bims-imicid 2022-05-08 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–05–08
27 papers selected by
Dylan Ryan, University of Cambridge

Intracellular infection and immune system cues rewire adipocytes to acquire immune function.
A FAsT contribution: Adipocytes rewire their metabolism to acquire immune functions.
An integrated toolbox to profile macrophage immunometabolism.
Microbiota-mediated skewing of tryptophan catabolism modulates CD4+ T cells in lupus-prone mice.
Glycolytic and lipid oxidative metabolic programs are essential for freshly-isolated regulatory T cells in mice with sepsis.
Therapeutic opportunities to modulate immune tolerance through the metabolism-chromatin axis.
Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice.
Rheumatoid arthritis T cell and muscle oxidative metabolism associate with exercise-induced changes in cardiorespiratory fitness.
Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer.
Letting go of damaged mitochondria.
Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity.
The Adipose Tissue Macrophages Central to Adaptive Thermoregulation.
Metabolic reprogramming by ex vivo glutamine inhibition endows CAR-T cells with less-differentiated phenotype and persistent antitumor activity.
Butyrate administration is not sufficient to improve immune reconstitution in antiretroviral-treated SIV-infected macaques.
BOXR1030, an anti-GPC3 CAR with exogenous GOT2 expression, shows enhanced T cell metabolism and improved anti-cell line derived tumor xenograft activity.
Immunometabolism and the modulation of immune responses and host defense: A role for methylglyoxal?
IP3R-mediated Ca2+ signaling controls B cell proliferation through metabolic reprogramming.
LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation.
IFNγ Regulates NAD+ Metabolism to Promote the Respiratory Burst in Human Monocytes.
HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
Molecular mechanism of crosstalk between immune and metabolic systems in metabolic syndrome.
Labile iron accumulation augments T follicular helper cell differentiation.
Mechanism Found for IDO1 Inhibitor Evasion.
Ceramide synthase 6 impacts T-cell allogeneic response and graft-versus-host disease through regulating N-RAS/ERK pathway.
Host succinate inhibits influenza virus infection through succinylation and nuclear retention of the viral nucleoprotein.
Impact of IDO1 and IDO2 on the B Cell Immune Response.
Identification of serum metabolites enhancing inflammatory responses in COVID-19.

Cell Metab. 2022 May 03. pii: S1550-4131(22)00135-8. [Epub ahead of print]34(5): 747-760.e6

Intracellular infection and immune system cues rewire adipocytes to acquire immune function.

George Caputa, Mai Matsushita, David E Sanin, Agnieszka M Kabat, Joy Edwards-Hicks, Katarzyna M Grzes, Roland Pohlmeyer, Michal A Stanczak, Angela Castoldi, Jovana Cupovic, Aaron J Forde, Petya Apostolova, Maximilian Seidl, Nikki van Teijlingen Bakker, Matteo Villa, Francesc Baixauli, Andrea Quintana, Alexandra Hackl, Lea Flachsmann, Fabian Hässler, Jonathan D Curtis, Annette E Patterson, Philipp Henneke, Erika L Pearce, Edward J Pearce.

  Adipose tissue (AT) plays a central role in systemic metabolic homeostasis, but its function during bacterial infection remains unclear. Following subcutaneous bacterial infection, adipocytes surrounding draining lymph nodes initiated a transcriptional response indicative of stimulation with IFN-γ and a shift away from lipid metabolism toward an immunologic function. Natural killer (NK) and invariant NK T (iNKT) cells were identified as sources of infection-induced IFN-γ in perinodal AT (PAT). IFN-γ induced Nos2 expression in adipocytes through a process dependent on nuclear-binding oligomerization domain 1 (NOD1) sensing of live intracellular bacteria. iNOS expression was coupled to metabolic rewiring, inducing increased diversion of extracellular L-arginine through the arginosuccinate shunt and urea cycle to produce nitric oxide (NO), directly mediating bacterial clearance. In vivo, control of infection in adipocytes was dependent on adipocyte-intrinsic sensing of IFN-γ and expression of iNOS. Thus, adipocytes are licensed by innate lymphocytes to acquire anti-bacterial functions during infection.

Keywords:  IFN-γ; NK cells; NOD1; NOS2; adipocyte; iNK T cells; infection; lymph node; metabolism; perinodal adipose tissue

DOI:  https://doi.org/10.1016/j.cmet.2022.04.008
Cell Metab. 2022 May 03. pii: S1550-4131(22)00134-6. [Epub ahead of print]34(5): 656-657

A FAsT contribution: Adipocytes rewire their metabolism to acquire immune functions.

Takumi Kobayashi, Dirk Brenner.

Adipose tissue has been linked to inflammation and various physiological processes. In this issue of Cell Metabolism, Caputa et al. describe that perinodal adipocytes adapt their metabolism to actively participate in an immune response against intracellular Listeria monocytogenes.

DOI: https://doi.org/10.1016/j.cmet.2022.04.007
Cell Rep Methods. 2022 Apr 25. 2(4): 100192

An integrated toolbox to profile macrophage immunometabolism.

Sanne G S Verberk, Kyra E de Goede, Friederike S Gorki, Xanthe A M H van Dierendonck, Rafael J Argüello, Jan Van den Bossche.

