bims-imicid 2022-01-23 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–01–23
23 papers selected by
Dylan Ryan, University of Cambridge

Magnesium sensing via LFA-1 regulates CD8+ T cell effector function.
The Trypanosoma brucei-Derived Ketoacids, Indole Pyruvate and Hydroxyphenylpyruvate, Induce HO-1 Expression and Suppress Inflammatory Responses in Human Dendritic Cells.
The role of itaconate in host defense and inflammation.
The Lysosomal Rag-Ragulator Complex Licenses RIPK1 and Caspase-8-mediated Pyroptosis by Yersinia.
Activation of TCA cycle restrains virus-metabolic hijacking and viral replication in mouse hepatitis virus-infected cells.
Microenvironmental influences on T cell immunity in cancer and inflammation.
Fighting in a wasteland: deleterious metabolites and antitumor immunity.
Immunometabolic rewiring in tumorigenesis and anti-tumor immunotherapy.
Irgm1 regulates metabolism and function in T cell subsets.
Immunometabolism at the service of traditional Chinese medicine.
Multi-Omics Profiling Identifies Pathways Associated With CD8+ T-Cell Activation in Severe Aplastic Anemia.
PPAR Ligands Induce Antiviral Effects Targeting Perturbed Lipid Metabolism during SARS-CoV-2, HCV, and HCMV Infection.
Lactate is a Key Mediator That Links Obesity to Insulin Resistance via Modulating Cytokine Production From Adipose Tissue.
Metabolic Reprogramming of Glioblastoma Cells during HCMV Infection Induces Secretome-Mediated Paracrine Effects in the Microenvironment.
A single-cell atlas reveals shared and distinct immune responses and metabolism during SARS-CoV-2 and HIV-1 infections.
CRISPR Interference Reveals That All-Trans-Retinoic Acid Promotes Macrophage Control of Mycobacterium tuberculosis by Limiting Bacterial Access to Cholesterol and Propionyl Coenzyme A.
The emerging roles of IL-36, IL-37, and IL-38 in diabetes mellitus and its complications.
TFEB signaling attenuates NLRP3-driven inflammatory responses in severe asthma.
NAMPT mitigates colitis severity by supporting redox-sensitive activation of phagocytosis in inflammatory macrophages.
TrpNet: Understanding Tryptophan Metabolism across Gut Microbiome.
Metformin ameliorates chronic colitis in a mouse model by regulating interferon-γ-producing lamina propria CD4+ T cells through AMPK activation.
Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies.
Pcyt2 deficiency causes age-dependant development of nonalcoholic steatohepatitis and insulin resistance that could be attenuated with phosphoethanolamine.

Cell. 2022 Jan 13. pii: S0092-8674(21)01561-0. [Epub ahead of print]

Magnesium sensing via LFA-1 regulates CD8+ T cell effector function.

Jonas Lötscher, Adrià-Arnau Martí I Líndez, Nicole Kirchhammer, Elisabetta Cribioli, Greta Giordano, Marcel P Trefny, Markus Lenz, Sacha I Rothschild, Paolo Strati, Marco Künzli, Claudia Lotter, Susanne H Schenk, Philippe Dehio, Jordan Löliger, Ludivine Litzler, David Schreiner, Victoria Koch, Nicolas Page, Dahye Lee, Jasmin Grählert, Dmitry Kuzmin, Anne-Valérie Burgener, Doron Merkler, Miklos Pless, Maria L Balmer, Walter Reith, Jörg Huwyler, Melita Irving, Carolyn G King, Alfred Zippelius, Christoph Hess.

  The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.

Keywords:  CAR T cells; Mg2+; T cell engaging antibodies; co-stimulation/LFA-1; immune control; integration of microenvironment and T cell function; magnesium; memory CD8 T cells; microenvironment; tumor-specific T cells

DOI:  https://doi.org/10.1016/j.cell.2021.12.039
Antioxidants (Basel). 2022 Jan 15. pii: 164. [Epub ahead of print]11(1):

The Trypanosoma brucei-Derived Ketoacids, Indole Pyruvate and Hydroxyphenylpyruvate, Induce HO-1 Expression and Suppress Inflammatory Responses in Human Dendritic Cells.

Hannah K Fitzgerald, Sinead A O'Rourke, Eva Desmond, Nuno G B Neto, Michael G Monaghan, Miriam Tosetto, Jayne Doherty, Elizabeth J Ryan, Glen A Doherty, Derek P Nolan, Jean M Fletcher, Aisling Dunne.

