bims-imicid 2022-08-14 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–08–14
24 papers selected by
Dylan Ryan, University of Cambridge

Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity.
TGFβ limits Myc-dependent TCR-induced metabolic reprogramming in CD8+ T cells.
Insights on how mitochondrial NAD(P)+ transhydrogenase plays a central metabolic role in proinflammatory macrophages.
Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity.
Metabolic regulation of T cell development.
Iron Deficiency and Overload Modulate the Inflammatory Responses and Metabolism of Alveolar Macrophages.
Immunometabolism of Immune Cells in Mucosal Environment Drives Effector Responses against Mycobacterium tuberculosis.
A tyrosine catabolic intermediate 4-hydroxyphenylpyruate attenuates murine endotoxic shock by blocking NLRP3 inflammasome activation.
COVID-19 metabolism: Mechanisms and therapeutic targets.
Mitochondrial pyruvate carrier: a metabolic-epigenetic checkpoint orchestrating T cell differentiation.
Monocyte Metabolism and Function in Patients Undergoing Cardiac Surgery.
Regulation of CD4+ and CD8+ T Cell Biology by Short-Chain Fatty Acids and Its Relevance for Autoimmune Pathology.
EGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance.
Immune-metabolic interactions in homeostasis and the progression to NASH.
Single Cell Analysis Reveals Reciprocal Tumor-Macrophage Intercellular Communications Related with Metabolic Reprogramming in Stem-like Gastric Cancer.
Dimethyl Itaconate Attenuates CFA-Induced Inflammatory Pain via the NLRP3/ IL-1β Signaling Pathway.
Aging Relevant Metabolite Itaconate Inhibits Inflammatory Bone Loss.
Dual specificity phosphatase 1 attenuates inflammation-induced cardiomyopathy by improving mitophagy and mitochondrial metabolism.
HAO1 negatively regulates liver macrophage activation via the NF-κB pathway in alcohol-associated liver disease.
Mfn2 is responsible for inhibition of the RIG-I/IRF7 pathway and activation of NLRP3 inflammasome in Seneca Valley virus-infected PK-15 cells to promote viral replication.
Modified highland barley regulates lipid metabolism, liver inflammation and gut microbiota in high-fat/cholesterol diet mice as revealed by LC-MS based metabonomics.
Dimethyl itaconic acid improves viability and steroidogenesis and supresses cytokine production in LPS-treated bovine ovarian granulosa cells by regulationg TLR4/nfkβ, NLRP3, JNK signaling pathways.
Immunometabolism characteristics and a potential prognostic risk model associated with TP53 mutations in breast cancer.
Cyclic nucleotide-induced helical structure activates a TIR immune effector.

Cell Syst. 2022 Jul 08. pii: S2405-4712(22)00276-9. [Epub ahead of print]

Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity.

Anoop T Ambikan, Hong Yang, Shuba Krishnan, Sara Svensson Akusjärvi, Soham Gupta, Magda Lourda, Maike Sperk, Muhammad Arif, Cheng Zhang, Hampus Nordqvist, Sivasankaran Munusamy Ponnan, Anders Sönnerborg, Carl Johan Treutiger, Liam O'Mahony, Adil Mardinoglu, Rui Benfeitas, Ujjwal Neogi.

  The clinical outcome and disease severity in coronavirus disease 2019 (COVID-19) are heterogeneous, and the progression or fatality of the disease cannot be explained by a single factor like age or comorbidities. In this study, we used system-wide network-based system biology analysis using whole blood RNA sequencing, immunophenotyping by flow cytometry, plasma metabolomics, and single-cell-type metabolomics of monocytes to identify the potential determinants of COVID-19 severity at personalized and group levels. Digital cell quantification and immunophenotyping of the mononuclear phagocytes indicated a substantial role in coordinating the immune cells that mediate COVID-19 severity. Stratum-specific and personalized genome-scale metabolic modeling indicated monocarboxylate transporter family genes (e.g., SLC16A6), nucleoside transporter genes (e.g., SLC29A1), and metabolites such as α-ketoglutarate, succinate, malate, and butyrate could play a crucial role in COVID-19 severity. Metabolic perturbations targeting the central metabolic pathway (TCA cycle) can be an alternate treatment strategy in severe COVID-19.

Keywords:  COVID-19; personalized genome-scale metabolic model; similarity network fusion

DOI:  https://doi.org/10.1016/j.cels.2022.06.006
Front Immunol. 2022 ;13 913184

TGFβ limits Myc-dependent TCR-induced metabolic reprogramming in CD8+ T cells.

Helen Carrasco Hope, Gabriella Pickersgill, Pierpaolo Ginefra, Nicola Vannini, Graham P Cook, Robert J Salmond.

  T cell activation is dependent upon the integration of antigenic, co-stimulatory and cytokine-derived signals and the availability and acquisition of nutrients from the environment. Furthermore, T cell activation is accompanied by reprogramming of cellular metabolism to provide the energy and building blocks for proliferation, differentiation and effector function. Transforming growth factor β (TGFβ) has pleiotropic effects on T cell populations, having both an essential role in the maintenance of immune tolerance but also context-dependent pro-inflammatory functions. We set out to define the mechanisms underpinning the suppressive effects of TGFβ on mouse CD8+ T cell activation. RNA-sequencing analysis of TCR-stimulated T cells determined that Myc-regulated genes were highly enriched within gene sets downregulated by TGFβ. Functional analysis demonstrated that TGFβ impeded TCR-induced upregulation of amino acid transporter expression, amino acid uptake and protein synthesis. Furthermore, TCR-induced upregulation of Myc-dependent glycolytic metabolism was substantially inhibited by TGFβ treatment with minimal effects on mitochondrial respiration. Thus, our data suggest that inhibition of Myc-dependent metabolic reprogramming represents a major mechanism underpinning the suppressive effects of TGFβ on CD8+ T cell activation.