  Macrophages are dynamic immune cells that can adopt several activation states. Fundamental to these functional activation states is the regulation of cellular metabolic processes. Especially in mice, metabolic alterations underlying pro-inflammatory or homeostatic phenotypes have been assessed using various techniques. However, researchers new to the field may encounter ambiguity in choosing which combination of techniques is best suited to profile immunometabolism. To address this need, we have developed a toolbox to assess cellular metabolism in a semi-high-throughput 96-well-plate-based format. Application of the toolbox to activated mouse and human macrophages enables fast metabolic pre-screening and robust measurement of extracellular fluxes, mitochondrial mass and membrane potential, and glucose and lipid uptake. Moreover, we propose an application of SCENITH technology for ex vivo metabolic profiling. We validate established activation-induced metabolic rewiring in mouse macrophages and report new insights into human macrophage metabolism. By thoroughly discussing each technique, we hope to guide readers with practical workflows for investigating immunometabolism.

Keywords:  immunometabolism; macrophages; metabolism; semi-high throughput screening; toolbox

DOI:  https://doi.org/10.1016/j.crmeth.2022.100192
iScience. 2022 May 20. 25(5): 104241

Microbiota-mediated skewing of tryptophan catabolism modulates CD4+ T cells in lupus-prone mice.

Josephine Brown, Georges Abboud, Longhuan Ma, Seung-Chul Choi, Nathalie Kanda, Leilani Zeumer-Spataro, Jean Lee, Weidan Peng, Joy Cagmat, Tamas Faludi, Mansour Mohamadzadeh, Timothy Garrett, Laura Mandik-Nayak, Alexander Chervonsky, Andras Perl, Laurence Morel.

  A skewed tryptophan metabolism has been reported in patients with lupus. Here, we investigated the mechanisms by which it occurs in lupus-susceptible mice, and how tryptophan metabolites exacerbate T cell activation. Metabolomic analyses demonstrated that tryptophan is differentially catabolized in lupus mice compared to controls and that the microbiota played a role in this skewing. There was no evidence for differential expression of tryptophan catabolic enzymes in lupus mice, further supporting a major contribution of the microbiota to skewing. However, isolated lupus T cells processed tryptophan differently, suggesting a contribution of T cell intrinsic factors. Functionally, tryptophan and its microbial product tryptamine increased T cell metabolism and mTOR activation, while kynurenine promoted interferon gamma production, all of which have been associated with lupus. These results showed that a combination of microbial and T cell intrinsic factors promotes the production of tryptophan metabolites that enhance inflammatory phenotypes in lupus T cells.

Keywords:  Biological sciences; Cell biology; Human metabolism; Immunology

DOI:  https://doi.org/10.1016/j.isci.2022.104241
RSC Adv. 2020 May 27. 10(35): 21000-21008

Glycolytic and lipid oxidative metabolic programs are essential for freshly-isolated regulatory T cells in mice with sepsis.

Xiaomei Zhu, WenQing Ji, Shubin Guo, Di Zhu, Yue Yang, Xin Liu.

Immunometabolism determines the fate and function of regulatory T cells. The metabolic phenotype of regulatory T cells (Treg) is affected by various factors. The relationship between Treg metabolism and function of mice with sepsis is not clear. We used liquid chromatography and tandem mass spectrometry (LC-MS/MS) to analyze the metabolic profiles of freshly-isolated spleen Treg cells in mice with sepsis. It was found that in severe infection, activated Treg cells depend on glycolysis and fatty acid oxidation, and inhibition of metabolic pathways has a significant impact on the number and quality of Treg cells. Understanding the metabolic characteristics of Treg cells in the real environment in the body helps to grasp the function of Treg cells and even the overall immune status. Targeting the metabolic pathway of Treg may provide a new method for the treatment of sepsis.

DOI: https://doi.org/10.1039/d0ra01947j
Trends Endocrinol Metab. 2022 May 01. pii: S1043-2760(22)00059-5. [Epub ahead of print]

Therapeutic opportunities to modulate immune tolerance through the metabolism-chromatin axis.

Anne Lise Ferrara, Antonietta Liotti, Antonio Pezone, Veronica De Rosa.

  The ability of the immune system to discriminate external stimuli from self-components - namely immune tolerance - occurs through a coordinated cascade of events involving a dense network of immune cells. Among them, CD4+CD25+ T regulatory cells are crucial to balance immune homeostasis and function. Growing evidence supports the notion that energy metabolites can dictate T cell fate and function via epigenetic modifications, which affect gene expression without altering the DNA sequence. Moreover, changes in cellular metabolism couple with activation of immune pathways and epigenetic remodeling to finely tune the balance between T cell activation and tolerance. This Review summarizes these aspects and critically evaluates novel possibilities for developing therapeutic strategies to modulate immune tolerance through metabolism via epigenetic drugs.

Keywords:  Foxp3; T regulatory cells; epigenetic regulation; immune tolerance; metabolic flexibility

DOI:  https://doi.org/10.1016/j.tem.2022.04.002
J Clin Invest. 2022 May 02. pii: e152391. [Epub ahead of print]132(9):

Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice.

Yu Pan, Shirong Cao, Jiaqi Tang, Juan P Arroyo, Andrew S Terker, Yinqiu Wang, Aolei Niu, Xiaofeng Fan, Suwan Wang, Yahua Zhang, Ming Jiang, David H Wasserman, Ming-Zhi Zhang, Raymond C Harris.

  Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in obesity leads to a state of low-grade chronic inflammation and dysregulated metabolism, resulting in insulin resistance and metabolic syndrome. Adipose tissue macrophages (ATMs) accumulate in obesity and are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. Macrophages are rich sources of cyclooxygenase (COX), the rate limiting enzyme for prostaglandin E2 (PGE2) production. When mice were fed a high-fat diet (HFD), ATMs increased expression of COX-2. Selective myeloid cell COX-2 deletion resulted in increased monocyte recruitment and proliferation of ATMs, leading to increased proinflammatory ATMs with decreased phagocytic ability. There were increased weight gain and adiposity, decreased peripheral insulin sensitivity and glucose utilization, increased adipose tissue inflammation and fibrosis, and abnormal adipose tissue angiogenesis. HFD pair-feeding led to similar increases in body weight, but mice with selective myeloid cell COX-2 still exhibited decreased peripheral insulin sensitivity and glucose utilization. Selective myeloid deletion of the macrophage PGE2 receptor subtype, EP4, produced a similar phenotype, and a selective EP4 agonist ameliorated the metabolic abnormalities seen with ATM COX-2 deletion. Therefore, these studies demonstrated that an ATM COX-2/PGE2/EP4 axis plays an important role in inhibiting adipose tissue dysfunction.

Keywords:  Adipose tissue; Eicosanoids; Inflammation; Metabolism; Obesity

DOI:  https://doi.org/10.1172/JCI152391
Sci Rep. 2022 May 06. 12(1): 7450

Rheumatoid arthritis T cell and muscle oxidative metabolism associate with exercise-induced changes in cardiorespiratory fitness.

Brian J Andonian, Alec Koss, Timothy R Koves, Elizabeth R Hauser, Monica J Hubal, David M Pober, Janet M Lord, Nancie J MacIver, E William St Clair, Deborah M Muoio, William E Kraus, David B Bartlett, Kim M Huffman.

Rheumatoid arthritis (RA) T cells drive autoimmune features via metabolic reprogramming that reduces oxidative metabolism. Exercise training improves cardiorespiratory fitness (i.e., systemic oxidative metabolism) and thus may impact RA T cell oxidative metabolic function. In this pilot study of RA participants, we took advantage of heterogeneous responses to a high-intensity interval training (HIIT) exercise program to identify relationships between improvements in cardiorespiratory fitness with changes in peripheral T cell and skeletal muscle oxidative metabolism. In 12 previously sedentary persons with seropositive RA, maximal cardiopulmonary exercise tests, fasting blood, and vastus lateralis biopsies were obtained before and after 10 weeks of HIIT. Following HIIT, improvements in RA cardiorespiratory fitness were associated with changes in RA CD4 + T cell basal and maximal respiration and skeletal muscle carnitine acetyltransferase (CrAT) enzyme activity. Further, changes in CD4 + T cell respiration were associated with changes in naïve CD4 + CCR7 + CD45RA + T cells, muscle CrAT, and muscle medium-chain acylcarnitines and fat oxidation gene expression profiles. In summary, modulation of cardiorespiratory fitness and molecular markers of skeletal muscle oxidative metabolism during exercise training paralleled changes in T cell metabolism. Exercise training that improves RA cardiorespiratory fitness may therefore be valuable in managing pathologically related immune and muscle dysfunction.Trial registration: ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.

DOI: https://doi.org/10.1038/s41598-022-11458-4
Cell Metab. 2022 Apr 23. pii: S1550-4131(22)00130-9. [Epub ahead of print]

Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer.

Sarah A Best, Patrick M Gubser, Shalini Sethumadhavan, Ariena Kersbergen, Yashira L Negrón Abril, Joshua Goldford, Katherine Sellers, Waruni Abeysekera, Alexandra L Garnham, Jackson A McDonald, Clare E Weeden, Dovile Anderson, David Pirman, Thomas P Roddy, Darren J Creek, Axel Kallies, Gillian Kingsbury, Kate D Sutherland.

  The tumor microenvironment (TME) contains a rich source of nutrients that sustains cell growth and facilitate tumor development. Glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert antitumor function. Immunotherapy unleashes T cell antitumor function, and although many solid tumors respond well, a significant proportion of patients do not benefit. In patients with KRAS-mutant lung adenocarcinoma, KEAP1 and STK11/Lkb1 co-mutations are associated with impaired response to immunotherapy. To investigate the metabolic and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape in these patients. Here, we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and activation of CD8 T cells. Thus, glutaminase inhibition negatively impacts CD8 T cells activated by anti-PD1 immunotherapy.

Keywords:  KEAP1; KRAS; STK11/Lkb1; glutaminase; glutamine; immune microenvironment; immunotherapy; lung adenocarcinoma; metabolism

DOI:  https://doi.org/10.1016/j.cmet.2022.04.003
Sci Signal. 2022 May 03. 15(732): eabq7456

Letting go of damaged mitochondria.

Wei Wong.

Thermogenesis requires that macrophages digest damaged mitochondria released by brown adipocytes.

DOI: https://doi.org/10.1126/scisignal.abq7456
Front Immunol. 2022 ;13 789366

Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity.

Linus Frick, Linda Hinterland, Kathrin Renner, Marion Vogl, Nathalie Babl, Simon Heckscher, Anna Weigert, Susanne Weiß, Joachim Gläsner, Raffaela Berger, Peter J Oefner, Katja Dettmer, Marina Kreutz, Valentin Schatz, Jonathan Jantsch.

