bims-imicid 2022-09-11 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–09–11
thirty papers selected by
Dylan Ryan, University of Cambridge

Methionine metabolism controls the B cell EBV epigenome and viral latency.
Methionine restriction forces Epstein-Barr virus out of latency.
Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2.
Metabolic regulation and function of T helper cells in neuroinflammation.
The Critical Role of AMPKα1 in Regulating Autophagy and Mitochondrial Respiration in IL-15-Stimulated mTORC1Weak Signal-Induced T Cell Memory: An Interplay between Yin (AMPKα1) and Yang (mTORC1) Energy Sensors in T Cell Differentiation.
Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.
NLRC3 Expression in Macrophage Impairs Glycolysis and Host Immune Defence by Modulating the NF-κB-NFAT5 Complex During Sepsis-induced Immunosuppression.
Alternative pathways driven by STING: From innate immunity to lipid metabolism.
Modulation of dendritic cell metabolism by an MPLA-adjuvanted allergen product for specific immunotherapy.
Gasdermin D Deficiency Does Not Protect Mice from High-Fat Diet-Induced Glucose Intolerance and Adipose Tissue Inflammation.
Immunometabolism Dysfunction in the Pathophysiology and Treatment of Rheumatoid Arthritis.
Na/K-ATPase suppresses LPS-induced pro-inflammatory signaling through Lyn.
SCD2-mediated cooperative activation of IRF3-IRF9 regulatory circuit controls type I interferon transcriptome in CD4+ T cells.
Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.
The role of microglia immunometabolism in neurodegeneration: Focus on molecular determinants and metabolic intermediates of metabolic reprogramming.
GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection.
Shikonin ameliorated mice colitis by inhibiting dimerization and tetramerization of PKM2 in macrophages.
Metabolic profiling reveals new serum signatures to discriminate lupus nephritis from systemic lupus erythematosus.
GPR92 activation in islet macrophages controls β cell function in a diet-induced obesity model.
Cardiac immune cell infiltration associates with abnormal lipid metabolism.
Spermidine protects against acute kidney injury by modulating macrophage NLRP3 inflammasome activation and mitochondrial respiration in an eIF5A hypusination-related pathway.
Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response.
Circulating Dickkopf1 parallels metabolic adaptations and predicts disease trajectories in patients with Covid-19.
Human dental pulp cells modulate CD8+ T cell proliferation and efficiently degrade extracellular ATP to adenosine in vitro.
(Pro)renin receptor inhibition attenuated liver steatosis, inflammation, and fibrosis in mice with steatohepatitis.
Aerobic Glycolysis Promotes an NF-κB-Mediated Increase in PD-L1 Expression.
Lactic Acid Regulation: A Potential Therapeutic Option in Rheumatoid Arthritis.
HIF-1 stabilization in T cells hampers the control of Mycobacterium tuberculosis infection.
Heat stress-induced intestinal barrier damage and dimethylglycine alleviates via improving the metabolism function of microbiota gut brain axis.
Comparison of metabolism and biological properties among positional isomers of quercetin glucuronide in LPS- and RANKL-challenged RAW264.7 cells.

Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00351-5. [Epub ahead of print]34(9): 1280-1297.e9

Methionine metabolism controls the B cell EBV epigenome and viral latency.

Rui Guo, Jin Hua Liang, Yuchen Zhang, Michael Lutchenkov, Zhixuan Li, Yin Wang, Vicenta Trujillo-Alonso, Rishi Puri, Lisa Giulino-Roth, Benjamin E Gewurz.

  Epstein-Barr virus (EBV) subverts host epigenetic pathways to switch between viral latency programs, colonize the B cell compartment, and reactivate. Within memory B cells, the reservoir for lifelong infection, EBV genomic DNA and histone methylation marks restrict gene expression. But this epigenetic strategy also enables EBV-infected tumors, including Burkitt lymphomas, to evade immune detection. Little is known about host cell metabolic pathways that support EBV epigenome landscapes. We therefore used amino acid restriction, metabolomic, and CRISPR approaches to identify that an abundant methionine supply and interconnecting methionine and folate cycles maintain Burkitt EBV gene silencing. Methionine restriction, or methionine cycle perturbation, hypomethylated EBV genomes and de-repressed latent membrane protein and lytic gene expression. Methionine metabolism also shaped EBV latency gene regulation required for B cell immortalization. Dietary methionine restriction altered murine Burkitt xenograft metabolomes and de-repressed EBV immunogens in vivo. These results highlight epigenetic/immunometabolism crosstalk supporting the EBV B cell life cycle and suggest therapeutic approaches.

Keywords:  dietary amino acid restriction; folate metabolism; gamma-herpesvirus; immunometabolism; lytic reactivation; methionine cycle; methionine metabolism; one-carbon metabolism; tumor virus; viral latency

DOI:  https://doi.org/10.1016/j.cmet.2022.08.008
Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00352-7. [Epub ahead of print]34(9): 1229-1231

Methionine restriction forces Epstein-Barr virus out of latency.

Sriraksha Bharadwaj Kashyap, Racheal Mulondo, Peter J Mullen.

EBV gene expression is repressed during viral latency to prevent an immune response, but it is not known how metabolism contributes to this silencing. In this issue of Cell Metabolism, Guo et al. describe how methionine restriction reactivates the expression of EBV genes, offering new therapeutic approaches against EBV-driven diseases.

DOI: https://doi.org/10.1016/j.cmet.2022.08.009
Nat Commun. 2022 Sep 05. 13(1): 5208

Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2.

Tianshi Feng, Xuemei Zhao, Ping Gu, Wah Yang, Cunchuan Wang, Qingyu Guo, Qiaoyun Long, Qing Liu, Ying Cheng, Jin Li, Cynthia Kwan Yui Cheung, Donghai Wu, Xinyu Kong, Yong Xu, Dewei Ye, Shuang Hua, Kerry Loomes, Aimin Xu, Xiaoyan Hui.

Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (Ldha), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1β (IL-1β). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1β was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.

DOI: https://doi.org/10.1038/s41467-022-32871-3
Semin Immunopathol. 2022 Sep 06.

Metabolic regulation and function of T helper cells in neuroinflammation.

Martina Spiljar, Vijay K Kuchroo.