Keywords:  T cell receptor; T cells; TGFβ (transforming growth factor-beta); cytokines; metabolism; signalling

DOI:  https://doi.org/10.3389/fimmu.2022.913184
Am J Physiol Cell Physiol. 2022 08 01. 323(2): C648-C649

Insights on how mitochondrial NAD(P)+ transhydrogenase plays a central metabolic role in proinflammatory macrophages.

Tiago R Figueira, Roger F Castilho.



Keywords:  Kreb’s cycle; immune cell; mitochondria; peroxide; redox balance

DOI:  https://doi.org/10.1152/ajpcell.00090.2022
J Hematol Oncol. 2022 Aug 10. 15(1): 104

Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity.

Yuheng Yan, Lan Huang, Yiming Liu, Ming Yi, Qian Chu, Dechao Jiao, Kongming Wu.

  Characterized by the expression of the critical transcription factor forkhead box protein P3, regulatory T (Treg) cells are an essential part of the immune system, with a dual effect on the pathogenesis of autoimmune diseases and cancer. Targeting Tregs to reestablish the proinflammatory and immunogenic tumor microenvironment (TME) is an increasingly attractive strategy for cancer treatment and has been emphasized in recent years. However, attempts have been significantly hindered by the subsequent autoimmunity after Treg ablation owing to systemic loss of their suppressive capacity. Cellular metabolic reprogramming is acknowledged as a hallmark of cancer, and emerging evidence suggests that elucidating the underlying mechanisms of how intratumoral Tregs acquire metabolic fitness and superior immunosuppression in the TME may contribute to clinical benefits. In this review, we discuss the common and distinct metabolic profiles of Tregs in peripheral tissues and the TME, as well as the differences between Tregs and other conventional T cells in their metabolic preferences. By focusing on the critical roles of different metabolic programs, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, fatty acid synthesis, and amino acid metabolism, as well as their essential regulators in modulating Treg proliferation, migration, and function, we hope to provide new insights into Treg cell-targeted antitumor immunotherapies.

Keywords:  Amino acid metabolism; Fatty acid oxidation; Fatty acid synthesis; Glycolysis; Immunotherapy; Oxidative phosphorylation; Regulatory T cell; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13045-022-01322-3
Front Immunol. 2022 ;13 946119

Metabolic regulation of T cell development.

Mengdi Zhang, Xiaoxi Lin, Zhou Yang, Xia Li, Zhiguang Zhou, Paul E Love, Jiaqi Huang, Bin Zhao.

  T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the transcriptional and posttranslational control of the intrathymic journey of T-cell precursors. However, over the last few years, compelling evidence has highlighted cell metabolism as a critical regulator in this process. Different thymocyte subsets are directed by distinct metabolic pathways and signaling networks to match the specific functional requirements of the stage. Here, we epitomize these metabolic alterations during the development of a T cell and review several recent works that provide insights into equilibrating metabolic quiescence and activation programs. Ultimately, understanding the interplay between cellular metabolism and T cell developmental programs may offer an opportunity to selectively regulate T cell subset functions and to provide potential novel therapeutic approaches to modulate autoimmunity.

Keywords:  T cell development; T cell metabolism; thymocyte metabolism; thymocytes; thymus

DOI:  https://doi.org/10.3389/fimmu.2022.946119
Nutrients. 2022 Jul 28. pii: 3100. [Epub ahead of print]14(15):

Iron Deficiency and Overload Modulate the Inflammatory Responses and Metabolism of Alveolar Macrophages.

Vivian Perng, Shya E Navazesh, Jungjae Park, Joseph R Arballo, Peng Ji.

  Alveolar macrophages (AM) are critical to defense against respiratory pathogens. This study evaluated cellular iron imbalance to immunometabolism in endotoxin-polarized porcine AMs (PAMs). PAMs collected from five 6-week-old pigs were treated with a basal media, iron chelator, or ferric ammonium citrate to maintain iron replete or induce iron deficiency or overload, respectively. After 24 h treatment, PAMs were challenged with saline or lipopolysaccharide (LPS) for 6 h. Cells were analyzed for gene, protein, and untargeted metabolome. Cytokines were determined in culture media. Data were assessed using two-way ANOVA. Treatments successfully induced iron deficiency and overload. The mRNA of DMT1 and ZIP14 was increased up to 300-fold by LPS, but unaffected by iron. Surprisingly, both iron deprivation and overload attenuated LPS-induced inflammation, showing less TNFα production and lower mRNA of pro- and anti-inflammatory cytokines than iron-replete PAMs. Forty-eight metabolites were altered by either or both main effects. LPS enhanced the glycolysis and polyol pathways. Iron deprivation disrupted the TCA cycle. Iron overload increased intracellular cholesterol. Interestingly, iron deprivation augmented, whereas iron overload diminished, LPS-induced itaconic acid production, which has anti-microbial and anti-inflammatory properties. Therefore, iron-deficient PAMs may be more resistant to intracellular pathogens which use PAMs as a conduit for infection.