  Local tissue acidosis affects anti-tumor immunity. In contrast, data on tissue pH levels in infected tissues and their impact on antimicrobial activity is sparse. In this study, we assessed the pH levels in cutaneous Leishmania lesions. Leishmania major-infected skin tissue displayed pH levels of 6.7 indicating that lesional pH is acidic. Next, we tested the effect of low extracellular pH on the ability of macrophages to produce leishmanicidal NO and to fight the protozoan parasite Leishmania major. Extracellular acidification led to a marked decrease in both NO production and leishmanicidal activity of lipopolysaccharide (LPS) and interferon γ (IFN-γ)-coactivated macrophages. This was not directly caused by a disruption of NOS2 expression, a shortage of reducing equivalents (NAPDH) or substrate (L-arginine), but by a direct, pH-mediated inhibition of NOS2 enzyme activity. Normalization of intracellular pH significantly increased NO production and antiparasitic activity of macrophages even in an acidic microenvironment. Overall, these findings indicate that low local tissue pH can curtail NO production and leishmanicidal activity of macrophages.

Keywords:  Leishmania; NO; NOS2; macrophages; pH

DOI:  https://doi.org/10.3389/fimmu.2022.789366
Front Immunol. 2022 ;13 884126

The Adipose Tissue Macrophages Central to Adaptive Thermoregulation.

Md Shamim Rahman, Heejin Jun.

  White fat stores excess energy, and thus its excessive expansion causes obesity. However, brown and beige fat, known as adaptive thermogenic fat, dissipates energy in the form of heat and offers a therapeutic potential to counteract obesity and metabolic disorders. The fat type-specific biological function is directed by its unique tissue microenvironment composed of immune cells, endothelial cells, pericytes and neuronal cells. Macrophages are major immune cells resident in adipose tissues and gained particular attention due to their accumulation in obesity as the primary source of inflammation. However, recent studies identified macrophages' unique role and regulation in thermogenic adipose tissues to regulate energy expenditure and systemic energy homeostasis. This review presents the current understanding of macrophages in thermogenic fat niches with an emphasis on discrete macrophage subpopulations central to adaptive thermoregulation.

Keywords:   brown adipocyte ; adipose tissue macrophage; beige adipocyte; obesity; thermogenesis

DOI:  https://doi.org/10.3389/fimmu.2022.884126
Cancer Lett. 2022 Apr 28. pii: S0304-3835(22)00194-X. [Epub ahead of print]538 215710

Metabolic reprogramming by ex vivo glutamine inhibition endows CAR-T cells with less-differentiated phenotype and persistent antitumor activity.

Luyan Shen, Yefei Xiao, Chaoting Zhang, Shance Li, Xia Teng, Likun Cui, Ting Liu, Nan Wu, Zheming Lu.

  The inadequate in vivo persistence of chimeric antigen receptor (CAR)-modified T cells has been shown to lead to poor therapeutic efficacy and disease recurrence. In vivo persistence is associated with the differentiation subsets infused, with less differentiated TN or TCM conferring superior renewal capacity and antitumor immunity compared to TEM or TEFF. However, ex vivo expanded CAR-T cells exhibit phenotypic heterogeneity with majority of TEM or TEFF subsets and very low populations of TN and TCM. The transition of differentiation subsets is closely correlated with T cell metabolism fitness. Effector T cell differentiation from TN or TCM requires glutamine uptake and metabolism. Using a CD19-specific CAR, we demonstrated that glutamine inhibition by adding the glutamine antagonist 6-Diazo-5-oxo-l-norleucine (DON) into the culture endows CAR-T cells with enhanced mitochondrial OXPHOS utilizing fatty acids and reduced glycolytic activity, and retains more TN or TCM subsets. DON- pretreated CAR-T cells exhibited stronger cytotoxic lysis in vitro and more robust elimination of tumor burdens in vivo. This study suggests that glutamine inhibition ex vivo would be a potential approach for modulating metabolism and differentiation state to improve the efficacy of CAR-T cell therapy.

Keywords:  Fatty acid oxidation; Glutamine antagonist; Glycolysis; Memory T cell; Mitochondrial OXPHOS

DOI:  https://doi.org/10.1016/j.canlet.2022.215710
Sci Rep. 2022 May 06. 12(1): 7491

Butyrate administration is not sufficient to improve immune reconstitution in antiretroviral-treated SIV-infected macaques.

Alexandra M Ortiz, Jennifer Simpson, Charlotte A Langner, Phillip J Baker, Cynthia Aguilar, Kelsie Brooks, Jacob K Flynn, Carol L Vinton, Andrew R Rahmberg, Heather D Hickman, Jason M Brenchley.

Defective gastrointestinal barrier function and, in turn, microbial translocation have been identified as significant contributors to persistent inflammation in antiretroviral (ARV)-treated people living with HIV. Metabolic supplementation of short-chain fatty acids (SCFAs), generally produced by the commensal microbiome, may improve these outcomes. Butyrate is a SCFA that is essential for the development and maintenance of intestinal immunity and has a known role in supporting epithelial integrity. Herein we assessed whether supplementation with the dietary supplement sodium butyrate would improve immune reconstitution and reduce inflammation in ARV-treated, simian immunodeficiency virus (SIV)-infected rhesus macaques. We demonstrate that butyrate supplementation does not significantly improve immune reconstitution, with no differences observed in systemic CD4+ T-cell frequencies, T-cell functionality or immune activation, microbial translocation, or transcriptional regulation. Our findings demonstrate that oral administration of sodium butyrate is insufficient to reduce persistent inflammation and microbial translocation in ARV-treated, SIV-infected macaques, suggesting that this therapeutic may not reduce co-morbidities and co-mortalities in treated people living with HIV.