  The extracellular parasite and causative agent of African sleeping sickness Trypanosoma brucei (T. brucei) has evolved a number of strategies to avoid immune detection in the host. One recently described mechanism involves the conversion of host-derived amino acids to aromatic ketoacids, which are detected at relatively high concentrations in the bloodstream of infected individuals. These ketoacids have been shown to directly suppress inflammatory responses in murine immune cells, as well as acting as potent inducers of the stress response enzyme, heme oxygenase 1 (HO-1), which has proven anti-inflammatory properties. The aim of this study was to investigate the immunomodulatory properties of the T. brucei-derived ketoacids in primary human immune cells and further examine their potential as a therapy for inflammatory diseases. We report that the T. brucei-derived ketoacids, indole pyruvate (IP) and hydroxyphenylpyruvate (HPP), induce HO-1 expression through Nrf2 activation in human dendritic cells (DC). They also limit DC maturation and suppress the production of pro-inflammatory cytokines, which, in turn, leads to a reduced capacity to differentiate adaptive CD4+ T cells. Furthermore, the ketoacids are capable of modulating DC cellular metabolism and suppressing the inflammatory profile of cells isolated from patients with inflammatory bowel disease. This study therefore not only provides further evidence of the immune-evasion mechanisms employed by T. brucei, but also supports further exploration of this new class of HO-1 inducers as potential therapeutics for the treatment of inflammatory conditions.

Keywords:  Trypanosoma brucei; anti-inflammatory therapies; aromatic ketoacids; dendritic cells; heme oxygenase 1; immunomodulation; inflammatory bowel disease

DOI:  https://doi.org/10.3390/antiox11010164
J Clin Invest. 2022 Jan 18. pii: e148548. [Epub ahead of print]132(2):

The role of itaconate in host defense and inflammation.

Christian G Peace, Luke Aj O'Neill.

Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function, cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because of the disturbance in the Krebs cycle is itaconate, which is derived from cis-aconitate by the enzyme cis-aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1). This Review focuses on itaconate's emergence as a key immunometabolite with diverse roles in immunity and inflammation. These roles include inhibition of succinate dehydrogenase (which controls levels of succinate, a metabolite with multiple roles in inflammation), inhibition of glycolysis at multiple levels (which will limit inflammation), activation of the antiinflammatory transcription factors Nrf2 and ATF3, and inhibition of the NLRP3 inflammasome. Itaconate and its derivatives have antiinflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis, pointing to possible itaconate-based therapeutics for a range of inflammatory diseases. This intriguing metabolite continues to yield fascinating insights into the role of metabolic reprogramming in host defense and inflammation.

DOI: https://doi.org/10.1172/JCI148548
Science. 2021 Jun 25. pii: eabg0269. [Epub ahead of print]372(6549):

The Lysosomal Rag-Ragulator Complex Licenses RIPK1 and Caspase-8-mediated Pyroptosis by Yersinia.

Zengzhang Zheng, Wanyan Deng, Yang Bai, Rui Miao, Shenglin Mei, Zhibin Zhang, Youdong Pan, Yi Wang, Rui Min, Fan Deng, Zeyu Wu, Wu Li, Pengcheng Chen, Tianchi Ma, Xiwen Lou, Judy Lieberman, Xing Liu.

Host cells initiate cell death programs to limit pathogen infection. Inhibition of transforming growth factor-β-activated kinase 1 (TAK1) by pathogenic Yersinia in macrophages triggers receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-dependent caspase-8 cleavage of gasdermin D (GSDMD) and inflammatory cell death (pyroptosis). A genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen to uncover mediators of caspase-8-dependent pyroptosis identified an unexpected role of the lysosomal FLCN-FNIP2-Rag-Ragulator supercomplex, which regulates metabolic signalling and the mechanistic target of rapamycin complex 1 (mTORC1). In response to Yersinia infection, FADD, RIPK1 and caspase-8 were recruited to Rag-Ragulator, causing RIPK1 phosphorylation and caspase-8 activation. Pyroptosis activation depended on Rag GTPase activity and lysosomal tethering of Rag-Ragulator, but not mTORC1. Thus, the lysosomal metabolic regulator Rag-Ragulator instructs the inflammatory response to Yersinia.

DOI: https://doi.org/10.1126/science.abg0269
Cell Biosci. 2022 Jan 18. 12(1): 7

Activation of TCA cycle restrains virus-metabolic hijacking and viral replication in mouse hepatitis virus-infected cells.

Sang R Lee, Jeong Yeon Roh, Jihoon Ryu, Hyun-Jin Shin, Eui-Ju Hong.

   BACKGROUND: One of coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused coronavirus disease 2019 (COVID-19) pandemic and threatened worldwide. However, therapy for COVID-19 has rarely been proven to possess specific efficacy. As the virus relies on host metabolism for its survival, several studies have reported metabolic intervention by SARS-CoV-2.
RESULTS: We investigated the coronavirus-metabolic hijacking using mouse hepatitis virus (MHV) as a surrogate for SARS-CoV-2. Based on the altered host metabolism by MHV infection, an increase of glycolysis with low mitochondrial metabolism, we tried to investigate possible therapeutic molecules which increase the TCA cycle. Endogenous metabolites and metabolic regulators were introduced to restrain viral replication by metabolic intervention. We observed that cells deprived of cellular energy nutrition with low glycolysis strongly suppress viral replication. Furthermore, viral replication was also significantly suppressed by electron transport chain inhibitors which exhaust cellular energy. Apart from glycolysis and ETC, pyruvate supplement suppressed viral replication by the TCA cycle induction. As the non-glucose metabolite, fatty acids supplement decreased viral replication via the TCA cycle. Additionally, as a highly possible therapeutic metabolite, nicotinamide riboside (NR) supplement, which activates the TCA cycle by supplying NAD+, substantially suppressed viral replication.
CONCLUSIONS: This study suggests that metabolite-mediated TCA cycle activation suppresses replication of coronavirus and suggests that NR might play a role as a novel therapeutic metabolite for coronavirus.