  Neuroinflammatory conditions such as multiple sclerosis (MS) are initiated by pathogenic immune cells invading the central nervous system (CNS). Autoreactive CD4+ T helper cells are critical players that orchestrate the immune response both in MS and in other neuroinflammatory autoimmune diseases including animal models that have been developed for MS. T helper cells are classically categorized into different subsets, but heterogeneity exists within these subsets. Untangling the more complex regulation of these subsets will clarify their functional roles in neuroinflammation. Here, we will discuss how differentiation, immune checkpoint pathways, transcriptional regulation and metabolic factors determine the function of CD4+ T cell subsets in CNS autoimmunity. T cells rely on metabolic reprogramming for their activation and proliferation to meet bioenergetic demands. This includes changes in glycolysis, glutamine metabolism and polyamine metabolism. Importantly, these pathways were recently also implicated in the fine tuning of T cell fate decisions during neuroinflammation. A particular focus of this review will be on the Th17/Treg balance and intra-subset functional states that can either promote or dampen autoimmune responses in the CNS and thus affect disease outcome. An increased understanding of factors that could tip CD4+ T cell subsets and populations towards an anti-inflammatory phenotype will be critical to better understand neuroinflammatory diseases and pave the way for novel treatment paradigms.

Keywords:  Experimental autoimmune encephalomyelitis; Immunometabolism; Multiple sclerosis; Neuroimmunology; Neuroinflammation; Th17 cells

DOI:  https://doi.org/10.1007/s00281-022-00959-z
Int J Mol Sci. 2022 Aug 23. pii: 9534. [Epub ahead of print]23(17):

The Critical Role of AMPKα1 in Regulating Autophagy and Mitochondrial Respiration in IL-15-Stimulated mTORC1Weak Signal-Induced T Cell Memory: An Interplay between Yin (AMPKα1) and Yang (mTORC1) Energy Sensors in T Cell Differentiation.

Anjuman Ara, Zhaojia Wu, Aizhang Xu, Khawaja Ashfaque Ahmed, Scot C Leary, Md Fahmid Islam, Rajni Chibbar, Yue Wu, Jim Xiang.

  Two common γ-chain family cytokines IL-2 and IL-15 stimulate the same mammalian target of rapamycin complex-1 (mTORC1) signaling yet induce effector T (TE) and memory T (TM) cell differentiation via a poorly understood mechanism(s). Here, we prepared in vitro IL-2-stimulated TE (IL-2/TE) and IL-15-stimulated TM (IL-15/TM) cells for characterization by flow cytometry, Western blotting, confocal microscopy and Seahorse-assay analyses. We demonstrate that IL-2 and IL-15 stimulate strong and weak mTORC1 signals, respectively, which lead to the formation of CD62 ligand (CD62L)- killer cell lectin-like receptor subfamily G member-1 (KLRG)+ IL-2/TE and CD62L+KLRG- IL-15/TM cells with short- and long-term survival following their adoptive transfer into mice. The IL-15/mTORC1Weak signal activates the forkhead box-O-1 (FOXO1), T cell factor-1 (TCF1) and Eomes transcriptional network and the metabolic adenosine monophosphate-activated protein kinase-α-1 (AMPKα1), Unc-51-like autophagy-activating kinase-1 (ULK1) and autophagy-related gene-7 (ATG7) axis, increasing the expression of mitochondrial regulators aquaporin-9 (AQP9), mitochondrial transcription factor-A (TFAM), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), carnitine palmitoyl transferase-1 (CPT1α), microtubule-associated protein light chain-3 II (LC3II), Complex I and ortic atrophy-1 (OPA1), leading to promoting mitochondrial biogenesis and fatty-acid oxidation (FAO). Interestingly, AMPKα1 deficiency abrogates these downstream responses to IL-15/mTORC1Weak signaling, leading to the upregulation of mTORC1 and hypoxia-inducible factor-1α (HIF-1α), a metabolic switch from FAO to glycolysis and reduced cell survival. Taken together, our data demonstrate that IL-15/mTORC1Weak signaling controls T-cell memory via activation of the transcriptional FOXO1-TCF1-Eomes and metabolic AMPKα1-ULK1-ATG7 pathways, a finding that may greatly impact the development of efficient vaccines and immunotherapies for the treatment of cancer and infectious diseases.

Keywords:  AMPKα1; FOXO1; IL-15; T-cell memory; autophagy; fatty acid oxidation; mTORC1; mitochondrial biogenesis

DOI:  https://doi.org/10.3390/ijms23179534
Cell Metab. 2022 Aug 30. pii: S1550-4131(22)00353-9. [Epub ahead of print]

Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.

Nicholas Borcherding, Wentong Jia, Rocky Giwa, Rachael L Field, John R Moley, Benjamin J Kopecky, Mandy M Chan, Bin Q Yang, Jessica M Sabio, Emma C Walker, Omar Osorio, Andrea L Bredemeyer, Terri Pietka, Jennifer Alexander-Brett, Sharon Celeste Morley, Maxim N Artyomov, Nada A Abumrad, Joel Schilling, Kory Lavine, Clair Crewe, Jonathan R Brestoff.

  Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress.

Keywords:  CD36; EXT1; aging; beige fat; brown adipose tissue; cell-free mitochondria; fatty acids; heparan sulfate; horizontal mitochondria transfer; intercellular mitochondria transfer; lipids; macrophage; mitochondria; obesity; palmitate; white adipose tissue

DOI:  https://doi.org/10.1016/j.cmet.2022.08.010
Mol Ther. 2022 Sep 05. pii: S1525-0016(22)00552-4. [Epub ahead of print]

NLRC3 Expression in Macrophage Impairs Glycolysis and Host Immune Defence by Modulating the NF-κB-NFAT5 Complex During Sepsis-induced Immunosuppression.

Jiqian Xu, Chenggang Gao, Yajun He, Xiangzhi Fang, Deyi Sun, Zhekang Peng, Hairong Xiao, Miaomiao Sun, Pei Zhang, Ting Zhou, Xiaobo Yang, Yuan Yu, Ruiting Li, Xiaojing Zou, Huaqing Shu, Yang Qiu, Xi Zhou, Shiying Yuan, Shanglong Yao, You Shang.

  Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis, however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional coactivator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harbouring a macrophage-specific NLRC3 deletion vector significantly improved the defence of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identifies potential therapeutic targets.

Keywords:  NLRC3; gene therapy; host immune defence; immunometabolism; macrophages; sepsis-induced immunosuppression

DOI:  https://doi.org/10.1016/j.ymthe.2022.08.023
Cytokine Growth Factor Rev. 2022 Sep 01. pii: S1359-6101(22)00071-5. [Epub ahead of print]

Alternative pathways driven by STING: From innate immunity to lipid metabolism.

Isabelle K Vila, Soumyabrata Guha, Joanna Kalucka, David Olagnier, Nadine Laguette.