DOI: https://doi.org/10.1038/s41598-022-11122-x
PLoS One. 2022 ;17(5): e0266980

BOXR1030, an anti-GPC3 CAR with exogenous GOT2 expression, shows enhanced T cell metabolism and improved anti-cell line derived tumor xenograft activity.

Taylor L Hickman, Eugene Choi, Kathleen R Whiteman, Sujatha Muralidharan, Tapasya Pai, Tyler Johnson, Avani Parikh, Taylor Friedman, Madaline Gilbert, Binzhang Shen, Luke Barron, Kathleen E McGinness, Seth A Ettenberg, Greg T Motz, Glen J Weiss, Amy Jensen-Smith.

PURPOSE: The solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models.
EXPERIMENTAL DESIGN: We evaluated GPC3 expression in human normal and tumor tissue specimens. We developed and evaluated BOXR1030, a novel CAR T therapeutic co-expressing glypican-3 (GPC3)-targeted CAR and exogenous glutamic-oxaloacetic transaminase 2 (GOT2) in terms of CAR T cell function both in vitro and in vivo.
RESULTS: Cell surface expression of tumor antigen GPC3 was observed by immunohistochemical staining in tumor biopsies from hepatocellular carcinoma, liposarcoma, squamous lung cancer, and Merkel cell carcinoma patients. Compared to control GPC3 CAR alone, BOXR1030 (GPC3-targeted CAR T cell that co-expressed GOT2) demonstrated superior in vivo efficacy in aggressive solid tumor xenograft models, and showed favorable attributes in vitro including an enhanced cytokine production profile, a less-differentiated T cell phenotype with lower expression of stress and exhaustion markers, an enhanced metabolic profile and increased proliferation in TME-like conditions.
CONCLUSIONS: Together, these results demonstrated that co-expression of GOT2 can substantially improve the overall antitumor activity of CAR T cells by inducing broad changes in cellular function and phenotype. These data show that BOXR1030 is an attractive approach to targeting select solid tumors. To this end, BOXR1030 will be explored in the clinic to assess safety, dose-finding, and preliminary efficacy (NCT05120271).

DOI: https://doi.org/10.1371/journal.pone.0266980
Biochim Biophys Acta Mol Basis Dis. 2022 Apr 30. pii: S0925-4439(22)00095-3. [Epub ahead of print]1868(8): 166425

Immunometabolism and the modulation of immune responses and host defense: A role for methylglyoxal?

Xiaodi Zhang, Casper G Schalkwijk, Kristiaan Wouters.

  The immune system plays an essential role in protecting the body against pathogens. Immune cells are activated during infections, resulting in a metabolic shift from oxidative phosphorylation to glycolysis. During glycolysis, methylglyoxal (MGO) can be formed as a by-product. As a highly reactive dicarbonyl compound, MGO can rapidly react with proteins to form advanced glycation end products (AGEs). MGO and MGO-derived AGEs have been implicated in the development of insulin resistance, type 2 diabetes and its complications and several other age-related inflammatory diseases. MGO has been found in adipose tissue, atherosclerosis plaques and inflamed livers. Aside from the potential harmful role of MGO, there are studies showing beneficial effects of MGO as a defense mechanism during infections and diseases. In this review, we summarize anti-microbial effects of MGO and the link between MGO and immune cell activation, as potential mediator during host defense.

Keywords:  Advanced glycation endproducts; Hyperglycemia; Immunity; Immunometabolism; Leukocytes; Methylglyoxal

DOI:  https://doi.org/10.1016/j.bbadis.2022.166425
iScience. 2022 May 20. 25(5): 104209

IP3R-mediated Ca2+ signaling controls B cell proliferation through metabolic reprogramming.

Huayuan Tang, Yali Li, Shijia Wang, Jing Ji, Xiangbin Zhu, Yutong Bao, Can Huang, Ye Luo, Lei Huang, Yan Gao, Chaoliang Wei, Jie Liu, Xi Fang, Lu Sun, Kunfu Ouyang.

  Emerging evidence shows that metabolic regulation may be a critical mechanism in B cell activation and function. As targets of several most widely used immunosuppressants, Ca2+ signaling and calcineurin may play an important role in regulating B cell metabolism. Here, we demonstrate that IP3R-mediated Ca2+ signaling and calcineurin regulate B cell proliferation and survival by activating metabolic reprogramming in response to B cell receptor (BCR) stimulation. Both IP3R-triple-knockout (IP3R-TKO) and calcineurin inhibition dramatically suppress the metabolic switch in oxidative phosphorylation and glycolysis of stimulated B cells through regulation of glucose uptake, glycolytic enzyme expression, and mitochondrial remodeling, leading to impaired cell-cycle entry and survival. In addition, IP3R-Ca2+ acts as a master regulator of the calcineurin-MEF2C-Myc pathway in driving B cell metabolic adaptations. As genetic defects of IP3Rs were recently identified as a new class of inborn errors of immunity, these results have important implications for understanding the pathogenesis of such diseases.

Keywords:  Cell biology; Immune response; Immunology

DOI:  https://doi.org/10.1016/j.isci.2022.104209
Front Microbiol. 2022 ;13 849020

LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation.