Keywords:  Coronavirus; Fatty acids; Glutamine; Glycolysis; MHV; Metabolism; Mitochondria; NR; Pyruvate; TCA cycle

DOI:  https://doi.org/10.1186/s13578-021-00740-z
Cell Mol Immunol. 2022 Jan 17.

Microenvironmental influences on T cell immunity in cancer and inflammation.

Darren R Heintzman, Emilie L Fisher, Jeffrey C Rathmell.

  T cell metabolism is dynamic and highly regulated. While the intrinsic metabolic programs of T cell subsets are integral to their distinct differentiation and functional patterns, the ability of cells to acquire nutrients and cope with hostile microenvironments can limit these pathways. T cells must function in a wide variety of tissue settings, and how T cells interpret these signals to maintain an appropriate metabolic program for their demands or if metabolic mechanisms of immune suppression restrain immunity is an area of growing importance. Both in inflamed and cancer tissues, a wide range of changes in physical conditions and nutrient availability are now acknowledged to shape immunity. These include fever and increased temperatures, depletion of critical micro and macro-nutrients, and accumulation of inhibitory waste products. Here we review several of these factors and how the tissue microenvironment both shapes and constrains immunity.

Keywords:  T cell; cancer; immunometabolism; inflammation; microenvironment

DOI:  https://doi.org/10.1038/s41423-021-00833-2
J Clin Invest. 2022 Jan 18. pii: e148549. [Epub ahead of print]132(2):

Fighting in a wasteland: deleterious metabolites and antitumor immunity.

McLane J Watson, Greg M Delgoffe.

As cancers progress, they produce a local environment that acts to redirect, paralyze, exhaust, or otherwise evade immune detection and destruction. The tumor microenvironment (TME) has long been characterized as a metabolic desert, depleted of essential nutrients such as glucose, oxygen, and amino acids, that starves infiltrating immune cells and renders them dysfunctional. While not incorrect, this perspective is only half the picture. The TME is not a metabolic vacuum, only consuming essential nutrients and never producing by-products. Rather, the by-products of depleted nutrients, "toxic" metabolites in the TME such as lactic acid, kynurenine, ROS, and adenosine, play an important role in shaping immune cell function and cannot be overlooked in cancer immunotherapy. Moreover, while the metabolic landscape is distinct, it is not unique, as these toxic metabolites are encountered in non-tumor tissues, where they evolutionarily shape immune cells and their response. In this Review, we discuss how depletion of essential nutrients and production of toxic metabolites shape the immune response within the TME and how toxic metabolites can be targeted to improve current cancer immunotherapies.

DOI: https://doi.org/10.1172/JCI148549
Mol Cancer. 2022 Jan 21. 21(1): 27

Immunometabolic rewiring in tumorigenesis and anti-tumor immunotherapy.

Xin Lian, Kailin Yang, Renliang Li, Maomao Li, Jing Zuo, Bohao Zheng, Wei Wang, Ping Wang, Shengtao Zhou.

  Cellular metabolism constitutes a fundamental process in biology. During tumor initiation and progression, each cellular component in the cancerous niche undergoes dramatic metabolic reprogramming, adapting to a challenging microenvironment of hypoxia, nutrient deprivation, and other stresses. While the metabolic hallmarks of cancer have been extensively studied, the metabolic states of the immune cells are less well elucidated. Here we review the metabolic disturbance and fitness of the immune system in the tumor microenvironment (TME), focusing on the impact of oncometabolites to the function of immune cells and the clinical significance of targeting metabolism in anti-tumor immunotherapy. Metabolic alterations in the immune system of TME offer novel therapeutic insight into cancer treatment.

Keywords:  Immune cells; Immunotherapy; Metabolic reprogramming; Oncometabolites; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-021-01486-5
Sci Rep. 2022 Jan 17. 12(1): 850

Irgm1 regulates metabolism and function in T cell subsets.

Yazan Alwarawrah, Keiko Danzaki, Amanda G Nichols, Brian E Fee, Cheryl Bock, Gary Kucera, Laura P Hale, Gregory A Taylor, Nancie J MacIver.

Immunity Related GTPases (IRG) are a family of proteins produced during infection that regulate membrane remodeling events in cells, particularly autophagy and mitophagy. The human IRGM gene has been strongly associated with Crohn's disease and other inflammatory diseases through Genome-Wide Association studies. Absence of Irgm1 in mice prompts intestinal inflammation, autoimmunity, and impaired immune control of pathogenic bacteria and protozoa. Although prior work has focused on a prominent role for IRGM/Irgm1 in regulating macrophage function, the work described here addresses a potential role of Irgm1 in regulating the function of mature T cells. Irgm1 was found to be highly expressed in T cells in a manner that varied with the particular T cell subset and increased with activation. Mice with a complete lack of Irgm1, or a conditional lack of Irgm1 specifically in T cells, displayed numerous changes in T cell numbers and function in all subsets examined, including CD4+ (Th1 and Treg) and CD8+ T cells. Related to changes in T cell number, apoptosis was found to be increased in Irgm1-deficient CD4+ and CD8+ T cells. Altered T cell metabolism appeared to be a key driver of the phenotypes: Glucose metabolism and glycolysis were increased in Irgm1-deficient CD4+ and CD8+ T cells, and muting these effects with glycolytic inhibitors partially restored T cell function and viability.