  The Stimulator of Interferon Genes (STING) is a major adaptor protein that is central to the initiation of type I interferon responses and proinflammatory signalling. STING-dependent signalling is triggered by the presence of cytosolic nucleic acids that are generated following pathogen infection or cellular stress. Beyond this central role in controlling immune responses through the production of cytokines and chemokines, recent reports have uncovered inflammation-independent STING functions. Amongst these, a rapidly growing body of evidence demonstrates a key role of STING in controlling metabolic pathways at several levels. Since immunity and metabolic homeostasis are tightly interconnected, these findings deepen our understanding of the involvement of STING in human pathologies. Here, we discuss these findings and reflect on their impact on our current understanding of how nucleic acid immunity controls homeostasis and promotes pathological outcomes.

Keywords:  Inflammation; Innate immunity; Lipid metabolism; Metabolism; STING

DOI:  https://doi.org/10.1016/j.cytogfr.2022.08.006
Front Immunol. 2022 ;13 916491

Modulation of dendritic cell metabolism by an MPLA-adjuvanted allergen product for specific immunotherapy.

Jennifer Zimmermann, Alexandra Goretzki, Clara Meier, Sonja Wolfheimer, Yen-Ju Lin, Hannah Rainer, Maren Krause, Saskia Wedel, Gerd Spies, Frank Führer, Stefan Vieths, Stephan Scheurer, Stefan Schülke.

   Background: Recently, bacterial components were shown to enhance immune responses by shifting immune cell metabolism towards glycolysis and lactic acid production, also known as the Warburg Effect. Currently, the effect of allergen products for immunotherapy (AIT) and commercial vaccines on immune cell metabolism is mostly unknown.
Objective: To investigate the effect of AIT products (adjuvanted with either MPLA or Alum) on myeloid dendritic cell (mDC) metabolism and activation.
Methods: Bone marrow-derived mDCs were stimulated with five allergoid-based AIT products (one adjuvanted with MPLA, four adjuvanted with Alum) and two MPLA-adjuvanted vaccines and analyzed for their metabolic activation, expression of cell surface markers, and cytokine secretion by ELISA. mDCs were pre-incubated with either immunological or metabolic inhibitors or cultured in glucose- or glutamine-free culture media and subsequently stimulated with the MPLA-containing AIT product (AIT product 1). mDCs were co-cultured with allergen-specific CD4+ T cells to investigate the contribution of metabolic pathways to the T cell priming capacity of mDCs stimulated with AIT product 1.
Results: Both the MPLA-containing AIT product 1 and commercial vaccines, but not the Alum-adjuvanted AIT products, activated Warburg metabolism and TNF-α secretion in mDCs. Further experiments focused on AIT product 1. Metabolic analysis showed that AIT product 1 increased glycolytic activity while also inducing the secretion of IL-1β, IL-10, IL-12, and TNF-α. Both rapamycin (mTOR-inhibitor) and SP600125 (SAP/JNK MAPK-inhibitor) dose-dependently suppressed the AIT product 1-induced Warburg Effect, glucose consumption, IL-10-, and TNF-α secretion. Moreover, both glucose- and glutamine deficiency suppressed secretion of all investigated cytokines (IL-1β, IL-10, and TNF-α). Glucose metabolism in mDCs was also critical for the (Th1-biased) T cell priming capacity of AIT product 1-stimulated mDCs, as inhibition of mTOR signaling abrogated their ability to induce Th1-responses.
Conclusion: The AIT product and commercial vaccines containing the adjuvant MPLA were shown to modulate the induction of immune responses by changing the metabolic state of mDCs. Better understanding the mechanisms underlying the interactions between cell metabolism and immune responses will allow us to further improve vaccine development and AIT.

Keywords:  MPLA: monophosphoryl lipid A; Warburg Effect; allergen specific immunotherapy; immune metabolism; vaccine

DOI:  https://doi.org/10.3389/fimmu.2022.916491
Mediators Inflamm. 2022 ;2022 7853482

Gasdermin D Deficiency Does Not Protect Mice from High-Fat Diet-Induced Glucose Intolerance and Adipose Tissue Inflammation.

Eun Bi Ma, Hafiz Muhammad Ahmad Javaid, Do-Hyeon Jung, Jong-Hwan Park, Joo Young Huh.

The adipose tissue NLRP3 inflammasome has recently emerged as a contributor to obesity-related metabolic inflammation. Recent studies have demonstrated that the activation of the NLRP3 inflammasome cleaves gasdermin D (GSDMD) and induces pyroptosis, a proinflammatory programmed cell death. However, whether GSDMD is involved in the regulation of adipose tissue function and the development of obesity-induced metabolic disease remains unknown. The aim of the present study was to investigate the role of GSDMD in adipose tissue inflammation as well as whole-body metabolism using GSDMD-deficient mice fed a high-fat diet (HFD) for 30 weeks. The effects of GSDMD deficiency on adipose tissue, liver, and isolated macrophages from wild-type (WT) and GSDMD knockout (KO) mice were examined. In addition, 3T3-L1 cells were used to examine the expression of GSDMD during adipogenesis. The results demonstrate that although HFD-induced inflammation was partly ameliorated in isolated macrophages and liver, adipose tissue remained unaffected by GSDMD deficiency. Compared with the WT HFD mice, GSDMD KO HFD mice exhibited a mild increase in HFD-induced glucose intolerance with increased systemic and adipose tissue IL-1β levels. Interestingly, GSDMD deficiency caused accumulation of fat mass when challenged with HFD, partly by suppressing the expression of peroxisome proliferator-activated receptor gamma (PPARγ). The expression of GSDMD mRNA and protein was dramatically suppressed during adipocyte differentiation and was inversely correlated with PPARγ expression. Together, these findings indicate that GSDMD is not a prerequisite for HFD-induced adipose tissue inflammation and suggest a noncanonical function of GSDMD in regulation of fat mass through PPARγ.

DOI: https://doi.org/10.1155/2022/7853482
Curr Med Chem. 2022 Sep 07.

Immunometabolism Dysfunction in the Pathophysiology and Treatment of Rheumatoid Arthritis.

Maryam Masoumi, Nader Hashemi, Fatemeh Moadab, Mojtaba Didehdar, Rahim Farahani, Hossein Khorramdelazad, Amirhossein Sahebkar, Thomas P Johnston, Jafar Karami.

  Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and joint damage. Systemic complications and progressive disability are burdens that lead to a significant socio-economic cost in patients with RA. Current RA biomarkers used in predicting, diagnosing, and monitoring the treatment of the disease have not been very successful. Moreover, only 60% of patients show a satisfactory response to current biological and conventional therapies. Studies on immunometabolism have suggested that dysregulated enzymes, transcription factors, metabolites, and metabolic pathways could be considered potential therapeutic targets for the treatment of RA. Factors such as the high concentration of various intermediate molecules arising from metabolism, hypoxia, lack of nutrients, and other metabolic alterations affect local immune responses and preserve a state of chronic inflammation in synovial tissues. Fortunately, in vitro and in vivo studies have shown that targeting specific metabolic pathways is associated with a decreased level of inflammation. Specifically, targeting metabolic intermediates, such as succinate or lactate, has shown promising clinical outcomes in RA treatment. These findings open an avenue for the identification of novel biomarkers for diagnosis, prognosis, and determining the success of various treatments in RA patients, as well as the discovery of new therapeutic targets.

