, Ting-Yu Wang, Jun Zhao, Bianca Espinosa, Yongzhen Liu, Shu Zhang, Ali Can Savas, Qizhi Liu, Mehrnaz Zarinfar, Stephanie Rice, Jill Henley, Lucio Comai, Nicholas A Graham, Casey Chen, Chao Zhang, Pinghui Feng.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolves rapidly under the pressure of host immunity, as evidenced by waves of emerging variants despite effective vaccinations, highlighting the need for complementing antivirals. We report that targeting a pyrimidine synthesis enzyme restores inflammatory response and depletes the nucleotide pool to impede SARS-CoV-2 infection. SARS-CoV-2 deploys Nsp9 to activate carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD) that catalyzes the rate-limiting steps of the de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. While RelA deamidation shuts down NF-κB activation and subsequent inflammatory response, it up-regulates key glycolytic enzymes to promote aerobic glycolysis that provides metabolites for de novo nucleotide synthesis. A newly synthesized small-molecule inhibitor of CAD restores antiviral inflammatory response and depletes the pyrimidine pool, thus effectively impeding SARS-CoV-2 replication. Targeting an essential cellular metabolic enzyme thus offers an antiviral strategy that would be more refractory to SARS-CoV-2 genetic changes.
    Keywords:  CAD; SARS-CoV-2; deamidation; inflammatory response; metabolism
    DOI:  https://doi.org/10.1073/pnas.2122897119
  20. Immunity. 2022 Jun 14. pii: S1074-7613(22)00235-7. [Epub ahead of print]55(6): 967-970
    cDC1 to cDC2: "Everything I do, Ido1 it for you".
    Mirja Tamara Prentzell, Christiane A Opitz.
      Distinct dendritic cell (DC) subsets exert specific functions in immune regulation, but their communication with each other has remained elusive. In this issue of Immunity, Gargaro et al. identify the IDO1-Kyn-AHR axis as a metabolic signaling pathway through which conventional DC subsets communicate and induce tolerogenicity.
    DOI:  https://doi.org/10.1016/j.immuni.2022.05.015
  21. Biochem J. 2022 Jun 17. 479(11): 1221-1235
    Endogenous glutamine is rate-limiting for anti-CD3 and anti-CD28 induced CD4+ T-cell proliferation and glycolytic activity under hypoxia and normoxia.
    Jonas A Wik, Azazul Chowdhury, Shrikant Kolan, Nasser E Bastani, Gaoyang Li, Kazi Alam, Franco Grimolizzi, Bjørn S Skålhegg.
      To meet the demand for energy and biomass, T lymphocytes (T cells) activated to proliferation and clonal expansion, require uptake and metabolism of glucose (Gluc) and the amino acid (AA) glutamine (Gln). Whereas exogenous Gln is converted to glutamate (Glu) by glutaminase (GLS), Gln is also synthesized from the endogenous pool of AA through Glu and activity of glutamine synthase (GS). Most of this knowledge comes from studies on cell cultures under ambient oxygen conditions (normoxia, 21% O2). However, in vivo, antigen induced T-cell activation often occurs under moderately hypoxic (1-4% O2) conditions and at various levels of exogenous nutrients. Here, CD4+ T cells were stimulated for 72 h with antibodies targeting the CD3 and CD28 markers at normoxia and hypoxia (1% O2). This was done in the presence and absence of the GLS and GS inhibitors, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and methionine sulfoximine (MSO) and at various combinations of exogenous Gluc, Gln and pyruvate (Pyr) for the last 12 h of stimulation. We found that T-cell proliferation, viability and levels of endogenous AA were significantly influenced by the availability of exogenous Gln, Gluc and Pyr as well as inhibition of GLS and GS. Moreover, inhibition of GLS and GS and levels of oxygen differentially influenced oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Finally, BPTES-dependent down-regulation of ECAR was associated with reduced hexokinase (HK) activity at both normoxia and hypoxia. Our results demonstrate that Gln availability and metabolism is rate-limiting for CD4+ T-cell activity.