Keywords:  alveolar macrophage; immunometabolism; iron deficiency; iron overload; itaconic acid

DOI:  https://doi.org/10.3390/nu14153100
Int J Mol Sci. 2022 Aug 01. pii: 8531. [Epub ahead of print]23(15):

Immunometabolism of Immune Cells in Mucosal Environment Drives Effector Responses against Mycobacterium tuberculosis.

Mohd Hatimi Tukiman, Mohd Nor Norazmi.

  Tuberculosis remains a major threat to global public health, with more than 1.5 million deaths recorded in 2020. Improved interventions against tuberculosis are urgently needed, but there are still gaps in our knowledge of the host-pathogen interaction that need to be filled, especially at the site of infection. With a long history of infection in humans, Mycobacterium tuberculosis (Mtb) has evolved to be able to exploit the microenvironment of the infection site to survive and grow. The immune cells are not only reliant on immune signalling to mount an effective response to Mtb invasion but can also be orchestrated by their metabolic state. Cellular metabolism was often overlooked in the past but growing evidence of its importance in the functions of immune cells suggests that it can no longer be ignored. This review aims to gain a better understanding of mucosal immunometabolism of resident effector cells, such as alveolar macrophages and mucosal-associated invariant T cells (MAIT cells), in response to Mtb infection and how Mtb manipulates them for its survival and growth, which could address our knowledge gaps while opening up new questions, and potentially be applied for future vaccination and therapeutic strategies.

Keywords:  glycolysis; gut-lung axis; immunometabolism; innate and adaptive immune cells; oxidative phosphorylation; tuberculosis

DOI:  https://doi.org/10.3390/ijms23158531
Int Immunopharmacol. 2022 Aug 06. pii: S1567-5769(22)00582-3. [Epub ahead of print]111 109098

A tyrosine catabolic intermediate 4-hydroxyphenylpyruate attenuates murine endotoxic shock by blocking NLRP3 inflammasome activation.

Yanxia Wei, Mengnan Liu, Jinzhi Han, Haohan Huang, Shihong Xu, Shenghan Zhang, Qiyue Jing, Hanying Wang, Huimin Bu, Yanbo Kou, Zhuanzhuan Liu, Kuiyang Zheng, Yugang Wang.

  The metabolic alterations of amino acid metabolism are closely associated with inflammatory response. However, relatively little is known about the roles of phenylalanine (Phe)/tyrosine (Tyr) catabolites during inflammation. Nitisinone (NTBC) is an orphan drug used to treat hereditary tyrosinemia type I potentially by changing Phe/Tyr metabolic flow. In this study, we used NTBC as a tool to investigate the potential role of the Phe/Tyr catabolic pathway in inflammatory responses. We found that NTBC was effective in tempering the bacterial endotoxin lipopolysaccharide (LPS)-induced septic shock in mice. Mechanistically, the protective effect was related to the accumulation of a Phe/Tyr catabolic intermediate, 4-hydroxyphenylpyruvate (4-HPP), induced by the NTBC treatment. 4-HPP could inhibit NLRP3 inflammasome priming and activation processes and therefore reduce IL-1β release and pyroptosis. Like NTBC, 4-HPP was also effective in attenuating endotoxic shock in mice. Our results suggest the Phe/Tyr catabolic pathway as a potential immunoregulatory hub that may be exploited therapeutically to alleviate inflammation.

Keywords:  4-HPP, metabolism; IL-1β; Immunometabolism; Inflammasome; Macrophage; Pyroptosis

DOI:  https://doi.org/10.1016/j.intimp.2022.109098
MedComm (2020). 2022 Sep;3(3): e157

COVID-19 metabolism: Mechanisms and therapeutic targets.

Tianshi Wang, Ying Cao, Haiyan Zhang, Zihao Wang, Cheuk Him Man, Yunfan Yang, Lingchao Chen, Shuangnian Xu, Xiaojing Yan, Quan Zheng, Yi-Ping Wang.

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dysregulates antiviral signaling, immune response, and cell metabolism in human body. Viral genome and proteins hijack host metabolic network to support viral biogenesis and propagation. However, the regulatory mechanism of SARS-CoV-2-induced metabolic dysfunction has not been elucidated until recently. Multiomic studies of coronavirus disease 2019 (COVID-19) revealed an intensive interaction between host metabolic regulators and viral proteins. SARS-CoV-2 deregulated cellular metabolism in blood, intestine, liver, pancreas, fat, and immune cells. Host metabolism supported almost every stage of viral lifecycle. Strikingly, viral proteins were found to interact with metabolic enzymes in different cellular compartments. Biochemical and genetic assays also identified key regulatory nodes and metabolic dependencies of viral replication. Of note, cholesterol metabolism, lipid metabolism, and glucose metabolism are broadly involved in viral lifecycle. Here, we summarized the current understanding of the hallmarks of COVID-19 metabolism. SARS-CoV-2 infection remodels host cell metabolism, which in turn modulates viral biogenesis and replication. Remodeling of host metabolism creates metabolic vulnerability of SARS-CoV-2 replication, which could be explored to uncover new therapeutic targets. The efficacy of metabolic inhibitors against COVID-19 is under investigation in several clinical trials. Ultimately, the knowledge of SARS-CoV-2-induced metabolic reprogramming would accelerate drug repurposing or screening to combat the COVID-19 pandemic.