Keywords:  Arthritis; Chronic; Immunometabolism; Inflammation; Rheumatoid; Treatment

DOI:  https://doi.org/10.2174/0929867329666220907151213
iScience. 2022 Sep 16. 25(9): 104963

Na/K-ATPase suppresses LPS-induced pro-inflammatory signaling through Lyn.

Jue Zhang, Jackie Chang, Mirza Ahmar Beg, Wenxin Huang, Yiqiong Zhao, Wen Dai, Xiaopeng Wu, Weiguo Cui, Sneha S Pillai, Hari Vishal Lakhani, Komal Sodhi, Joseph I Shapiro, Daisy Sahoo, Ze Zheng, Roy L Silverstein, Yiliang Chen.

  Na/K-ATPase (NKA), besides its ion transporter function, is a signal transducer by regulating Src family kinases (SFK). The signaling NKA contributes to oxidized LDL-induced macrophage foam cell formation and interacts with TLR4. However, its role in lipopolysaccharides (LPS)-induced signaling and glycolytic switch in macrophages remains unclear. Using peritoneal macrophages from NKA α1 haploinsufficient mice (NKA α1+/-), we found that NKA α1 haploinsufficiency led to enhanced LPS-stimulated NF-κB pathway, ROS signaling, and pro-inflammatory cytokines. Intraperitoneal injection of LPS resulted in more severe lung inflammation and injury with lower survival rate in NKA α1+/- mice. Additionally, LPS induced a higher extent of the metabolic switch from oxidative phosphorylation to glycolysis. Mechanistically, NKA α1 interacted with TLR4 and Lyn. The presence of NKA α1 in this complex attenuated Lyn activation by LPS, which subsequently restricted the downstream ROS and NF-κB signaling. In conclusion, we demonstrated that NKA α1 suppresses LPS-induced macrophage pro-inflammatory signaling through Lyn.

Keywords:  Biological sciences; immunology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2022.104963
Front Immunol. 2022 ;13 904875

SCD2-mediated cooperative activation of IRF3-IRF9 regulatory circuit controls type I interferon transcriptome in CD4+ T cells.

Toshio Kanno, Keisuke Miyako, Takahiro Nakajima, Satoru Yokoyama, Shigemi Sasamoto, Hikari K Asou, Osamu Ohara, Toshinori Nakayama, Yusuke Endo.

  Type I interferons (type I-IFN) are critical for the host defense to viral infection, and at the same time, the dysregulation of type I-IFN responses leads to autoinflammation or autoimmunity. Recently, we reported that the decrease in monounsaturated fatty acid caused by the genetic deletion of Scd2 is essential for the activation of type I-IFN signaling in CD4+ Th1 cells. Although interferon regulatory factor (IRF) is a family of homologous proteins that control the transcription of type I-IFN and interferon stimulated genes (ISGs), the member of the IRF family that is responsible for the type I-IFN responses induced by targeting of SCD2 remains unclear. Here, we report that the deletion of Scd2 triggered IRF3 activation for type I-IFN production, resulting in the nuclear translocation of IRF9 to induce ISG transcriptome in Th1 cells. These data led us to hypothesize that IRF9 plays an essential role in the transcriptional regulation of ISGs in Scd2-deleted (sgScd2) Th1 cells. By employing ChIP-seq analyses, we found a substantial percentage of the IRF9 target genes were shared by sgScd2 and IFNβ-treated Th1 cells. Importantly, our detailed analyses identify a unique feature of IRF9 binding in sgScd2 Th1 cells that were not observed in IFNβ-treated Th1 cells. In addition, our combined analyses of transcriptome and IRF9 ChIP-seq revealed that the autoimmunity related genes, which increase in patient with SLE, were selectively increased in sgScd2 Th1 cells. Thus, our findings provide novel mechanistic insights into the process of fatty acid metabolism that is essential for the type I-IFN response and the activation of the IRF family in CD4+ T cells.

Keywords:  CD4+ T cells; ChIP-seq; IFR9; IRF3; RNA-seq; SCD2; fatty acid metabolism

DOI:  https://doi.org/10.3389/fimmu.2022.904875
Nat Commun. 2022 Sep 06. 13(1): 4981

Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.

Qiang Feng, Zhida Liu, Xuexin Yu, Tongyi Huang, Jiahui Chen, Jian Wang, Jonathan Wilhelm, Suxin Li, Jiwon Song, Wei Li, Zhichen Sun, Baran D Sumer, Bo Li, Yang-Xin Fu, Jinming Gao.

Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.

DOI: https://doi.org/10.1038/s41467-022-32521-8
Biomed Pharmacother. 2022 Sep;pii: S0753-3322(22)00801-0. [Epub ahead of print]153 113412

The role of microglia immunometabolism in neurodegeneration: Focus on molecular determinants and metabolic intermediates of metabolic reprogramming.

Qixue Wang, Mengna Lu, Xinyu Zhu, Xinyi Gu, Ting Zhang, Chenyi Xia, Li Yang, Ying Xu, Mingmei Zhou.

  Microglia, resident macrophages that act as the brain's innate immune cells, play a key role in initiating a defense response to the infection or neuroinflammation of the host. Once a broad spectrum of dangers is confronted, microglia get triggered and transform their role against immune stimuli. Recent studies have shown that remarkable metabolic changes present in activated microglia affect their immune function. Given that the important role of microglia in the progression of neurodegeneration is widely recognized, it is crucial to know whether metabolic reprogramming of microglia also presents in neurodegeneration and how this may influence their role in neurodegeneration progression. This paper provides an overview of the metabolic reprogramming of microglia, the major pathways involved in recent advances in five major neurodegenerative diseases of aging (NDAs), including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), etc. And then we elucidated their impacts on the disease progression of neurodegeneration. Furthermore, growing evidence suggests that microbiota-derived metabolites, including acetate, N6-carboxymethyllysine (CML), and isoamylamine (IAA), regulate metabolic pathways and functions of microglia, and play a crucial role in cellular homeostasis. We shed light on this topic and concluded these metabolites are potential therapeutic targets for NDAs.

Keywords:  Immunometabolism; Metabolic reprogramming; Microglia; Neurodegeneration; Neuroinflammation; Phenotype

DOI:  https://doi.org/10.1016/j.biopha.2022.113412
J Exp Med. 2022 Nov 07. pii: e20220504. [Epub ahead of print]219(11):

GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection.