DOI: https://doi.org/10.1038/s41598-021-04442-x
Pharmacol Res. 2022 Jan 13. pii: S1043-6618(22)00026-3. [Epub ahead of print]176 106081

Immunometabolism at the service of traditional Chinese medicine.

He-Rong Cui, Ji-Yuan Zhang, Xue-Hao Cheng, Jia-Xin Zheng, Qi Zhang, Rui Zheng, Liang-Zhen You, Dong-Ran Han, Hong-Cai Shang.

  To enhance therapeutic efficacy and reduce adverse effects, ancient practitioners of traditional Chinese medicine (TCM) prescribe combinations of plant species/animal species and minerals designated "TCM formulae" developed based on TCM theory and clinical experience. TCM formulae have been shown to exert curative effects on complex diseases via immune regulation but the underlying mechanisms remain unknown at present. Considerable progress in the field of immunometabolism, referring to alterations in the intracellular metabolism of immune cells that regulate their function, has been made over the past decade. The core context of immunometabolism is regulation of the allocation of metabolic resources supporting host defense and survival, which provides a critical additional dimension and emerging insights into how the immune system and metabolism influence each other during disease progression. This review summarizes research findings on the significant association between the immune function and metabolic remodeling in health and disease as well as the therapeutic modulatory effects of TCM formulae on immunometabolism. Progressive elucidation of the immunometabolic mechanisms involved during the course of TCM treatment continues to aid in the identification of novel potential targets against pathogenicity. In this report, we have provided a comprehensive overview of the benefits of TCM based on regulation of immunometabolism that are potentially applicable for the treatment of modern diseases.

Keywords:  6-gingerol (PubChem CID: 442793); Aconitine (PubChem CID: 245005); Astragaloside (PubChem CID: 5488387); Calycosin glucoside (PubChem CID: 5318267); Disease; Ferulic acid (PubChem CID: 445858); Glycyrrhizic acid (PubChem CID: 14982); Hypoaconitine (PubChem CID: 441737); Immune cell; Immunometabolism; Liquiritin (PubChem CID: 503737); Mesaconitine (PubChem CID: 441747); Metabolic pathway; TCM formulae

DOI:  https://doi.org/10.1016/j.phrs.2022.106081
Front Genet. 2021 ;12 790990

Multi-Omics Profiling Identifies Pathways Associated With CD8+ T-Cell Activation in Severe Aplastic Anemia.

Xing You, Qiong Yang, Kai Yan, Song-Rong Wang, Rong-Rong Huang, Shun-Qing Wang, Cai-Yue Gao, Liang Li, Zhe-Xiong Lian.

  Severe aplastic anemia (SAA) is an autoimmune disease characterized by immune-mediated destruction of hematopoietic stem and progenitor cells. Autoreactive CD8+ T cells have been reported as the effector cells; however, the mechanisms regulating their cell activation in SAA remain largely unknown. Here, we performed proteomics and metabolomics analyses of plasma and bone marrow supernatant, together with transcriptional analysis of CD8+ T cells from SAA patients and healthy donors, to find key pathways that are involved in pathogenic CD8+ T-cell activation. We identified 21 differential proteins and 50 differential metabolites in SAA patients that were mainly involved in energy metabolism, complement and coagulation cascades, and HIF-1α signaling pathways. Interestingly, we found that these pathways are also enriched in T cells from SAA patients by analyzing available single-cell RNA sequencing data. Moreover, CD8+ T cells from SAA patients contain a highly activated CD38+ subset, which was increased in the bone marrow of SAA patients and a murine model of SAA. This subset presented enriched genes associated with the glycolysis or gluconeogenesis pathway, HIF-1α signaling pathway, and complement associated pathways, all of which were of importance in T-cell activation. In conclusion, our study reveals new pathways that may regulate CD8+ T-cell activation in SAA patients and provides potential therapeutic targets for SAA treatment.

Keywords:  T cells; aplastic anemia; metabolomics; multi-omics; proteomics; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fgene.2021.790990
Biology (Basel). 2022 Jan 11. pii: 114. [Epub ahead of print]11(1):

PPAR Ligands Induce Antiviral Effects Targeting Perturbed Lipid Metabolism during SARS-CoV-2, HCV, and HCMV Infection.

Marialuigia Fantacuzzi, Rosa Amoroso, Alessandra Ammazzalorso.