Keywords:  SARS‐CoV‐2; antiviral response; metabolic reprogramming; mitochondria metabolism; posttranslational modification

DOI:  https://doi.org/10.1002/mco2.157
Signal Transduct Target Ther. 2022 Aug 12. 7(1): 280

Mitochondrial pyruvate carrier: a metabolic-epigenetic checkpoint orchestrating T cell differentiation.

Yu Chen, Jingchun Wang, Yongsheng Li.

DOI: https://doi.org/10.1038/s41392-022-01101-z
Front Cardiovasc Med. 2022 ;9 853967

Monocyte Metabolism and Function in Patients Undergoing Cardiac Surgery.

Daniel Mayer, Marc Altvater, Judith Schenz, Rawa Arif, Matthias Karck, Florian Leuschner, Markus A Weigand, Florian Uhle, Christoph Lichtenstern.

   Objective: Cardiopulmonary bypass (CPB) can lead to systemic inflammation, which is associated with higher morbidity. Therefore, we investigated the metabolism of isolated blood monocytes before and after CPB compared to healthy controls.
Methods: In this prospective, monocentric, observational study, we included 30 patients undergoing CPB and 20 controls. We isolated monocytes from heparinized blood and investigated their metabolism by using Seahorse technology before (t0), 4 h (t4), and 24 h (t24) after the start of the CPB. We also examined programmed cell death 1 ligand (PD-L1), PD-L2, V-domain Ig suppressor of T cell activation (VISTA), and human leukocyte antigen-DR isotype (HLA-DR) using fluorescence-activated cell sorting analysis. Additionally, we investigated plasma cytokine levels in patients without and after ex vivo stimulation.
Results: CPB-induced inflammatory responses are shown by significantly elevated plasma interleukin-6 levels in the CPB group compared to baseline and controls [t0: 0 ng/ml (95%CI 0-0 ng/ml); t4: 0.16 ng/ml (95%CI 0.1-0.197 ng/ml), p < 0.0001; t24: 0.11 ng/ml (95% CI 0.1-0.16 ng/ml), p < 0.0001, and controls: 0 ng/ml (95% CI 0-0 ng/ml)]. The cytokine release in the ex vivo stimulation is reduced for lipopolysaccharide stimulation at t4 [t0: 35.68 ng/ml (95% CI 22.17-46.57 ng/ml) vs. t4: 15.02 (95% CI 10.25-24.78 ng/ml), p < 0.0001]. Intracellular metabolism of monocytes after CPB showed a protracted shift to aerobic glycolysis [t0: 179.2 pmol/min (95% CI 138.0-205.1 pmol/min) vs. t24: 250.1 pmol/min (95% CI 94.8-300.2 pmol/min), p < 0.0001]. Additionally, we observed an altered metabolism in monocytes in patients undergoing cardiac surgery compared to controls even before any surgical procedure [t0: 179.2 pmol/min (95% CI 138.0-205.1) vs. controls 97.4 (95% CI 59.13-144.6 pmol/min), p = 0.0031].
Conclusion: After CPB, patients' monocytes show a shift in metabolism from oxidative phosphorylation to aerobic glycolysis, which is associated with energy-demanding and proinflammatory processes. This is the first study to show changes in monocyte immunometabolism in cardiac surgery. Monocytes of patients undergoing cardiac surgery were leaning toward aerobic glycolysis even before any surgical procedure was conducted. Leaving the question of the pathophysiological mechanisms for future studies to be investigated and paving the way for potential therapy approaches preventing inflammatory effects of CPB.

Keywords:  Warburg effect; cardiac surgery; immune reaction; immunometabolism; inflammation; monocytes

DOI:  https://doi.org/10.3389/fcvm.2022.853967
Int J Mol Sci. 2022 Jul 27. pii: 8272. [Epub ahead of print]23(15):

Regulation of CD4+ and CD8+ T Cell Biology by Short-Chain Fatty Acids and Its Relevance for Autoimmune Pathology.

Carmen Schiweck, Sharmili Edwin Thanarajah, Mareike Aichholzer, Silke Matura, Andreas Reif, Elske Vrieze, Andreas Weigert, Alexander Visekruna.

  The gut microbiota encodes a broad range of enzymes capable of synthetizing various metabolites, some of which are still uncharacterized. One well-known class of microbiota-derived metabolites are the short-chain fatty acids (SCFAs) such as acetate, propionate, butyrate and valerate. SCFAs have long been considered a mere waste product of bacterial metabolism. Novel results have challenged this long-held dogma, revealing a central role for microbe-derived SCFAs in gut microbiota-host interaction. SCFAs are bacterial signaling molecules that act directly on host T lymphocytes by reprogramming their metabolic activity and epigenetic status. They have an essential biological role in promoting differentiation of (intestinal) regulatory T cells and in production of the anti-inflammatory cytokine interleukin-10 (IL-10). These small molecules can also reach the circulation and modulate immune cell function in remote tissues. In experimental models of autoimmune and inflammatory diseases, such as inflammatory bowel disease, multiple sclerosis or diabetes, a strong therapeutic potential of SCFAs through the modulation of effector T cell function was observed. In this review, we discuss current research activities toward understanding a relevance of microbial SCFA for treating autoimmune and inflammatory pathologies from in vitro to human studies.