Yongheng Yang, Mengyun Li, Yongtao Ma, Wei Ye, Yue Si, Xuyang Zheng, He Liu, Linfeng Cheng, Liang Zhang, Hui Zhang, Xijing Zhang, Yingfeng Lei, Lixin Shen, Fanglin Zhang, Hongwei Ma.

  As the global prototypical zoonotic hantavirus, Hantaan virus (HTNV) is prevalent in Asia and is the leading causative agent of severe hemorrhagic fever with renal syndrome (HFRS), which has profound morbidity and mortality. Macrophages are crucial components of the host innate immune system and serve as the first line of defense against HTNV infection. Previous studies indicated that the viral replication efficiency in macrophages determines hantavirus pathogenicity, but it remains unknown which factor manipulates the macrophage activation pattern and the virus-host interaction process. Here, we performed the transcriptomic analysis of HTNV-infected mouse bone marrow-derived macrophages and identified the long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1), especially the isoform NEAT1-2, as one of the lncRNAs that is differentially expressed at the early phase. Based on coculture experiments, we revealed that silencing NEAT1-2 hinders inflammatory macrophage activation and facilitates HTNV propagation, while enhancing NEAT1-2 transcription effectively restrains viral replication. Furthermore, sterol response element binding factor-2 (SREBP2), which controls the cholesterol metabolism process, was found to stimulate macrophages by promoting the production of multiple inflammatory cytokines upon HTNV infection. NEAT1-2 could potentiate SREBP2 activity by upregulating Srebf1 expression and interacting with SREBP2, thus stimulating inflammatory macrophages and limiting HTNV propagation. More importantly, we demonstrated that the NEAT1-2 expression level in patient monocytes was negatively correlated with viral load and HFRS disease progression. Our results identified a function and mechanism of action for the lncRNA NEAT1 in heightening SREBP2-mediated macrophage activation to restrain hantaviral propagation and revealed the association of NEAT1 with HFRS severity.

Keywords:  HFRS; Hantaan virus; NEAT1; SREBP2; hantavirus; inflammatory macrophage; lncRNA

DOI:  https://doi.org/10.3389/fmicb.2022.849020
Blood Adv. 2022 May 02. pii: bloodadvances.2021005776. [Epub ahead of print]

IFNγ Regulates NAD+ Metabolism to Promote the Respiratory Burst in Human Monocytes.

Katelyn J McCann, Stephen M Christensen, Devon H Colby, Peter J McGuire, Ian A Myles, Christa S Zerbe, Clifton L Dalgard, Gauthaman Sukumar, Warren J Leonard, Beth A McCormick, Steven M Holland.

IFNγ is an essential and pleiotropic activator of human monocytes, but little is known about the changes in cellular metabolism required for IFNγ-induced activation. We sought to elucidate the mechanisms by which IFNγ reprograms monocyte metabolism to support its immunologic activities. We found that IFNγ increased oxygen consumption rates (OCR) in monocytes, indicative of reactive oxygen species generation by both mitochondria and NADPH oxidase. Transcriptional profiling revealed that this oxidative phenotype was driven by IFNγ-induced reprogramming of NAD+ metabolism, which is dependent on nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ salvage to generate NADH and NADPH for oxidation by mitochondrial complex I and NADPH oxidase, respectively. Consistent with this pathway, monocytes from patients with gain-of-function mutations in STAT1 demonstrated higher than normal OCR. Whereas chemical or genetic disruption of mitochondrial complex I (rotenone treatment or Leigh Syndrome patient monocytes) or NADPH oxidase (DPI treatment or chronic granulomatous disease (CGD) patient monocytes) reduced OCR. Interestingly, inhibition of NAMPT in healthy monocytes completely abrogated the IFNγ-induced oxygen consumption, comparable to levels observed in CGD monocytes. These data identify an IFNγ-induced, NAMPT-dependent, NAD+ salvage pathway that is critical for IFNγ activation of human monocytes.

DOI: https://doi.org/10.1182/bloodadvances.2021005776
J Clin Invest. 2022 May 02. pii: e153153. [Epub ahead of print]132(9):

HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.

Yanxin Fan, Marta Murgia, Monika I Linder, Yoko Mizoguchi, Cong Wang, Marcin Łyszkiewicz, Natalia Ziȩtara, Yanshan Liu, Stephanie Frenz, Gabriela Sciuccati, Armando Partida-Gaytan, Zahra Alizadeh, Nima Rezaei, Peter Rehling, Sven Dennerlein, Matthias Mann, Christoph Klein.

  The relevance of molecular mechanisms governing mitochondrial proteostasis to the differentiation and function of hematopoietic and immune cells is largely elusive. Through dissection of the network of proteins related to HCLS1-associated protein X-1, we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB. As shown by stable isotope labeling by amino acids in cell culture (SILAC) proteomics, CLPB and HAX1 control the balance of mitochondrial protein synthesis and persistence crucial for proper mitochondrial function. Impaired mitochondrial protein dynamics are associated with decreased abundance of the serine-threonine kinase PRKD2 and HSP27 phosphorylated on serines 78 and 82. Cellular defects in HAX1-/- cells can be functionally reconstituted by HSP27. Thus, mitochondrial proteostasis emerges as a critical molecular and metabolic mechanism governing the differentiation and function of neutrophil granulocytes.

