bims-imicid 2024-01-21 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024‒01‒21
25 papers selected by
Dylan Ryan, University of Cambridge

Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.
Macrophages undergo functionally significant reprograming of nucleotide metabolism upon classical activation.
Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus.
Acetyl-CoA production by Mediator-bound 2-ketoacid dehydrogenases boosts de novo histone acetylation and is regulated by nitric oxide.
CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity.
Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer.
Advances in macrophage and T cell metabolic reprogramming and immunotherapy in the tumor microenvironment.
Metabolic waypoints during T cell differentiation.
Butyrate Prevents the Pathogenic Anemia-Inflammation Circuit by Facilitating Macrophage Iron Export.
Metabolism Serves as a Bridge Between Cardiomyocytes and Immune Cells in Cardiovascular Diseases.
Metabolic drives affecting Th17/Treg gene expression changes and differentiation: impact on immune-microenvironment regulation.
Adipose-tissue regulatory T cells are a consortium of subtypes that evolves with age and diet.
Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis.
Niche-specific control of tissue function by regulatory T cells-Current challenges and perspectives for targeting metabolic disease.
Protein 4.1R regulates M1 macrophages polarization via glycolysis, alleviating sepsis-induced liver injury in mice.
Impaired immune tolerance mediated by reduced Tfr cells in rheumatoid arthritis linked to gut microbiota dysbiosis and altered metabolites.
Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthma.
The link between dysregulated immunometabolism and vascular damage: Implications for the development of atherosclerosis in SLE and other rheumatic diseases.
Mechanistic role of quercetin as inhibitor for adenosine deaminase enzyme in rheumatoid arthritis: systematic review.
Nutrient sensing in macrophages linked to reorganized tumor vasculature.
Copper regulates the host innate immune response against bacterial infection via activation of ALPK1 kinase.
Reduced mitochondrial-encoded NADH dehydrogenase 6 gene expression drives inflammatory CD4+T cells in patients with systemic lupus erythematosus.
EGFR-driven lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth.
Host-derived organic acids enable gut colonization of the honey bee symbiont Snodgrassella alvi.
PRDM16 regulates γδT17 cell differentiation via controlling type 17 program and lipid-dependent cell fitness.

Cell Metab. 2024 Jan 13. pii: S1550-4131(23)00467-9. [Epub ahead of print]

Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.

Jia-Yao Fu, Shi-Jia Huang, Bao-Li Wang, Jun-Hao Yin, Chang-Yu Chen, Jia-Bao Xu, Yan-Lin Chen, Shuo Xu, Ting Dong, Hao-Nan Zhou, Xin-Yi Ma, Yi-Ping Pu, Hui Li, Xiu-Juan Yang, Li-Song Xie, Zhi-Jun Wang, Qi Luo, Yan-Xiong Shao, Lei Ye, Zi-Rui Zong, Xin-Di Wei, Wan-Wen Xiao, Shu-Tong Niu, Yi-Ming Liu, He-Ping Xu, Chuang-Qi Yu, Sheng-Zhong Duan, Ling-Yan Zheng.

  Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.

Keywords:  KAT6A; T helper 17 cells; autoimmune; effector T cell response; glucose metabolism; histone acetylation

DOI:  https://doi.org/10.1016/j.cmet.2023.12.016
bioRxiv. 2023 Dec 27. pii: 2023.12.27.573447. [Epub ahead of print]

Macrophages undergo functionally significant reprograming of nucleotide metabolism upon classical activation.

Steven V John, Gretchen L Seim, Billy J Erazo-Flores, John Steill, Jack Freeman, James A Votava, Nicholas L Arp, Xin Qing, Ron Stewart, Laura J Knoll, Jing Fan.