Keywords:  RCT; T cell; immune system; intervention; short chain fatty acid

DOI:  https://doi.org/10.3390/ijms23158272
Nat Commun. 2022 Aug 10. 13(1): 4684

EGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance.

Shirong Cao, Yu Pan, Jiaqi Tang, Andrew S Terker, Juan Pablo Arroyo Ornelas, Guan-Nan Jin, Yinqiu Wang, Aolei Niu, Xiaofeng Fan, Suwan Wang, Raymond C Harris, Ming-Zhi Zhang.

Obesity and obesity-related health complications are increasing in prevalence. Adipose tissue from obese subjects has low-grade, chronic inflammation, leading to insulin resistance. Adipose tissue macrophages (ATMs) are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. In response to a high fat diet (HFD), ATM numbers initially increase by proliferation of resident macrophages, but subsequent increases also result from infiltration in response to chemotactic signals from inflamed adipose tissue. To elucidate the underlying mechanisms regulating the increases in ATMs and their proinflammatory phenotype, we investigated the role of activation of ATM epidermal growth factor receptor (EGFR). A high fat diet increased expression of EGFR and its ligand amphiregulin in ATMs. Selective deletion of EGFR in ATMs inhibited both resident ATM proliferation and monocyte infiltration into adipose tissue and decreased obesity and development of insulin resistance. Therefore, ATM EGFR activation plays an important role in adipose tissue dysfunction.

DOI: https://doi.org/10.1038/s41467-022-32348-3
Trends Endocrinol Metab. 2022 Aug 09. pii: S1043-2760(22)00132-1. [Epub ahead of print]

Immune-metabolic interactions in homeostasis and the progression to NASH.

Joanne A Hoogerland, Bart Staels, David Dombrowicz.

  The incidence of non-alcoholic fatty liver disease (NAFLD) has increased significantly over the past two decades. NAFLD ranges from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) and predisposes to fibrosis and hepatocellular carcinoma (HCC). The importance of the immune system in hepatic physiology and in the progression of NAFLD is increasingly recognized. At homeostasis, the liver participates in immune defense against pathogens and in tolerance of gut-derived microbial compounds. Hepatic immune cells also respond to metabolic stimuli and have a role in NAFLD progression to NASH. In this review, we discuss how metabolic perturbations affect immune cell phenotype and function in NAFL and NASH, and then focus on the role of immune cells in liver homeostasis and in the development of NASH.

Keywords:  NAFLD; NASH; immunology; liver; metabolism

DOI:  https://doi.org/10.1016/j.tem.2022.07.001
Cells. 2022 Aug 02. pii: 2373. [Epub ahead of print]11(15):

Single Cell Analysis Reveals Reciprocal Tumor-Macrophage Intercellular Communications Related with Metabolic Reprogramming in Stem-like Gastric Cancer.

Ji-Yong Sung, Jae-Ho Cheong.

  Metabolic alterations and direct cell-cell interactions in the tumor microenvironment (TME) affect the prognostic molecular landscape of tumors; thus, it is imperative to investigate metabolic activity at the single-cell level rather than in bulk samples to understand the high-resolution mechanistic influences of cell-type specific metabolic pathway alterations on tumor cells. To investigate tumor metabolic reprogramming and intercellular communication at the single-cell level, we analyzed eighty-four metabolic pathways, seven metabolic signatures, and tumor-stroma cell interaction using 21,084 cells comprising gastric cancer and paired normal tissue. High EMT-score cells and stem-like subtype tumors showed elevated glycosaminoglycan metabolism, which was associated with poor patient outcome. Adenocarcinoma and macrophage cells had higher reactive oxidative species levels than the normal controls; they largely constituted the highest stemness cluster. They were found to reciprocally communicate through the common ligand RPS19. Consequently, ligand-target regulated transcriptional reprogramming resulted in HS6ST2 expression in adenocarcinoma cells and SERPINE1 expression in macrophages. Gastric cancer patients with increased SERPINE1 and HS6ST2 expression had unfavorable prognoses, suggesting these as potential drug targets. Our findings indicate that malignant stem-like/EMT cancer cell state might be regulated through reciprocal cancer cell-macrophage intercellular communication and metabolic reprogramming in the heterogeneous TME of gastric cancer at the single-cell level.

Keywords:  cancer stemness; gastric cancer; glycan metabolism; immunometabolism; single cell

DOI:  https://doi.org/10.3390/cells11152373
Front Pharmacol. 2022 ;13 938979

Dimethyl Itaconate Attenuates CFA-Induced Inflammatory Pain via the NLRP3/ IL-1β Signaling Pathway.

Jiaqi Lin, Jinxuan Ren, Bin Zhu, Yi Dai, Dave Schwinn Gao, Suyun Xia, Zhenzhen Cheng, Yangyuxin Huang, Lina Yu.