Eduardo P Amaral, Taylor W Foreman, Sivaranjani Namasivayam, Kerry L Hilligan, Keith D Kauffman, Caio Cesar Barbosa Bomfim, Diego L Costa, Beatriz Barreto-Duarte, Clarissa Gurgel-Rocha, Monique Freire Santana, Marcelo Cordeiro-Santos, Elsa Du Bruyn, Catherine Riou, Kate Aberman, Robert John Wilkinson, Daniel L Barber, Katrin D Mayer-Barber, Bruno B Andrade, Alan Sher.

Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation-mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.

DOI: https://doi.org/10.1084/jem.20220504
Front Pharmacol. 2022 ;13 926945

Shikonin ameliorated mice colitis by inhibiting dimerization and tetramerization of PKM2 in macrophages.

Baoyuan Huang, Qiumei Wang, Lin Jiang, Shuru Lu, Chengcheng Li, Chunqi Xu, Caiyan Wang, Enxin Zhang, Xiaojun Zhang.

  Dysregulated immune response plays a pivotal role in Ulcerative colitis. In lamina propria of inflammatory colonic mucosa, macrophages tend to polarize into M1 type and metabolically reprogram to aerobic glycolysis. PKM2 orchestrates glucose metabolic switch in macrophages, which tetramer has high pyruvate kinase activity, while which dimer mainly works as a protein kinase to stabilize HIF-1α and mediate anabolism. Shikonin is a potent PKM2 inhibitor derived from traditional Chinese medicine Arnebiae Radix with anti-inflammatory and anticarcinogen activities. However, it is unclear which conformation of PKM2 is inhibited by Shikonin, and whether this inhibition mediates pharmacological effect of Shikonin. In this study, we examined the efficacy of Shikonin on dextran sulfate sodium-induced mice colitis and determined the states of PKM2 aggregation after Shikonin treatment. Results showed that Shikonin dose-dependently alleviated mice colitis, down-regulated expression of F4/80, iNOS and CD86, decreased IFN-γ, IL-1β, IL-6 and TNF-α, while increased IL-10 in mice colon. Furthermore, Shikonin suppressed the pyruvate, lactate production and glucose consumption, inhibited the pyruvate kinase activity and nuclear translocation of PKM2, and decreased both dimerization and tetramerization of PKM2 in macrophages. In vitro assay revealed that Shikonin bounded to PKM2 protein, inhibited the formation of both dimer and tetramer, while promoted aggregation of PKM2 macromolecular polymer. TEPP-46, an activator of PKM2 tetramerization, attenuated the ameliorative effect of Shikonin on disuccinimidyl suberate mice. In summary, Shikonin improved mice colitis, which mechanism may be mediated by inhibiting dimerization and tetramerization of PKM2, suppressing aerobic glycolysis reprogram, improving mitochondrial dynamic, and therefore alleviating inflammatory response of macrophages.

Keywords:  PKM2; macrophage; polymer; shikonin; ulcerative colitis

DOI:  https://doi.org/10.3389/fphar.2022.926945
Front Immunol. 2022 ;13 967371

Metabolic profiling reveals new serum signatures to discriminate lupus nephritis from systemic lupus erythematosus.

Yamei Zhang, Lingling Gan, Jie Tang, Dan Liu, Gang Chen, Bei Xu.

   Background: Lupus nephritis (LN) occurs in 50% of patients with systemic lupus erythematosus (SLE), causing considerable morbidity and even mortality. Previous studies had shown the potential of metabolic profiling in the diagnosis of SLE or LN. However, few metabonomics studies have attempted to distinguish SLE from LN based on metabolic changes. The current study was designed to find new candidate serum signatures that could differentiate LN from SLE patients using a non-targeted metabonomics method based on ultra high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).
Method: Metabolic profiling of sera obtained from 21 healthy controls, 52 SLE patients and 43 LN patients. We used SPSS 25.0 for statistical analysis. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and metabolic pathway analysis were used to analyze the metabolic data.
Results: Upon comparison of SLE and LN groups, 28 differential metabolites were detected, the majority of which were lipids and amino acids. Glycerolphospholipid metabolism, pentose and glucuronate interconversions and porphyrin and chlorophyll metabolism were obviously enriched in LN patients versus those with SLE. Among the 28 characteristic metabolites, five key serum metabolites including SM d34:2, DG (18:3(9Z,12Z,15Z)/20:5(5Z,8Z,11Z,14Z,17Z)/0:0), nervonic acid, Cer-NS d27:4, and PC (18:3(6Z,9Z,12Z)/18:3(6Z,9Z,12Z) performed higher diagnostic performance in discriminating LN from SLE (all AUC > 0.75). Moreover, combined analysis of neuritic acid, C1q, and CysC (AUC = 0.916) produced the best combined diagnosis.
Conclusion: This study identified five serum metabolites that are potential indicators for the differential diagnosis of SLE and LN. Glycerolphospholipid metabolism may play an important role in the development of SLE to LN. The metabolites we screened can provide more references for the diagnosis of LN and more support for the pathophysiological study of SLE progressed to LN.

Keywords:  high performance liquid chromatography tandem mass spectrometry; lupus nephritis; non-targeted metabonomics; serum signatures; systemic lupus erythematosus

DOI:  https://doi.org/10.3389/fimmu.2022.967371
J Clin Invest. 2022 Sep 06. pii: e160097. [Epub ahead of print]

GPR92 activation in islet macrophages controls β cell function in a diet-induced obesity model.

Camila O de Souza, Vivian A Paschoal, Xue-Nan Sun, Lavanya Vishvanath, Qianbin Zhang, Mengle Shao, Toshiharu Onodera, Shiuhwei Chen, Nolwenn Joffin, Lorena Ma Bueno, Rana K Gupta, Da Young Oh.

  The molecular mechanisms underlying obesity-induced increase in β cell mass, and the resulting β cell dysfunction need to be elucidated further. Our study revealed that GPR92, expressed in islet macrophages, is modulated by dietary interventions in metabolic tissues. Therefore, we aimed to define the role of GPR92 in islet inflammation by using high fat diet (HFD)-induced obese mouse model. GPR92 knockout mice exhibited glucose intolerance and reduced insulin level, despite the enlarged pancreatic islets, and increased islet macrophage content and inflammation level (compared to those in wild type mice). These results indicate that the lack of GPR92 in islet macrophages can cause β cell dysfunction, leading to disrupted glucose homeostasis. Alternatively, GPR92 agonist, farnesyl pyrophosphate (FPP) stimulation results in the inhibition of HFD-induced islet inflammation and increased insulin secretion in WT mice, but not in GPR92 KO mice. Thus, our study suggests that GPR92 can be a potential target to alleviate β cell dysfunction via the inhibition of islet inflammation associated with the progression of diabetes.