    Keywords:  BPTES; CD4+ T cells; glutamine; hypoxia; metabolism; normoxia
    DOI:  https://doi.org/10.1042/BCJ20220144
  22. Nat Commun. 2022 Jun 17. 13(1): 3489
    Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling.
    Teng Huang, Jia Song, Jia Gao, Jia Cheng, Hao Xie, Lu Zhang, Yu-Han Wang, Zhichao Gao, Yi Wang, Xiaohui Wang, Jinhan He, Shiwei Liu, Qilin Yu, Shu Zhang, Fei Xiong, Qing Zhou, Cong-Yi Wang.
      Aberrant amino acid metabolism is a common event in obesity. Particularly, subjects with obesity are characterized by the excessive plasma kynurenine (Kyn). However, the primary source of Kyn and its impact on metabolic syndrome are yet to be fully addressed. Herein, we show that the overexpressed indoleamine 2,3-dioxygenase 1 (IDO1) in adipocytes predominantly contributes to the excessive Kyn, indicating a central role of adipocytes in Kyn metabolism. Depletion of Ido1 in adipocytes abrogates Kyn accumulation, protecting mice against obesity. Mechanistically, Kyn impairs lipid homeostasis in adipocytes via activating the aryl hydrocarbon receptor (AhR)/Signal transducer and activator of transcription 3 /interleukin-6 signaling. Genetic ablation of AhR in adipocytes abolishes the effect of Kyn. Moreover, supplementation of vitamin B6 ameliorated Kyn accumulation, protecting mice from obesity. Collectively, our data support that adipocytes are the primary source of increased circulating Kyn, while elimination of accumulated Kyn could be a viable strategy against obesity.
    DOI:  https://doi.org/10.1038/s41467-022-31126-5
  23. Sci Signal. 2022 Jun 14. 15(738): eabq5594
    Voltage-gated Ca2+ channel proteins do not function as ion channels in T cells.
    Michael D Cahalan.
      Calcium (Ca2+) signaling has long been known to be crucial for T cell activation. Erdogmus et al. tested the function of voltage-gated Ca2+ channel (CaV) proteins and discovered a nonchannel function mediated by an accessory subunit but found no evidence for CaV channel activity in T cells.
    DOI:  https://doi.org/10.1126/scisignal.abq5594
  24. Front Immunol. 2022 ;13 885782
    Metabolomic Investigation of Ultraviolet Ray-Inactivated White Spot Syndrome Virus-Induced Trained Immunity in Marsupenaeus japonicus.
    Shaoqing Zang, Li-Xia Lv, Chen-Fei Liu, Peng Zhang, Cang Li, Jin-Xing Wang.
      Trained immunity is driven by metabolism and epigenetics in innate immune cells in mammals. The phenomenon of trained immunity has been identified in invertebrates, including shrimp, but the underlying mechanisms remain unclear. To elucidate mechanisms of trained immunity in shrimp, the metabolomic changes in hemolymph of Marsupenaeus japonicus trained by the UV-inactivated white spot syndrome virus (UV-WSSV) were analyzed using tandem gas chromatography-mass/mass spectrometry. The metabolomic profiles of shrimp trained with UV-WSSV followed WSSV infection showed significant differences comparison with the control groups, PBS injection followed WSSV infection. 16 differential metabolites in total of 154 metabolites were identified, including D-fructose-6-phosphate, D-glucose-6-phosphate, and D-fructose-6-phosphate, and metabolic pathways, glycolysis, pentose phosphate pathway, and AMPK signaling pathway were enriched in the UV-WSSV trained groups. Further study found that histone monomethylation and trimethylation at H3K4 (H3K4me1 and H3K4me3) were involved in the trained immunity. Our data suggest that the UV-WSSV induced trained immunity leads to metabolism reprogramming in the shrimp and provide insights for WSSV control in shrimp aquaculture.