  Itaconate plays a prominent role in anti-inflammatory effects and has gradually been ushered as a promising drug candidate for treating inflammatory diseases. However, its significance and underlying mechanism for inflammatory pain remain unexplored. In the current study, we investigated the effects and mechanisms of Dimethyl Itaconate (DI, a derivative of itaconate) on Complete Freund's adjuvant (CFA)-induced inflammatory pain in a rodent model. Here, we demonstrated that DI significantly reduced mechanical allodynia and thermal hyperalgesia. The DI-attenuated neuroinflammation was evident with the amelioration of infiltrative macrophages in peripheral sites of the hind paw and the dorsal root ganglion. Concurrently, DI hindered the central microglia activation in the spinal cord. Mechanistically, DI inhibited the expression of pro-inflammatory factors interleukin (IL)-1β and tumor necrosis factor alpha (TNF-α) and upregulated anti-inflammatory factor IL-10. The analgesic mechanism of DI was related to the downregulation of the nod-like receptor protein 3 (NLRP3) inflammasome complex and IL-1β secretion. This study suggested possible novel evidence for prospective itaconate utilization in the management of inflammatory pain.

Keywords:  IL-1β; NLRP3 inflammasome complex; dimethyl itaconate; inflammatory pain; macrophages; microglia

DOI:  https://doi.org/10.3389/fphar.2022.938979
Front Endocrinol (Lausanne). 2022 ;13 885879

Aging Relevant Metabolite Itaconate Inhibits Inflammatory Bone Loss.

Yuting Wang, Song Li, Liming Zhao, Peng Cheng, Jian Liu, Fengjing Guo, Jun Xiao, Wentao Zhu, Anmin Chen.

  Progressive bone loss during aging makes osteoporosis one of the most common and life impacting conditions in geriatric populations. The bone homeostasis is maintained through persistent remodeling mediated by bone-forming osteoblast and bone-resorbing osteoclast. Inflammaging, a condition characterized by increased pro-inflammatory markers in the blood and other tissues during aging, has been reported to be associated with skeletal stem/progenitor cell dysfunction, which will result in impaired bone formation. However, the role of age-related inflammation and metabolites in regulation of osteoclast remains largely unknown. In the present study, we observed dichotomous phenotypes of anti-inflammatory metabolite itaconate in responding to inflammaging. Itaconate is upregulated in macrophages during aging but has less reactivity in responding to RANKL stimulation in aged macrophages. We confirmed the inhibitory effect of itaconate in regulating osteoclast differentiation and activation, and further verified the rescue role of itaconate in lipopolysaccharides induced inflammatory bone loss animal model. Our findings revealed that itaconate is a crucial regulatory metabolite during inflammaging that inhibits osteoclast to maintain bone homeostasis.

Keywords:  aging; inflammation; itaconate; osteoclast; osteoporosis

DOI:  https://doi.org/10.3389/fendo.2022.885879
Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00136-3. [Epub ahead of print] 101567

Dual specificity phosphatase 1 attenuates inflammation-induced cardiomyopathy by improving mitophagy and mitochondrial metabolism.

Ying Tan, Yue Zhang, Jing He, Feng Wu, Di Wu, Nengxian Shi, Weifeng Liu, Ziying Li, Wenqian Liu, Hao Zhou, Wenting Chen.

   OBJECTIVES: Dual specificity phosphatase 1 (DUSP1) is regarded as an anti-inflammatory factor in cardiovascular disorders. Mitophagy removes damaged mitochondria and thus promotes mitochondrial regeneration. We investigated whether DUSP1 could attenuate inflammation-induced cardiomyopathy by improving mitophagy.
METHODS: Lipopolysaccharide was used to induce septic cardiomyopathy in wild-type (WT) and DUSP1 transgenic (DUSP1TG) mice.
RESULTS: Echocardiography revealed that lipopolysaccharide impaired heart function by reducing the cardiac systolic and diastolic capacities of WT mice. Freshly isolated single cardiomyocytes from lipopolysaccharide-treated WT mice also exhibited reduced contractile/relaxation parameters. However, DUSP1 overexpression not only maintained the mechanical properties of cardiomyocytes, but also improved heart performance. Lipopolysaccharide upregulated myocardial inflammatory gene transcription and adhesive factor expression, which increased myocardial neutrophil accumulation and cardiomyocyte apoptosis in WT mice. DUSP1 overexpression inhibited the inflammatory response and therefore promoted cardiomyocyte survival. Lipopolysaccharide disrupted mitochondrial respiration and metabolism in WT cardiomyocytes, but DUSP1 overexpression restored mitochondrial metabolism, maintained the mitochondrial membrane potential and inhibited mitochondrial reactive oxygen species production, possibly by increasing FUN14 domain-containing 1 (FUNDC1)-dependent mitophagy. Silencing of FUNDC1 abolished the protective effects of DUSP1 overexpression on cardiomyocytes and their mitochondria following lipopolysaccharide treatment.
CONCLUSION: These results demonstrated that DUSP1 is a novel anti-inflammatory factor that protects against septic cardiomyopathy by improving FUNDC1-induced mitophagy.

Keywords:  DUSP1; FUNDC1; mitochondria; mitophagy; septic cardiomyopathy

DOI:  https://doi.org/10.1016/j.molmet.2022.101567
Cell Signal. 2022 Aug 08. pii: S0898-6568(22)00198-X. [Epub ahead of print] 110436

HAO1 negatively regulates liver macrophage activation via the NF-κB pathway in alcohol-associated liver disease.

Hao Chen, Xiaofeng Li, Yingyin Sun, Yan Du, Sha Wu, Yuanyuan Wu, Huiping Liu, Yaru Liu, Yongmei Wang, Qihang Zhao, Shi Yin.