  The manipulation of host metabolisms by viral infections has been demonstrated by several studies, with a marked influence on the synthesis and utilization of glucose, nucleotides, fatty acids, and amino acids. The ability of virus to perturb the metabolic status of the infected organism is directly linked to the outcome of the viral infection. A great deal of research in recent years has been focusing on these metabolic aspects, pointing at modifications induced by virus, and suggesting novel strategies to counteract the perturbed host metabolism. In this review, our attention is turned on PPARs, nuclear receptors controlling multiple metabolic actions, and on the effects played by PPAR ligands during viral infections. The role of PPAR agonists and antagonists during SARS-CoV-2, HCV, and HCMV infections will be analyzed.

Keywords:  HCMV; HCV; PPAR; SARS-CoV-2; antiviral drug; lipid metabolism; viral infection

DOI:  https://doi.org/10.3390/biology11010114
Diabetes. 2022 Jan 14. pii: db210535. [Epub ahead of print]

Lactate is a Key Mediator That Links Obesity to Insulin Resistance via Modulating Cytokine Production From Adipose Tissue.

Yijun Lin, Meijuan Bai, Shuo Wang, Lingling Chen, Zixuan Li, Chenchen Li, Peijuan Cao, Yan Chen.

Numerous evidences indicate that inflammation in adipose tissue is the primary cause of systemic insulin resistance induced by obesity. Obesity-associated changes in circulating LPS level and hypoxia/HIF-1α activation have been proposed to be involved in boosting obesity-induced inflammation. However, what triggers obesity-induced inflammation is poorly understood. In this study, we pinpoint lactate as a key trigger to mediate obesity-induced inflammation and systemic insulin resistance. Specific deletion of Slc16a1 that encodes MCT1, the primary lactate transporter in adipose tissues, robustly elevates blood levels of pro-inflammatory cytokines and aggravates systemic insulin resistance without alteration of adiposity in mice fed high-fat diet. Slc16a1 deletion in adipocytes elevates intracellular lactate level while reducing circulating lactate concentration. Mechanistically, lactate retention due to Slc16a1 deletion initiates adipocyte apoptosis and cytokine release. The locally recruited macrophages amplify the inflammation by release of pro-inflammatory cytokines to the circulation, leading to insulin resistance in peripheral tissues. This study, therefore, indicates that lactate within adipocytes has a key biological function linking obesity to insulin resistance, and harnessing lactate in adipocytes can be a promising strategy to break this deadly link.

DOI: https://doi.org/10.2337/db21-0535
Viruses. 2022 Jan 07. pii: 103. [Epub ahead of print]14(1):

Metabolic Reprogramming of Glioblastoma Cells during HCMV Infection Induces Secretome-Mediated Paracrine Effects in the Microenvironment.

Mark A A Harrison, Emily M Hochreiner, Brooke P Benjamin, Sean E Lawler, Kevin J Zwezdaryk.

  Glioblastoma (GBM) is an aggressive primary central nervous system neoplasia with limited therapeutic options and poor prognosis. Following reports of cytomegalovirus (HCMV) in GBM tumors, the anti-viral drug Valganciclovir was administered and found to significantly increase the longevity of GBM patients. While these findings suggest a role for HCMV in GBM, the relationship between them is not clear and remains controversial. Treatment with anti-viral drugs may prove clinically useful; however, their results do not explain the underlying mechanism between HCMV infection and GBM progression. We hypothesized that HCMV infection would metabolically reprogram GBM cells and that these changes would allow for increased tumor progression. We infected LN-18 GBM cells and employed a Seahorse Bioanalyzer to characterize cellular metabolism. Increased mitochondrial respiration and glycolytic rates were observed following infection. These changes were accompanied by elevated production of reactive oxygen species and lactate. Due to lactate's numerous tumor-promoting effects, we examined the impact of paracrine signaling of HCMV-infected GBM cells on uninfected stromal cells. Our results indicated that, independent of viral transmission, the secretome of HCMV-infected GBM cells was able to alter the expression of key metabolic proteins and epigenetic markers. This suggests a mechanism of action where reprogramming of GBM cells alters the surrounding tumor microenvironment to be permissive to tumor progression in a manner akin to the Reverse-Warburg Effect. Overall, this suggests a potential oncomodulatory role for HCMV in the context of GBM.

Keywords:  aerobic glycolysis; glioblastoma (GBM); human cytomegalovirus (HCMV); lactate; metabolism; oxidative phosphorylation (OXPHOS); reactive oxygen species; tumor microenvironment

DOI:  https://doi.org/10.3390/v14010103
bioRxiv. 2022 Jan 11. pii: 2022.01.10.475725. [Epub ahead of print]

A single-cell atlas reveals shared and distinct immune responses and metabolism during SARS-CoV-2 and HIV-1 infections.

Tony Pan, Guoshuai Cao, Erting Tang, Yu Zhao, Pablo Penaloza-MacMaster, Yun Fang, Jun Huang.