Keywords:  Diabetes; G proteincoupled receptors; Inflammation; Islet cells; Metabolism

DOI:  https://doi.org/10.1172/JCI160097
Front Cardiovasc Med. 2022 ;9 948332

Cardiac immune cell infiltration associates with abnormal lipid metabolism.

Vincenza Cifarelli, Ondrej Kuda, Kui Yang, Xinping Liu, Richard W Gross, Terri A Pietka, Gyu Seong Heo, Deborah Sultan, Hannah Luehmann, Josie Lesser, Morgan Ross, Ira J Goldberg, Robert J Gropler, Yongjian Liu, Nada A Abumrad.

  CD36 mediates the uptake of long-chain fatty acids (FAs), a major energy substrate for the myocardium. Under excessive FA supply, CD36 can cause cardiac lipid accumulation and inflammation while its deletion reduces heart FA uptake and lipid content and increases glucose utilization. As a result, CD36 was proposed as a therapeutic target for obesity-associated heart disease. However, more recent reports have shown that CD36 deficiency suppresses myocardial flexibility in fuel preference between glucose and FAs, impairing tissue energy balance, while CD36 absence in tissue macrophages reduces efferocytosis and myocardial repair after injury. In line with the latter homeostatic functions, we had previously reported that CD36-/- mice have chronic subclinical inflammation. Lipids are important for the maintenance of tissue homeostasis and there is limited information on heart lipid metabolism in CD36 deficiency. Here, we document in the hearts of unchallenged CD36-/- mice abnormalities in the metabolism of triglycerides, plasmalogens, cardiolipins, acylcarnitines, and arachidonic acid, and the altered remodeling of these lipids in response to an overnight fast. The hearts were examined for evidence of inflammation by monitoring the presence of neutrophils and pro-inflammatory monocytes/macrophages using the respective positron emission tomography (PET) tracers, 64Cu-AMD3100 and 68Ga-DOTA-ECL1i. We detected significant immune cell infiltration in unchallenged CD36-/- hearts as compared with controls and immune infiltration was also observed in hearts of mice with cardiomyocyte-specific CD36 deficiency. Together, the data show that the CD36-/- heart is in a non-homeostatic state that could compromise its stress response. Non-invasive immune cell monitoring in humans with partial or total CD36 deficiency could help evaluate the risk of impaired heart remodeling and disease.

Keywords:  CD36; PET tracers; cardiac inflammation; eicosanoids; lipidomics; macrophage

DOI:  https://doi.org/10.3389/fcvm.2022.948332
Mol Med. 2022 09 04. 28(1): 103

Spermidine protects against acute kidney injury by modulating macrophage NLRP3 inflammasome activation and mitochondrial respiration in an eIF5A hypusination-related pathway.

Xianzhi Li, Xiaojun Zhou, Xigao Liu, Xiaoyun Li, Xianzhou Jiang, Benkang Shi, Shuo Wang.

   BACKGROUND: Acute kidney injury (AKI) is still a critical problem in clinical practice, with a heavy burden for national health system around the world. It is notable that sepsis is the predominant cause of AKI for patients in the intensive care unit and the mortality remains considerably high. The treatment for AKI relies on supportive therapies and almost no specific treatment is currently available. Spermidine is a naturally occurring polyamine with pleiotropic effects. However, the renoprotective effect of spermidine and the underlying mechanism remain elusive.
METHODS: We employed mice sepsis-induced AKI model and explored the potential renoprotective effect of spermidine in vivo with different administration time and routes. Macrophage depleting was utilized to probe the role of macrophage. In vitro experiments were conducted to examine the effect of spermidine on macrophage cytokine secretion, NLRP3 inflammasome activation and mitochondrial respiration.
RESULTS: We confirmed that spermidine improves AKI with different administration time and routes and that macrophages serves as an essential mediator in this protective effect. Meanwhile, spermidine downregulates NOD-like receptor protein 3 (NLRP3) inflammasome activation and IL-1 beta production in macrophages directly. Mechanically, spermidine enhances mitochondrial respiration capacity and maintains mitochondria function which contribute to the NLRP3 inhibition. Importantly, we showed that eukaryotic initiation factor 5A (eIF5A) hypusination plays an important role in regulating macrophage bioactivity.
CONCLUSIONS: Spermidine administration practically protects against sepsis-induced AKI in mice and macrophages serve as an essential mediator in this protective effect. Our study identifies spermidine as a promising pharmacologic approach to prevent AKI.

Keywords:  Acute kidney injury; Macrophage; NLRP3; Polyamine; Spermidine

DOI:  https://doi.org/10.1186/s10020-022-00533-1
Commun Biol. 2022 Sep 09. 5(1): 944

Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response.

Isabelle Weinhofer, Agnieszka Buda, Markus Kunze, Zsofia Palfi, Matthäus Traunfellner, Sarah Hesse, Andrea Villoria-Gonzalez, Jörg Hofmann, Simon Hametner, Günther Regelsberger, Ann B Moser, Florian Eichler, Stephan Kemp, Jan Bauer, Jörn-Sven Kühl, Sonja Forss-Petter, Johannes Berger.

Very long-chain fatty acids (VLCFA) are critical for human cytomegalovirus replication and accumulate upon infection. Here, we used Epstein-Barr virus (EBV) infection of human B cells to elucidate how herpesviruses target VLCFA metabolism. Gene expression profiling revealed that, despite a general induction of peroxisome-related genes, EBV early infection decreased expression of the peroxisomal VLCFA transporters ABCD1 and ABCD2, thus impairing VLCFA degradation. The mechanism underlying ABCD1 and ABCD2 repression involved RNA interference by the EBV-induced microRNAs miR-9-5p and miR-155, respectively, causing significantly increased VLCFA levels. Treatment with 25-hydroxycholesterol, an antiviral innate immune modulator produced by macrophages, restored ABCD1 expression and reduced VLCFA accumulation in EBV-infected B-lymphocytes, and, upon lytic reactivation, reduced virus production in control but not ABCD1-deficient cells. Finally, also other herpesviruses and coronaviruses target ABCD1 expression. Because viral infection might trigger neuroinflammation in X-linked adrenoleukodystrophy (X-ALD, inherited ABCD1 deficiency), we explored a possible link between EBV infection and cerebral X-ALD. However, neither immunohistochemistry of post-mortem brains nor analysis of EBV seropositivity in 35 X-ALD children supported involvement of EBV in the onset of neuroinflammation. Collectively, our findings indicate a previously unrecognized, pivotal role of ABCD1 in viral infection and host defence, prompting consideration of other viral triggers in cerebral X-ALD.

DOI: https://doi.org/10.1038/s42003-022-03867-y
J Clin Endocrinol Metab. 2022 Sep 08. pii: dgac514. [Epub ahead of print]

Circulating Dickkopf1 parallels metabolic adaptations and predicts disease trajectories in patients with Covid-19.