  Inflammation is a key factor contributing to the progression of alcohol-associated liver disease (ALD). Accumulating data have shown that ethyl alcohol (EtOH) induced liver macrophages activation along with an inflammatory response that contributes to the development of ALD. The liver-specific peroxisomal enzyme hydroxyacid oxidase 1 (HAO1) has been found to be associated with chronic liver disease. But the role of HAO1 remains unknown in ALD. In our study, HAO1 was found to be decreased in ALD patients and EtOH-fed mice. Interestingly, HAO1 expression was reduced in primary hepatocytes, whereas HAO1 was elevated in peripheral blood monocytes from ALD patients and EtOH-fed mice liver macrophages as well as LPS-treated RAW264.7 cells. Moreover, HAO1 knockdown exacerbated the inflammatory response, while HAO1 overexpression inhibited inflammation in LPS-stimulated RAW264.7 cells. Additionally, overexpression or silencing of HAO1 in vitro significantly affected NF-κB signaling pathway. Collectively, the results revealed a key role of HAO1-mediated macrophage activation and may provide a potential target for treating ALD.

Keywords:  Alcohol-associated liver disease; HAO1; Inflammation; Macrophages; NF-κB pathway

DOI:  https://doi.org/10.1016/j.cellsig.2022.110436
Front Immunol. 2022 ;13 955671

Mfn2 is responsible for inhibition of the RIG-I/IRF7 pathway and activation of NLRP3 inflammasome in Seneca Valley virus-infected PK-15 cells to promote viral replication.

HuiDan Deng, Song Zhu, Ling Zhu, Jing Sun, YuChun Ding, FengQin Li, ZhiJie Jian, Jun Zhao, LiShuang Deng, JunLiang Deng, YouTian Deng, HongRui Guo, XianGang Sun, Si Yuan Lai, HuaQiao Tang, HengMin Cui, Liang Peng Ge, ZhiWen Xu.

  Seneca Valley virus (SVV), a non-enveloped positive single-stranded virus can cause vesicular disease in swine. However, the mechanisms by which SVV activates an innate immune response remain unknown. Mitofusin-2 (MFN2), a mitochondria-shaping protein regulating mitochondrial fusion and fission, plays a crucial role in innate immune responses. But, the roles of Mfn2 in SVV infection have not been elucidated. Here, we show that SVV inhibited Mfn2 expression and NLRP3 inflammasome, activating RIG-I/IRF7 signaling pathway to increase IFN-λ3 expression. Overexpression of Mfn2 inhibited RIG-I/IRF7 signaling pathway, thus decreasing IFN-λ3 expression and promoting SVV replication. Interestingly, overexpression of Mfn2 also activated NLRP3 inflammasome but did not inhibit SVV proliferation. That may mean the RIG-I/IRF7 signaling pathway plays a more important role in SVV proliferation in PK-15 cells. This study could provide important insights into the modulation of host metabolism during SVV infection and provide a strong theoretical basis for a better understanding of the pathogenic mechanism and immune activation mechanism of SVV.

Keywords:  Mfn2; NLRP3 inflammasome; RIG-I signaling pathway; SVV; innate immune response

DOI:  https://doi.org/10.3389/fimmu.2022.955671
Food Funct. 2022 Aug 11.

Modified highland barley regulates lipid metabolism, liver inflammation and gut microbiota in high-fat/cholesterol diet mice as revealed by LC-MS based metabonomics.

Xiang Li, Yan Du, Chengping Zhang, Zhaoxin Tu, Li Wang.

Highland barley (HB) displays a series of properties including regulation of lipid metabolism and attenuation of liver injury. Our study aimed to investigate the effect of modified highland barley (MHB) including fluidized highland barley (HB-1), extruded and puffed highland barley (HB-2), and ultrafine pulverized highland barley (HB-3) on lipid metabolism, liver inflammation, gut microbiota and metabolite profiles in mice fed with a high-fat/cholesterol diet (HFCD). 6 treatment groups were fed a normal control diet or an HFCD with or without MHB supplementation for 10 weeks. Results showed that MHB significantly improved lipid parameters, liver function and injury and blood glucose indexes related to hyperlipidemia compared with the HFCD group. In addition, MHB recovered the disorder of gut microbiota by increasing the Bacteroidetes/Firmicutes ratio and Lactobacillus and Allobaculum abundances and decreasing Proteobacteria abundance related to lipid metabolism bacteria. MHB reversed the decrease of short-chain fatty acid levels caused by the HFCD. Fecal metabolomics analysis showed that the important differential metabolites between HB-1 and HFCD were deoxycholic acid, myclobutanil and dibutyl phthalate, and the important differential metabolic pathways were arachidonic acid metabolism, ABC transporters and biosynthesis of unsaturated fatty acids. Results suggested that MHB especially HB-1 were better effective dietary intervention candidates to ameliorate hyperlipidemia compared with HB.

DOI: https://doi.org/10.1039/d2fo00882c
Res Vet Sci. 2022 Aug 01. pii: S0034-5288(22)00226-0. [Epub ahead of print]152 89-98

Dimethyl itaconic acid improves viability and steroidogenesis and supresses cytokine production in LPS-treated bovine ovarian granulosa cells by regulationg TLR4/nfkβ, NLRP3, JNK signaling pathways.

Mohammad Reza Tabandeh, Sadegh Jozaie, Zohre Ghotbedin, Saad Gorani.