SARS-CoV-2 and HIV-1 are RNA viruses that have killed millions of people worldwide. Understanding the similarities and differences between these two infections is critical for understanding disease progression and for developing effective vaccines and therapies, particularly for 38 million HIV-1 + individuals who are vulnerable to SARS-CoV-2 co-infection. Here, we utilized single-cell transcriptomics to perform a systematic comparison of 94,442 PBMCs from 7 COVID-19 and 9 HIV-1 + patients in an integrated immune atlas, in which 27 different cell types were identified using an accurate consensus single-cell annotation method. While immune cells in both cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activities, and downregulated mitophagy. Our results elucidate transcriptional signatures associated with COVID-19 and HIV-1 that may reveal insights into fundamental disease biology and potential therapeutic targets to treat these viral infections.
Highlights: COVID-19 and HIV-1 + patients show disease-specific inflammatory immune signatures COVID-19 patients show more productive humoral responses than HIV-1 + patients SARS-CoV-2 elicits more enriched IFN-I signaling relative to HIV-IDivergent, impaired metabolic programs distinguish SARS-CoV-2 and HIV-1 infections.

DOI: https://doi.org/10.1101/2022.01.10.475725
mBio. 2022 Jan 18. e0368321

CRISPR Interference Reveals That All-Trans-Retinoic Acid Promotes Macrophage Control of Mycobacterium tuberculosis by Limiting Bacterial Access to Cholesterol and Propionyl Coenzyme A.

Gregory H Babunovic, Michael A DeJesus, Barbara Bosch, Michael R Chase, Thibault Barbier, Amy K Dickey, Bryan D Bryson, Jeremy M Rock, Sarah M Fortune.

  Macrophages are a protective replicative niche for Mycobacterium tuberculosis (Mtb) but can kill the infecting bacterium when appropriately activated. To identify mechanisms of clearance, we compared levels of bacterial restriction by human macrophages after treatment with 26 compounds, including some currently in clinical trials for tuberculosis. All-trans-retinoic acid (ATRA), an active metabolite of vitamin A, drove the greatest increase in Mtb control. Bacterial clearance was transcriptionally and functionally associated with changes in macrophage cholesterol trafficking and lipid metabolism. To determine how these macrophage changes affected bacterial control, we performed the first Mtb CRISPR interference screen in an infection model, identifying Mtb genes specifically required to survive in ATRA-activated macrophages. These data showed that ATRA treatment starves Mtb of cholesterol and the downstream metabolite propionyl coenzyme A (propionyl-CoA). Supplementation with sources of propionyl-CoA, including cholesterol, abrogated the restrictive effect of ATRA. This work demonstrates that targeting the coupled metabolism of Mtb and the macrophage improves control of infection and that it is possible to genetically map the mode of bacterial death using CRISPR interference. IMPORTANCE Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, is a leading cause of death due to infectious disease. Improving the immune response to tuberculosis holds promise for fighting the disease but is limited by our lack of knowledge as to how the immune system kills M. tuberculosis. Our research identifies a potent way to make relevant immune cells more effective at fighting M. tuberculosis and then uses paired human and bacterial genomic methods to determine the mechanism of that improved bacterial clearance.

Keywords:  CRISPR interference; Mycobacterium tuberculosis; cholesterol; macrophages; nutritional immunity; propionyl-CoA; retinoic acid

DOI:  https://doi.org/10.1128/mbio.03683-21
Endocr Metab Immune Disord Drug Targets. 2022 Jan 13.

The emerging roles of IL-36, IL-37, and IL-38 in diabetes mellitus and its complications.

Guoqing Huang, Mingcai Li, Xiaoqing Tian, Qiankai Jin, Yushan Mao, Yan Li.

  Diabetes mellitus is a metabolic disease caused by a combination of genetics and environmental factors. The importance of the inflammatory response occurring in the pancreas and adipose tissue in the occurrence and progression of diabetes has been gradually accepted. Excess blood glucose and free fatty acids produce large amounts of inflammatory cytokines and chemokines through oxidative stress and endoplasmic reticulum stress. There is sufficient evidence that proinflammatory mediators, such as interleukin (IL)-1β, IL-6, macrophage chemotactic protein-1, and tumor necrosis factor-α, are engaged in the insulin resistance in peripheral adipose tissue and the apoptosis of pancreatic β-cells. IL-36, IL-37, and IL-38, as new members of the IL-1 family, play an indispensable effect in the regulation of immune system homeostasis and are involved in the pathogenesis of inflammatory and autoimmune diseases. Recently, the abnormal expression of IL-36, IL-37, and IL-38 in diabetes has been reported. In this review, we discuss the emerging functions, potential mechanisms, and future research directions on the role of IL-36, IL-37, and IL-38 in diabetes mellitus and its complications.

Keywords:  IL-36; IL-37; IL-38; complications; diabetes mellitus; inflammation

DOI:  https://doi.org/10.2174/1871530322666220113142533
Allergy. 2022 Jan 17.

TFEB signaling attenuates NLRP3-driven inflammatory responses in severe asthma.

Efthymia Theofani, Maria Semitekolou, Konstantinos Samitas, Annie Mais, Ioanna E Galani, Vasiliki Triantafyllia, Joanna Lama, Ioannis Morianos, Athanasios Stavropoulos, Se-Jin Jeong, Evangelos Andreakos, Babak Razani, Nikoletta Rovina, Georgina Xanthou.