During an immune response, macrophages systematically rewire their metabolism in specific ways to support their diversve functions. However, current knowledge of macrophage metabolism is largely concentrated on central carbon metabolism. Using multi-omics analysis, we identified nucleotide metabolism as one of the most significantly rewired pathways upon classical activation. Further isotopic tracing studies revealed several major changes underlying the substantial metabolomic alterations: 1) de novo synthesis of both purines and pyrimidines is shut down at several specific steps; 2) nucleotide degradation activity to nitrogenous bases is increased but complete oxidation of bases is reduced, causing a great accumulation of nucleosides and bases; and 3) cells gradually switch to primarily relying on salvaging the nucleosides and bases for maintaining most nucleotide pools. Mechanistically, the inhibition of purine nucleotide de novo synthesis is mainly caused by nitric oxide (NO)-driven inhibition of the IMP synthesis enzyme ATIC, with NO-independent transcriptional downregulation of purine synthesis genes augmenting the effect. The inhibition of pyrimidine nucleotide de novo synthesis is driven by NO-driven inhibition of CTP synthetase (CTPS) and transcriptional downregulation of thymidylate synthase (TYMS). For the rewiring of degradation, purine nucleoside phosphorylase (PNP) and uridine phosphorylase (UPP) are transcriptionally upregulated, increasing nucleoside degradation activity. However, complete degradation of purine bases by xanthine oxidoreductase (XOR) is inhibited by NO, diverting flux into nucleotide salvage. Inhibiting the activation-induced switch from nucleotide de novo synthesis to salvage by knocking out the purine salvage enzyme hypoxanthine-guanine phosporibosyl transferase ( Hprt ) significantly alters the expression of genes important for activated macrophage functions, suppresses macrophage migration, and increases pyroptosis. Furthermore, knocking out Hprt or Xor increases proliferation of the intracellular parasite Toxoplasma gondii in macrophages. Together, these studies comprehensively reveal the characteristics, the key regulatory mechanisms, and the functional importance of the dynamic rewiring of nucleotide metabolism in classically activated macrophages.

DOI: https://doi.org/10.1101/2023.12.27.573447
JCI Insight. 2024 Jan 16. pii: e170316. [Epub ahead of print]

Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus.

S Marina Casalino-Matsuda, Fei Chen, Francisco J Gonzalez-Gonzalez, Hiroaki Matsuda, Aisha Nair, Hiam Abdala-Valencia, G R Scott Budinger, Jin-Tang Dong, Greg J Beitel, Peter Hs Sporn.

  Hypercapnia, elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that elevated CO2 increases the mortality of bacterial and viral pneumonia in mice. Here, we show that normoxic hypercapnia downregulates innate immune and antiviral gene programs in alveolar macrophages (AMØs). We also show that zinc finger homeobox 3 (Zfhx3), a mammalian ortholog of zfh2, which mediates hypercapnic immune suppression in Drosophila, is expressed in mouse and human macrophages. Deletion of Zfhx3 in the myeloid lineage blocked the suppressive effect of hypercapnia on immune gene expression in AMØs and decreased viral replication, inflammatory lung injury and mortality in hypercapnic mice infected with influenza A virus. Our results establish Zfhx3 as the first known mammalian mediator of CO2 effects on immune gene expression and lay the basis for future studies to identify therapeutic targets to interrupt hypercapnic immunosuppression in patients with advanced lung disease.

Keywords:  Immunology; Influenza; Innate immunity; Macrophages; Pulmonology

DOI:  https://doi.org/10.1172/jci.insight.170316
Mol Cell. 2024 Jan 10. pii: S1097-2765(23)01079-1. [Epub ahead of print]

Acetyl-CoA production by Mediator-bound 2-ketoacid dehydrogenases boosts de novo histone acetylation and is regulated by nitric oxide.

Marta Russo, Francesco Gualdrini, Veronica Vallelonga, Elena Prosperini, Roberta Noberini, Silvia Pedretti, Carolina Borriero, Pierluigi Di Chiaro, Sara Polletti, Gabriele Imperato, Mattia Marenda, Chiara Ghirardi, Fabio Bedin, Alessandro Cuomo, Simona Rodighiero, Tiziana Bonaldi, Nico Mitro, Serena Ghisletti, Gioacchino Natoli.

  Histone-modifying enzymes depend on the availability of cofactors, with acetyl-coenzyme A (CoA) being required for histone acetyltransferase (HAT) activity. The discovery that mitochondrial acyl-CoA-producing enzymes translocate to the nucleus suggests that high concentrations of locally synthesized metabolites may impact acylation of histones and other nuclear substrates, thereby controlling gene expression. Here, we show that 2-ketoacid dehydrogenases are stably associated with the Mediator complex, thus providing a local supply of acetyl-CoA and increasing the generation of hyper-acetylated histone tails. Nitric oxide (NO), which is produced in large amounts in lipopolysaccharide-stimulated macrophages, inhibited the activity of Mediator-associated 2-ketoacid dehydrogenases. Elevation of NO levels and the disruption of Mediator complex integrity both affected de novo histone acetylation within a shared set of genomic regions. Our findings indicate that the local supply of acetyl-CoA generated by 2-ketoacid dehydrogenases bound to Mediator is required to maximize acetylation of histone tails at sites of elevated HAT activity.