Keywords:  Cell Biology; Immunology; Mitochondria; Neutrophils

DOI:  https://doi.org/10.1172/JCI153153
Inflamm Regen. 2022 May 01. 42(1): 13

Molecular mechanism of crosstalk between immune and metabolic systems in metabolic syndrome.

Rumi Hachiya, Miyako Tanaka, Michiko Itoh, Takayoshi Suganami.

  Chronic inflammation is currently considered as a molecular basis of metabolic syndrome. Particularly, obesity-induced inflammation in adipose tissue is the origin of chronic inflammation of metabolic syndrome. Adipose tissue contains not only mature adipocytes with large lipid droplets, but also a variety of stromal cells including adipocyte precursors, vascular component cells, immune cells, and fibroblasts. However, crosstalk between those various cell types in adipose tissue in obesity still remains to be fully understood. We focus on two innate immune receptors, Toll-like receptor 4 (TLR4) and macrophage-inducible C-type lectin (Mincle). We provided evidence that adipocyte-derived saturated fatty acids (SFAs) activate macrophage TLR4 signaling pathway, thereby forming a vicious cycle of inflammatory responses during the development of obesity. Intriguingly, the TLR4 signaling pathway is modulated metabolically and epigenetically: SFAs augment TLR4 signaling through the integrated stress response and chromatin remodeling, such as histone methylation, regulates dynamic transcription patterns downstream of TLR4 signaling. Another innate immune receptor Mincle senses cell death, which is a trigger of chronic inflammatory diseases including obesity. Macrophages form a histological structure termed "crown-like structure (CLS)", in which macrophages surround dead adipocytes to engulf cell debris and residual lipids. Mincle is exclusively expressed in macrophages forming the CLS in obese adipose tissue and regulates adipocyte death-triggered adipose tissue fibrosis. In addition to adipose tissue, we found a structure similar to CLS in the liver of nonalcoholic steatohepatitis (NASH) and the kidney after acute kidney injury. This review article highlights the recent progress of the crosstalk between immune and metabolic systems in metabolic syndrome, with a focus on innate immune receptors.

Keywords:  Crown-like structure; Fatty acids; Metabolic syndrome; Mincle; Obesity; TLR4

DOI:  https://doi.org/10.1186/s41232-022-00198-7
J Clin Invest. 2022 May 02. pii: e159472. [Epub ahead of print]132(9):

Labile iron accumulation augments T follicular helper cell differentiation.

Yogesh Scindia, Borna Mehrad, Laurence Morel.

T follicular helper (Tfh) cells are a subset of CD4+ T cells that are essential in the pathogenesis of systemic lupus erythematosus (SLE). Notably, iron is required for activated CD4+ T lymphocytes to sustain high proliferation and metabolism. In this issue of the JCI, Gao et al. showed that CD4+ T cells from patients with SLE accumulated iron, augmenting their differentiation into Tfh cells and correlating with disease activity. Using human cells and murine models, the authors demonstrated that miR-21 was overexpressed in lupus T cells and inhibited 3-hydroxybutyrate dehydrogenase-2 (BDH2). The subsequent loss of BDH2 drove labile iron to accumulate in the cytoplasm and promoted TET enzyme activity, BCL6 gene demethylation, and Tfh cell differentiation. This work identifies a role for iron in CD4+ T cell biology and the development of pathogenic effectors in SLE. We await future investigations that could determine whether modulating iron levels could regulate Tfh cells in human health and disease.

DOI: https://doi.org/10.1172/JCI159472
Cancer Discov. 2022 May 03. OF1

Mechanism Found for IDO1 Inhibitor Evasion.

Researchers have pinpointed metabolic alterations that may allow tumors to evade the IDO1 inhibitor epacadostat. Tumor cells enlisted an alternative pathway to break down tryptophan, the target of IDO1, and increased the activity of pathways that generate NAD+. The metabolic changes also suppressed CD8+ T cells.

DOI: https://doi.org/10.1158/2159-8290.CD-NB2022-0033
Leukemia. 2022 May 05.

Ceramide synthase 6 impacts T-cell allogeneic response and graft-versus-host disease through regulating N-RAS/ERK pathway.

M Hanief Sofi, Linlu Tian, Steven Schutt, Imran Khan, Hee-Jin Choi, Yongxia Wu, David Bastian, Taylor Ticer, Mohamed Faisal Kassir, Firdevs Cansu Atilgan, Jisun Kim, Xiaohui Sui, Aleksandra Zivkovic, Shikhar Mehrotra, John P O'Bryan, Holger Stark, Paul J Martin, Besim Ogretmen, Xue-Zhong Yu.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for various hematologic malignancies, predominantly through potent graft-versus-leukemia (GVL) effect. However, the mortality after allo-HCT is because of relapse of primary malignancy and followed by graft-vs-host-disease (GVHD) as a major cause of transplant-related mortality. Hence, strategies to limit GVHD while preserving the GVL effect are highly desirable. Ceramide, which serves a central role in sphingolipid metabolism, is generated by ceramide synthases (CerS1-6). In this study, we found that genetic or pharmacologic targeting of CerS6 prevented and reversed chronic GVHD (cGVHD). Furthermore, specific inhibition of CerS6 with ST1072 significantly ameliorated acute GVHD (aGVHD) while preserving the GVL effect, which differed from FTY720 that attenuated aGVHD but impaired GVL activity. At the cellular level, blockade of CerS6 restrained donor T cells from migrating into GVHD target organs and preferentially reduced activation of donor CD4 T cells. At the molecular level, CerS6 was required for optimal TCR signaling, CD3/PKCθ co-localization, and subsequent N-RAS activation and ERK signaling, especially on CD4+ T cells. The current study provides rationale and means for targeting CerS6 to control GVHD and leukemia relapse, which would enhance the efficacy of allo-HCT as an immunotherapy for hematologic malignancies in the clinic.