   BACKGROUND: NLRP3-driven inflammatory responses by circulating and lung-resident monocytes are critical drivers of asthma pathogenesis. Autophagy restrains NLRP3-induced monocyte activation in asthma models. Yet, the effects of autophagy and its master regulator, transcription factor EB (TFEB), on monocyte responses in human asthma remain unexplored. Here, we investigated whether activation of autophagy and TFEB signaling suppress inflammatory monocyte responses in asthmatic individuals.
METHODS: Peripheral blood CD14+ monocytes from asthmatic patients (n=83) and healthy controls (n=46) were stimulated with LPS/ATP to induce NLRP3 activation with or without the autophagy inducer, rapamycin. ASC specks, caspase-1 activation, IL-1β and IL-18 levels, mitochondrial function, ROS release and mTORC1 signaling were examined. Autophagy was evaluated by LC3 puncta formation, p62/SQSTM1 degradation and TFEB activation. In a severe asthma (SA) model, we investigated the role of NLRP3 signaling using Nlrp3-/- mice and/or MCC950 administration, and the effects of TFEB activation using myeloid-specific TFEB-overexpressing mice or administration of the TFEB activator, trehalose.
RESULTS: We observed increased NLRP3 inflammasome activation, concomitant with impaired autophagy in circulating monocytes that correlated with asthma severity. SA patients also exhibited mitochondrial dysfunction and ROS accumulation. Autophagy failed to inhibit NLRP3-driven monocyte responses, due to defective TFEB activation and excessive mTORC1 signaling. NLRP3 blockade restrained inflammatory cytokine release and linked airway disease. TFEB activation restored impaired autophagy, attenuated NLRP3-driven pulmonary inflammation and ameliorated SA phenotype.
CONCLUSIONS: Our studies uncover a crucial role for TFEB-mediated reprogramming of monocyte inflammatory responses, raising the prospect that this pathway can be therapeutically harnessed for the management of SA.

Keywords:  NLRP3; TFEB; asthma; autophagy; monocytes

DOI:  https://doi.org/10.1111/all.15221
Redox Biol. 2022 Jan 15. pii: S2213-2317(22)00009-X. [Epub ahead of print]50 102237

NAMPT mitigates colitis severity by supporting redox-sensitive activation of phagocytosis in inflammatory macrophages.

Sun Mi Hong, A-Yeon Lee, Sung-Min Hwang, Yu-Jin Ha, Moo-Jin Kim, Seongki Min, Won Hwang, Gyesoon Yoon, So Mee Kwon, Hyun Goo Woo, Hee-Hoon Kim, Won-Il Jeong, Han-Ming Shen, Sin-Hyeog Im, Dakeun Lee, You-Sun Kim.

  Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway and plays a crucial role in the maintenance of the NAD+ pool during inflammation. Considering that macrophages are essential for tissue homeostasis and inflammation, we sought to examine the functional impact of NAMPT in inflammatory macrophages, particularly in the context of inflammatory bowel disease (IBD). In this study, we show that mice with NAMPT deletion within the myeloid compartment (Namptf/fLysMCre+/-, Nampt mKO) have more pronounced colitis with lower survival rates, as well as numerous uncleared apoptotic corpses within the mucosal layer. Nampt-deficient macrophages exhibit reduced phagocytic activity due to insufficient NAD+ abundance, which is required to produce NADPH for the oxidative burst. Nicotinamide mononucleotide (NMN) treatment rescues NADPH levels in Nampt mKO macrophages and sustains superoxide generation via NADPH oxidase. Consequently, Nampt mKO mice fail to clear dead cells during tissue repair, leading to substantially prolonged chronic colitis. Moreover, systemic administration of NMN, to supply NAD+, effectively suppresses the disease severity of DSS-induced colitis. Collectively, our findings suggest that activation of the NAMPT-dependent NAD+ biosynthetic pathway, via NMN administration, is a potential therapeutic strategy for managing inflammatory diseases.

Keywords:  Colitis; Inflammatory bowel disease; Macrophage; NAD(+); NAMPT; Phagocytic activity

DOI:  https://doi.org/10.1016/j.redox.2022.102237
Metabolites. 2021 Dec 23. pii: 10. [Epub ahead of print]12(1):

TrpNet: Understanding Tryptophan Metabolism across Gut Microbiome.

Yao Lu, Jasmine Chong, Shiqian Shen, Joey-Bahige Chammas, Lorraine Chalifour, Jianguo Xia.