Nikolai P Jaschke, Alexander M Funk, Sophie Jonas, Romy M Riffel, Anupam Sinha, Andrew Wang, Sophie Pählig, Maura Hofmann, Heidi Altmann, Simone Von Bonin, Thea Koch, Peter Spieth, Kristin Tausche, Katja Akgün, Martina Rauner, Romy Kronstein-Wiedemann, Marcus Odendahl, Torsten Tonn, Andy Göbel, Lorenz C Hofbauer, Tilman D Rachner.

   BACKGROUND AND AIMS: Coronavirus disease 19 (Covid-19) trajectories show high interindividual variability, ranging from asymptomatic manifestations to fatal outcomes, the latter of which may be fueled by immunometabolic maladaptation of the host. Reliable identification of patients, who are at risk of severe disease remains challenging. We hypothesized that serum concentrations of Dickkopf1 (DKK1) indicate disease outcomes in SARS-CoV-2 infected individuals.
METHODS: We recruited hospitalized patients with PCR-confirmed SARS-CoV-2 infection and included 80 individuals, for whom blood samples from two independent time points were available. DKK1 serum concentrations were measured by ELISA in paired samples. Clinical data was extracted from patient charts and correlated with DKK1 levels. Publicly available datasets were screened for changes in cellular DKK1 expression upon SARS-CoV-2 infection. Plasma metabolites were profiled by NMR spectroscopy in an unbiased fashion and correlated with DKK1 data. Kaplan Meier and Cox regression analysis were used to investigate the prognostic value of DKK1 levels in the context of Covid-19.
RESULTS: We report that serum levels of DKK1 predict disease outcomes in patients with Covid-19. Circulating DKK1 concentrations are characterized by high interindividual variability and change as a function of time during SARS-CoV-2 infection, which is linked to platelet counts. We further find that the metabolic signature associated with SARS-CoV-2 infection resembles fasting metabolism and is mirrored by circulating DKK1 abundance. Patients with low DKK1 levels are twice as likely to die from Covid-19 than those with high levels and DKK1 predicts mortality independent of markers of inflammation, renal function and platelet numbers.
CONCLUSION: Our study suggests a potential clinical use of circulating DKK1 as a predictor of disease outcomes in patients with Covid-19. These results require validation in additional cohorts.

Keywords:  Covid-19; DKK1; Dickkopf1; SARS-CoV-2; immunometabolism; metabolism; platelets; viral immunity

DOI:  https://doi.org/10.1210/clinem/dgac514
Cell Immunol. 2022 Aug 13. pii: S0008-8749(22)00114-9. [Epub ahead of print]380 104589

Human dental pulp cells modulate CD8+ T cell proliferation and efficiently degrade extracellular ATP to adenosine in vitro.

Parimah Ahmadi, Ming Yan, Andreas Bauche, Ralf Smeets, Christa E Müller, Friedrich Koch-Nolte, Friedrich Haag, Ralf Fliegert, Lan Kluwe, Julian Schulze Zur Wiesch, Philip Hartjen.

  The pulp of human teeth contains a population of self-renewing stem cells that can regulate the functions of immune cells. When applied to patients, these cells can protect tissues from damage by excessive inflammation. We confirm that dental pulp cells effectively inhibit the proliferation and activation of cytotoxic T cells in vitro, and show that they carry high levels of CD73, a key enzyme in the conversion of pro-inflammatory extracellular ATP to immunosuppressive adenosine. Given their accessibility and abundance, as well as their potential for allogeneic administration, dental pulp cells provide a valuable source for immunomodulatory therapy.

Keywords:  Adenine nucleotides; Adenosine; CD73; CD8(+) T cells; Cell-based immunotherapy; Dental pulp cells; Immunosuppression; Mesenchymal stem cells; Tregs; purinergic signaling

DOI:  https://doi.org/10.1016/j.cellimm.2022.104589
FASEB J. 2022 Oct;36(10): e22526

(Pro)renin receptor inhibition attenuated liver steatosis, inflammation, and fibrosis in mice with steatohepatitis.

Yun-Cheng Hsieh, Pei-Shan Wu, Yi-Tsung Lin, Yi-Hsiang Huang, Ming-Chih Hou, Kuei-Chuan Lee, Han-Chieh Lin.

  The (Pro)renin receptor (PRR) is reportedly involved in hepatic lipid metabolism and hepatocyte PRR knockdown protects mice against hepatosteatosis. However, the impact of PRR inhibition on liver inflammation and fibrosis in nonalcoholic steatohepatitis (NASH) remains unclear. Herein, C57BL/6 mice were fed a normal chow diet or fast food diet (FFD) for 24 weeks. Lentivirus-mediated PRR short hairpin RNA (shRNA) or handle region peptide (HRP), a PRR blocker, was administered for PRR inhibition. Mouse primary hepatocytes were cultured with palmitic acid, prorenin, siRNA-targeted PRR, and HRP. In FFD-fed mice, PRR inhibition via lentivirus-mediated PRR knockdown or HRP significantly attenuated liver steatosis, inflammation, and fibrosis. Mechanistically, PRR knockdown or HRP decreased hepatic acetyl-CoA carboxylase (ACC) abundance and upregulated peroxisome proliferator-activated receptor-alpha (PPARα). HRP treatment also decreased hepatic PRR expression. In addition, intrahepatic oxidative stress, apoptosis and inflammatory cell recruitment were ameliorated by PRR knockdown or HRP treatment, along with suppression of proinflammatory cytokine expression. PRR inhibition downregulated the hepatic expression of profibrotic factors, as well as TGF-β1/SMAD3 pathway. In primary mouse hepatocytes, PRR knockdown with siRNA or HRP downregulated cellular ACC and increased PPARα expression. In conclusion, our findings revealed that PRR inhibition attenuated hepatic steatosis, inflammation, and fibrosis in mice with NASH. Accordingly, targeting PRR signaling may serve as a potential treatment for NASH.

Keywords:  chronic liver injury; gene silencing; handle region peptide; lipid metabolism; nonalcoholic fatty liver disease

DOI:  https://doi.org/10.1096/fj.202200594R
Cancer Discov. 2022 Sep 09. OF1

Aerobic Glycolysis Promotes an NF-κB-Mediated Increase in PD-L1 Expression.

High glucose in the GBM tumor microenvironment promotes immune evasion by increasing PD-L1 expression.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-0164
J Immunol Res. 2022 ;2022 2280973

Lactic Acid Regulation: A Potential Therapeutic Option in Rheumatoid Arthritis.