DOI: https://doi.org/10.1038/s41375-022-01581-6
EMBO J. 2022 May 04. e108306

Host succinate inhibits influenza virus infection through succinylation and nuclear retention of the viral nucleoprotein.

Antoine Guillon, Deborah Brea-Diakite, Adeline Cezard, Alan Wacquiez, Thomas Baranek, Jérôme Bourgeais, Frédéric Picou, Virginie Vasseur, Léa Meyer, Christophe Chevalier, Adrien Auvet, José M Carballido, Lydie Nadal Desbarats, Florent Dingli, Andrei Turtoi, Audrey Le Gouellec, Florence Fauvelle, Amélie Donchet, Thibaut Crépin, Pieter S Hiemstra, Christophe Paget, Damarys Loew, Olivier Herault, Nadia Naffakh, Ronan Le Goffic, Mustapha Si-Tahar.

  Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria-derived succinate that accumulated both in the respiratory fluids of virus-challenged mice and of patients with influenza pneumonia. Notably, succinate displays a potent antiviral activity in vitro as it inhibits the multiplication of influenza A/H1N1 and A/H3N2 strains and strongly decreases virus-triggered metabolic perturbations and inflammatory responses. Moreover, mice receiving succinate intranasally showed reduced viral loads in lungs and increased survival compared to control animals. The antiviral mechanism involves a succinate-dependent posttranslational modification, that is, succinylation, of the viral nucleoprotein at the highly conserved K87 residue. Succinylation of viral nucleoprotein altered its electrostatic interactions with viral RNA and further impaired the trafficking of viral ribonucleoprotein complexes. The finding that succinate efficiently disrupts the influenza replication cycle opens up new avenues for improved treatment of influenza pneumonia.

Keywords:  antiviral; influenza; metabokine; signaling; virus

DOI:  https://doi.org/10.15252/embj.2021108306
Front Immunol. 2022 ;13 886225

Impact of IDO1 and IDO2 on the B Cell Immune Response.

Lauren M F Merlo, Weidan Peng, Laura Mandik-Nayak.

  Indoleamine-2,3-dioxygenase (IDO)1 and IDO2 are closely related tryptophan catabolizing enzymes that have immunomodulatory properties. Although initially studied as modifiers of T cell activity, emerging evidence suggests IDO1 and IDO2 also have important roles as modulators of B cell function. In this context, IDO1 and IDO2 appear to play opposite roles, with IDO1 inhibiting and IDO2 driving inflammatory B cell responses. In this mini review, we discuss the evidence for IDO1 and IDO2 modulation of B cell function, focusing on the effect of these enzymes on autoimmunity, allergic responses, protective immunity, and response to pathogens. We summarize strategies to target IDO1 and/or IDO2 as potential therapeutics for inflammatory autoimmune disease and highlight outstanding questions and areas that require future study.

Keywords:  B cells; IDO1; IDO2; autoimmunity; inflammation

DOI:  https://doi.org/10.3389/fimmu.2022.886225
Sci China Life Sci. 2022 Apr 28.

Identification of serum metabolites enhancing inflammatory responses in COVID-19.

Chen-Song Zhang, Bingchang Zhang, Mengqi Li, Xiaoyan Wei, Kai Gong, Zhiyong Li, Xiangyang Yao, Jianfeng Wu, Cixiong Zhang, Mingxia Zhu, Lei Zhang, Xiufeng Sun, Yi-Hong Zhan, Zhengye Jiang, Wenpeng Zhao, Wei Zhong, Xinguo Zhuang, Dawang Zhou, Hai-Long Piao, Sheng-Cai Lin, Zhanxiang Wang.

  Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a strong production of inflammatory cytokines such as TNF and IL-6, which underlie the severity of the disease. However, the molecular mechanisms responsible for such a strong immune response remains unclear. Here, utilizing targeted tandem mass spectrometry to analyze serum metabolome and lipidome in COVID-19 patients at different temporal stages, we identified that 611 metabolites (of 1,039) were significantly altered in COVID-19 patients. Among them, two metabolites, agmatine and putrescine, were prominently elevated in the serum of patients; and 2-quinolinecarboxylate was changed in a biphasic manner, elevated during early COVID-19 infection but levelled off. When tested in mouse embryonic fibroblasts (MEFs) and macrophages, these 3 metabolites were found to activate the NF-κB pathway that plays a pivotal role in governing cytokine production. Importantly, these metabolites were each able to cause strong increase of TNF and IL-6 levels when administered to wildtype mice, but not in the mice lacking NF-κB. Intriguingly, these metabolites have little effects on the activation of interferon regulatory factors (IRFs) for the production of type I interferons (IFNs) for antiviral defenses. These data suggest that circulating metabolites resulting from COVID-19 infection may act as effectors to elicit the peculiar systemic inflammatory responses, exhibiting severely strong proinflammatory cytokine production with limited induction of the interferons. Our study may provide a rationale for development of drugs to alleviate inflammation in COVID-19 patients.

Keywords:  COVID-19; inflammation; metabolites

DOI:  https://doi.org/10.1007/s11427-021-2099-7