    Keywords:  GC–MS/MS; WSSV; metabolites; shrimp; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2022.885782
  25. Am J Respir Crit Care Med. 2022 Jun 14.
    Macrophage-NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension.
    Ruaa Al-Qazazi, Patricia D A Lima, Sasha Z Prisco, Francois Potus, Asish Dasgupta, Kuang-Hueih Chen, Lian Tian, Rachel Et Bentley, Jeff Mewburn, Ashley Y Martin, Danchen Wu, Oliver Jones, Donald H Maurice, Sebastien Bonnet, Steeve Provencher, Kurt W Prins, Stephen L Archer.
       RATIONALE: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3-macrophage activation may promote RVF in PAH.
    OBJECTIVES: Evaluating the contribution of the NLRP3 inflammasome in RV-macrophages to PAH-RVF.
    METHODS: Rats with decompensated RV hypertrophy (RVH) [monocrotaline (MCT) and Sugen-5416 hypoxia (SuHx)] were compared with compensated RVH rats [pulmonary artery banding (PAB)]. Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptide (ANP) and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and in vitro strategies. MCT-rats were treated with SC-144 (a GP130 antagonist) and MCC950 (an NLRP3 inhibitor). Macrophage-NLRP3 activity was evaluated in PAH-RVF patients.
    MEASUREMENTS AND MAIN RESULTS: Macrophages, fibrosis, and ANP were increased in MCT and SuHx-RVs but not LVs or PAB rats. While MCT-RV macrophages were inflammatory, lung macrophages were anti-inflammatory. CCR2+ macrophages (monocyte-derived) were increased in MCT- and SuHx-RVs and highly expressed NLRP3. The macrophage-NLRP3 pathway was upregulated in PAH patients' decompensated RVs. Cultured MCT-monocytes showed NLRP3 activation, and in co-culture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. In vivo, MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV-macrophages and NLRP3 content, prevented STAT3 activation, and improved RV function without regressing pulmonary vascular disease.
    CONCLUSION: NLRP3-macrophage activation occurs in the decompensated RV in preclinical PAH models and PAH patients. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH-RVF results from RV inflammation rather than solely from elevated RV afterload suggest a new therapeutic paradigm. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
    Keywords:  CCR2; MCC950; SC-144; interleukin-1β; mitochondrial fission
    DOI:  https://doi.org/10.1164/rccm.202110-2274OC
  26. Sci Rep. 2022 Jun 15. 12(1): 9977
    Mitochondrial complex I dysfunction alters the balance of soluble and membrane-bound TNF during chronic experimental colitis.
    Ainize Peña-Cearra, Miguel Angel Pascual-Itoiz, Jose Luis Lavín, Miguel Fuertes, Itziar Martín-Ruiz, Janire Castelo, Ainhoa Palacios, Diego Barriales, Asier Fullaondo, Ana M Aransay, Hector Rodríguez, Juan Anguita, Leticia Abecia.
      Inflammatory bowel disease (IBD) is a complex, chronic, relapsing and heterogeneous disease induced by environmental, genomic, microbial and immunological factors. MCJ is a mitochondrial protein that regulates the metabolic status of macrophages and their response to translocated bacteria. Previously, an acute murine model of DSS-induced colitis showed increased disease severity due to MCJ deficiency. Unexpectedly, we now show that MCJ-deficient mice have augmented tumor necrosis factor α converting enzyme (TACE) activity in the context of chronic inflammation. This adaptative change likely affects the balance between soluble and transmembrane TNF and supports the association of the soluble form and a milder phenotype. Interestingly, the general shifts in microbial composition previously observed during acute inflammation were absent in the chronic model of inflammation in MCJ-deficient mice. However, the lack of the mitochondrial protein resulted in increased alpha diversity and the reduction in critical microbial members associated with inflammation, such as Ruminococcus gnavus, which could be associated with TACE activity. These results provide evidence of the dynamic metabolic adaptation of the colon tissue to chronic inflammatory changes mediated by the control of mitochondrial function.
    DOI:  https://doi.org/10.1038/s41598-022-13480-y
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