Qianlei Wang, James Asenso, Ning Xiao, Jinzhang Gao, Feng Xiao, Jiajie Kuai, Wei Wei, Chun Wang.

Rheumatoid arthritis (RA) is a chronic, persistent autoimmune disease that causes severe joint tissue damage and irreversible disability. Cumulative evidence suggests that patients suffering from RA for long durations are at risk of functional damage to cardiovascular, kidney, lung, and other tissues. This seriously affects the quality of work and life of patients. To date, no clear etiology of RA has been found. Recent studies have revealed that the massive proliferation of synoviocytes and immune cells requires a large amount of energy supply. Rapid energy supply depends on the anaerobic glucose metabolic pathway in both RA animal models and clinical patients. Anaerobic glycolysis can increase intracellular lactic acid (LA) content. LA induces the overexpression of monocarboxylate transporters (MCTs) in cell membranes. MCTs rapidly transport LA from the intracellular to the intercellular or articular cavity. Hence, a relatively high accumulation of LA could be formed in the intercellular and articular cavities of inflammatory joints. Moreover, LA contributes to the migration and activation of immune cells. Immune cells proliferate and secrete interleukins (IL) including IL-1, IL-2, IL-13, IL-17, and other inflammatory factors. These inflammatory factors enhance the immune inflammatory response of the body and aggravate the condition of RA patients. In this paper, the effects of LA on RA pathogenesis will be summarized from the perspective of the production, transport, and metabolism of synoviocytes and immune cells. Additionally, the drugs involved in the production, transport, and metabolism of LA are highlighted.

DOI: https://doi.org/10.1155/2022/2280973
Nat Commun. 2022 Sep 05. 13(1): 5093

HIF-1 stabilization in T cells hampers the control of Mycobacterium tuberculosis infection.

Ruining Liu, Victoria Muliadi, Wenjun Mou, Hanxiong Li, Juan Yuan, Johan Holmberg, Benedict J Chambers, Nadeem Ullah, Jakob Wurth, Mohammad Alzrigat, Susanne Schlisio, Berit Carow, Lars Gunnar Larsson, Martin E Rottenberg.

The hypoxia-inducible factors (HIFs) regulate the main transcriptional pathway of response to hypoxia in T cells and are negatively regulated by von Hippel-Lindau factor (VHL). But the role of HIFs in the regulation of CD4 T cell responses during infection with M. tuberculosis isn't well understood. Here we show that mice lacking VHL in T cells (Vhl cKO) are highly susceptible to infection with M. tuberculosis, which is associated with a low accumulation of mycobacteria-specific T cells in the lungs that display reduced proliferation, altered differentiation and enhanced expression of inhibitory receptors. In contrast, HIF-1 deficiency in T cells is redundant for M. tuberculosis control. Vhl cKO mice also show reduced responses to vaccination. Further, VHL promotes proper MYC-activation, cell-growth responses, DNA synthesis, proliferation and survival of CD4 T cells after TCR activation. The VHL-deficient T cell responses are rescued by the loss of HIF-1α, indicating that the increased susceptibility to M. tuberculosis infection and the impaired responses of Vhl-deficient T cells are HIF-1-dependent.

DOI: https://doi.org/10.1038/s41467-022-32639-9
Ecotoxicol Environ Saf. 2022 Sep 06. pii: S0147-6513(22)00893-4. [Epub ahead of print]244 114053

Heat stress-induced intestinal barrier damage and dimethylglycine alleviates via improving the metabolism function of microbiota gut brain axis.

Zhenxin Wang, Dan Shao, Shu Wu, Zhigang Song, Shourong Shi.

  Heat stress, a widely occurred in subtropical climate regions, causes ecosystem destruction, and intestine injury in humans and animals. As an important compound in the metabolic pathway of choline, dimethylglycine (DMG) shows anti-inflammatory effects. This study examines the beneficial effects of dietary DMG against heat stress-induced intestine injury and further explores the underlying molecular mechanisms using a broiler model. Here, we showed that DMG supplements exhibited positive effects to growth performance, as evidenced by the significantly increased body weight and feed conversion rate. These therapeutic effects attributed to repaired gut barrier integrity, increased content of anti-inflammatory cytokines IL-10, decreased content of pro-inflammatory cytokines IL-6, and down-regulated gene expression of the NF-κB signaling pathway. DMG treatment led to the reshaping of the gut microbiota composition, mainly increasing the short-chain fatty acid (SCFAs) strains such as Faecalibacterium, and Marvinbryantia. DMG treatment also increased two main members of SCFAs, including acetate acid and isobutyrate. Particularly, distinct effects were found which mediated the tryptophan metabolism in intestines such as increased tryptophan and 5-HT, which further alleviate the occurrence of intestinal barrier damage caused by heat stress. Additionally, DMG treatment promoted neuroendocrine function and stimulated the hypothalamic neurotransmitter metabolism by activating tryptophan metabolism in the hypothalamus. Overall, DMG supplementation effectively reduced the occurrence of intestinal inflammation induced by heat stress through modulating cecal microbial communities and improving the metabolism function of microbiota gut brain axis. Our findings revealed a novel mechanism by which gut microbiota could improve host health.

Keywords:  Dimethylglycine; Heat stress; Inflammation; Intestinal barrier; Microbiota gut brain

DOI:  https://doi.org/10.1016/j.ecoenv.2022.114053
Biosci Biotechnol Biochem. 2022 Sep 09. pii: zbac150. [Epub ahead of print]

Comparison of metabolism and biological properties among positional isomers of quercetin glucuronide in LPS- and RANKL-challenged RAW264.7 cells.

Miyu Nishikawa, Yuriko Kada, Mirai Kimata, Toshiyuki Sakaki, Shinichi Ikushiro.

  The major quercetin metabolite, quercetin-3-glucuronide, exerts various biological activities, including anti-inflammatory effects. This study aimed to evaluate the metabolic profiles and biological properties of the positional isomers of quercetin monoglucuronides (Q3G, Q7G, Q3'G, and Q4'G) in activated macrophages. In addition to quercetin aglycone, Q7G was more cytotoxic than the other quercetin monoglucuronides (QGs), which corresponded to its lower stability under neutral pH conditions. Q3G was most effective in inhibiting both LPS-dependent induction of IL-6 and RANKL-dependent activation of tartrate-resistant acid phosphatase; however, Q3'G and Q4'G may also help exert biological activities without potential cytotoxicity. The deconjugation efficacy to generate quercetin aglycone differed among QGs, with the highest efficacy in Q3G. These results suggest that the chemical or biological properties and metabolic profiles may depend on the stability of QGs to generate quercetin aglycone using β-glucuronidase.

Keywords:  RAW264.7 cells; deconjugation; positional isomers; quercetin glucuronide

DOI:  https://doi.org/10.1093/bbb/zbac150