  Crosstalk between the gut microbiome and the host plays an important role in animal development and health. Small compounds are key mediators in this host-gut microbiome dialogue. For instance, tryptophan metabolites, generated by biotransformation of tryptophan through complex host-microbiome co-metabolism can trigger immune, metabolic, and neuronal effects at local and distant sites. However, the origin of tryptophan metabolites and the underlying tryptophan metabolic pathway(s) are not well characterized in the current literature. A large number of the microbial contributors of tryptophan metabolism remain unknown, and there is a growing interest in predicting tryptophan metabolites for a given microbiome. Here, we introduce TrpNet, a comprehensive database and analytics platform dedicated to tryptophan metabolism within the context of host (human and mouse) and gut microbiome interactions. TrpNet contains data on tryptophan metabolism involving 130 reactions, 108 metabolites and 91 enzymes across 1246 human gut bacterial species and 88 mouse gut bacterial species. Users can browse, search, and highlight the tryptophan metabolic pathway, as well as predict tryptophan metabolites on the basis of a given taxonomy profile using a Bayesian logistic regression model. We validated our approach using two gut microbiome metabolomics studies and demonstrated that TrpNet was able to better predict alterations in in indole derivatives compared to other established methods.

Keywords:  co-metabolism; genome-scale metabolic model; gut microbiome; indole derivatives; network; tryptophan metabolism

DOI:  https://doi.org/10.3390/metabo12010010
FASEB J. 2022 Feb;36(2): e22139

Metformin ameliorates chronic colitis in a mouse model by regulating interferon-γ-producing lamina propria CD4+ T cells through AMPK activation.

Masahiro Takahara, Akinobu Takaki, Sakiko Hiraoka, Kensuke Takei, Eriko Yasutomi, Shoko Igawa, Shumpei Yamamoto, Shohei Oka, Masayasu Ohmori, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Keita Harada, Heiichiro Udono, Hiroyuki Okada.

  Metformin, a commonly prescribed drug for type 2 diabetes mellitus, has been shown to activate AMP-activated protein kinase (AMPK). Notably, AMPK activation has recently been observed to be associated with anti-inflammatory responses. Metformin is also reported to elicit anti-inflammatory responses in CD4+ T cells, resulting in improvement in experimental chronic inflammatory diseases, such as systemic lupus erythematosus. To investigate the effect of metformin on inflammatory bowel disease (IBD), we developed a T cell-transfer model of chronic colitis in which SCID mice were injected with CD4+ CD45RBhigh T cells to induce colitis. We examined the effects of metformin via in vitro and in vivo experiments on lamina propria (LP) CD4+ T cells. We observed that metformin suppresses the frequency of interferon (IFN) -γ-producing LP CD4+ T cells in vitro, which were regulated by AMPK activation, a process possibly induced by the inhibition of oxidative phosphorylation. Furthermore, we examined the effects of metformin on an in vivo IBD model. Metformin-treated mice showed AMPK activation in LP CD4+ T cells and ameliorated colitis. Our study demonstrates that metformin-induced AMPK activation in mucosal CD4+ T cells contributes to the improvement of IBD by suppressing IFN-γ production. Moreover, our results indicate that AMPK may be a target molecule for the regulation of mucosal immunity and inflammation. Thus, AMPK-activating drugs such as metformin may be potential therapeutic agents for the treatment of IBD.

Keywords:  AMP-activated protein kinase; chronic colitis; metformin; oxidative phosphorylation

DOI:  https://doi.org/10.1096/fj.202100831RR
J Clin Invest. 2022 Jan 18. pii: e148552. [Epub ahead of print]132(2):

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies.

George Robinson, Ines Pineda-Torra, Coziana Ciurtin, Elizabeth C Jury.

Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.

DOI: https://doi.org/10.1172/JCI148552
Sci Rep. 2022 Jan 20. 12(1): 1048

Pcyt2 deficiency causes age-dependant development of nonalcoholic steatohepatitis and insulin resistance that could be attenuated with phosphoethanolamine.

Sophie Grapentine, Rathnesh K Singh, Poulami Basu, Sugashan Sivanesan, Gabriela Mattos, Oreoluwa Oresajo, Jasmine Cheema, Wendwesen Demeke, Vernon W Dolinsky, Marica Bakovic.

The mechanisms of NASH development in the context of age and genetics are not fully elucidated. This study investigates the age-dependent liver defects during NASH development in mice with heterozygous deletion of Pcyt2 (Pcyt2+/-), the rate limiting enzyme in phosphatidylethanolamine (PE) synthesis. Further, the therapeutic potential of Pcyt2 substrate, phosphoethanolamine (PEtn), is examined. Pcyt2+/- were investigated at 2 and 6-8 months (mo) of age and in addition, 6-mo old Pcyt2+/- with developed NASH were supplemented with PEtn for 8 weeks and glucose and fatty acid metabolism, insulin signaling, and inflammation were examined. Heterozygous ablation of Pcyt2 causes changes in liver metabolic regulators from young age, prior to the development of liver disease which does not occur until adulthood. Only older Pcyt2+/- experiences perturbed glucose and fatty acid metabolism. Older Pcyt2+/- liver develops NASH characterized by increased glucose production, accumulation of TAG and glycogen, and increased inflammation. Supplementation with PEtn reverses Pcyt2+/- steatosis, inflammation, and other aspects of NASH, showing that was directly caused by Pcyt2 deficiency. Pcyt2 deficiency is a novel mechanism of metabolic dysregulation due to reduced membrane ethanolamine phospholipid synthesis, and the metabolite PEtn offers therapeutic potential for NASH reversion.

DOI: https://doi.org/10.1038/s41598-022-05140-y