  The stimulation of pro-inflammatory pathways by lipopolysaccharide (LPS) endotoxins is a key player in the pathological mechanisms involved in the development of ovarian dysfunctions in dairy cows. Dimethyl itaconate acid (DMIA) is a novel immunometabolite that has recently emerged as a regulator of inflammatory responses in mammals. The present study was undertaken to determine the anti-inflammatory effects of DMIA on bovine granulosa cells (GCs) and to explore its possible molecular mechanisms. The ovarian GCs were obtained from small follicles of dairy cows. The GCs were stimulated with 1 μg/mL LPS for 4 h and then treated with 250 μM DMIA for 12 h. The viability, production of pro-inflammatory cytokines, activation of inflammatory signaling pathways and synthesis of steroid hormones were evaluated in treated GCs. Our results showed that DMIA reduced the inflammatory responses in LPS stimulated GCs by down-regulating the expression of nod-like receptor family pyrin domain containing 3 inflammasome, and toll-like receptor 4 and by suppressing the phosphorylation of nuclear factor kappa B and c-Jun N-terminal kinase proteins. DMIA also attenuated the increased production of pro inflammatory cytokines (interleukin 6, tumor necrosis factor α and interleukin 1 beta (p < 0.01) in LPS stimulated GCs. Exposure of LPS stimulated GCs to DMIA improved the impaired steroidogenesis by up-regulation of steroid synthesis genes including 3-beta-hydroxysteroid dehydrogenase, follicle stimulating hormone receptor and cytochrome P450 aromatase. The results of the present study highlight the potential role of itaconic acid for the improvement of GCs inflammation in dairy cows with ovarian dysfunctions.

Keywords:  Dimethyl itaconate acid; Granulosa cells; Inflammatory pathways; Lipopolysaccharide; Steroidogenesis

DOI:  https://doi.org/10.1016/j.rvsc.2022.07.024
Front Immunol. 2022 ;13 946468

Immunometabolism characteristics and a potential prognostic risk model associated with TP53 mutations in breast cancer.

Mengping Jiang, Xiangyan Wu, Shengnan Bao, Xi Wang, Fei Qu, Qian Liu, Xiang Huang, Wei Li, Jinhai Tang, Yongmei Yin.

  TP53, a gene with high-frequency mutations, plays an important role in breast cancer (BC) development through metabolic regulation, but the relationship between TP53 mutation and metabolism in BC remains to be explored. Our study included 1,066 BC samples from The Cancer Genome Atlas (TCGA) database, 415 BC cases from the Gene Expression Omnibus (GEO) database, and two immunotherapy cohorts. We identified 92 metabolic genes associated with TP53 mutations by differential expression analysis between TP53 mutant and wild-type groups. Univariate Cox analysis was performed to evaluate the prognostic effects of 24 TP53 mutation-related metabolic genes. By unsupervised clustering and other bioinformatics methods, the survival differences and immunometabolism characteristics of the distinct clusters were illustrated. In a training set from TCGA cohort, we employed the least absolute shrinkage and selection operator (LASSO) regression method to construct a metabolic gene prognostic model associated with TP53 mutations, and the GEO cohort served as an external validation set. Based on bioinformatics, the connections between risk score and survival prognosis, tumor microenvironment (TME), immunotherapy response, metabolic activity, clinical characteristics, and gene characteristics were further analyzed. It is imperative to note that our model is a powerful and robust prognosis factor in comparison to other traditional clinical features and also has high accuracy and clinical usefulness validated by receiver operating characteristic (ROC) and decision curve analysis (DCA). Our findings deepen our understanding of the immune and metabolic characteristics underlying the TP53 mutant metabolic gene profile in BC, laying a foundation for the exploration of potential therapies targeting metabolic pathways. In addition, our model has promising predictive value in the prognosis of BC.

Keywords:  TP53; breast cancer; immune heterogeneity; metabolic heterogeneity; prognostic model

DOI:  https://doi.org/10.3389/fimmu.2022.946468
Nature. 2022 Aug 10.

Cyclic nucleotide-induced helical structure activates a TIR immune effector.

Gaëlle Hogrel, Abbie Guild, Shirley Graham, Hannah Rickman, Sabine Grüschow, Quentin Bertrand, Laura Spagnolo, Malcolm F White.

Cyclic nucleotide signalling is a key component of antiviral defence in all domains of life. Viral detection activates a nucleotide cyclase to generate a second messenger, resulting in activation of effector proteins. This is exemplified by the metazoan cGAS-STING innate immunity pathway1, which originated in bacteria2. These defence systems require a sensor domain to bind the cyclic nucleotide and are often coupled with an effector domain that, when activated, causes cell death by destroying essential biomolecules3. One example is the Toll/interleukin-1 receptor (TIR) domain, which degrades the essential cofactor NAD+ when activated in response to infection in plants and bacteria2,4,5 or during programmed nerve cell death6. Here we show that a bacterial antiviral defence system generates a cyclic tri-adenylate that binds to a TIR-SAVED effector, acting as the 'glue' to allow assembly of an extended superhelical solenoid structure. Adjacent TIR subunits interact to organize and complete a composite active site, allowing NAD+ degradation. Activation requires extended filament formation, both in vitro and in vivo. Our study highlights an example of large-scale molecular assembly controlled by cyclic nucleotides and reveals key details of the mechanism of TIR enzyme activation.

DOI: https://doi.org/10.1038/s41586-022-05070-9