Keywords:  2-ketoacid dehydrogenases; LPS; LPS tolerance; Mediator; acetylation; chromatin; lipopolysaccharide; macrophages; nitric oxide; pyruvate dehydrogenase

DOI:  https://doi.org/10.1016/j.molcel.2023.12.033
Cell Mol Immunol. 2024 Jan 18.

CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity.

G Aaron Holling, Colin A Chavel, Anand P Sharda, Mackenzie M Lieberman, Caitlin M James, Shivana M Lightman, Jason H Tong, Guanxi Qiao, Tiffany R Emmons, Thejaswini Giridharan, Shengqi Hou, Andrew M Intlekofer, Richard M Higashi, Teresa W M Fan, Andrew N Lane, Kevin H Eng, Brahm H Segal, Elizabeth A Repasky, Kelvin P Lee, Scott H Olejniczak.

  Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.

Keywords:  ARS2; CD8 T cells; Immunometabolism; PKM2; mRNA splicing

DOI:  https://doi.org/10.1038/s41423-024-01124-2
J Clin Invest. 2024 Jan 16. pii: e175445. [Epub ahead of print]134(2):

Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer.

Corey Dussold, Kaylee Zilinger, Jillyn Turunen, Amy B Heimberger, Jason Miska.

Immunometabolism is a burgeoning field of research that investigates how immune cells harness nutrients to drive their growth and functions. Myeloid cells play a pivotal role in tumor biology, yet their metabolic influence on tumor growth and antitumor immune responses remains inadequately understood. This Review explores the metabolic landscape of tumor-associated macrophages, including the immunoregulatory roles of glucose, fatty acids, glutamine, and arginine, alongside the tools used to perturb their metabolism to promote antitumor immunity. The confounding role of metabolic inhibitors on our interpretation of myeloid metabolic phenotypes will also be discussed. A binary metabolic schema is currently used to describe macrophage immunological phenotypes, characterizing inflammatory M1 phenotypes, as supported by glycolysis, and immunosuppressive M2 phenotypes, as supported by oxidative phosphorylation. However, this classification likely underestimates the variety of states in vivo. Understanding these nuances will be critical when developing interventional metabolic strategies. Future research should focus on refining drug specificity and targeted delivery methods to maximize therapeutic efficacy.

DOI: https://doi.org/10.1172/JCI175445
PeerJ. 2024 ;12 e16825

Advances in macrophage and T cell metabolic reprogramming and immunotherapy in the tumor microenvironment.

Hua Cheng, Yongbin Zheng.

  Macrophages and T cells in the tumor microenvironment (TME) play an important role in tumorigenesis and progression. However, TME is also characterized by metabolic reprogramming, which may affect macrophage and metabolic activity of T cells and promote tumor escape. Immunotherapy is an approach to fight tumors by stimulating the immune system in the host, but requires support and modulation of cellular metabolism. In this process, the metabolic roles of macrophages and T cells become increasingly important, and their metabolic status and interactions play a critical role in the success of immunotherapy. Therefore, understanding the metabolic state of T cells and macrophages in the TME and the impact of metabolic reprogramming on tumor therapy will help optimize subsequent immunotherapy strategies.

Keywords:  Immunotherapy; Macrophages; Metabolic reprogramming; T cells; Tumor microenvironment

DOI:  https://doi.org/10.7717/peerj.16825
Nat Immunol. 2024 Jan 18.

Metabolic waypoints during T cell differentiation.

Drew Wilfahrt, Greg M Delgoffe.

This Review explores the interplay between T cell activation and cell metabolism and highlights how metabolites serve two pivotal functions in shaping the immune response. Traditionally, T cell activation has been characterized by T cell antigen receptor-major histocompatibility complex interaction (signal 1), co-stimulation (signal 2) and cytokine signaling (signal 3). However, recent research has unveiled the critical role of metabolites in this process. Firstly, metabolites act as signal propagators that aid in the transmission of core activation signals, such as specific lipid species that are crucial at the immune synapse. Secondly, metabolites also function as unique signals that influence immune differentiation pathways, such as amino acid-induced mTORC1 signaling. Metabolites also play a substantial role in epigenetic remodeling, by directly modifying histones, altering gene expression and influencing T cell behavior. This Review discusses how T cells integrate nutrient sensing with activating stimuli to shape their differentiation and sensitivity to metabolites. We underscore the integration of immunological and metabolic inputs in T cell function and suggest that metabolite availability is a fundamental determinant of adaptive immune responses.

DOI: https://doi.org/10.1038/s41590-023-01733-5
Adv Sci (Weinh). 2024 Jan 18. e2306571

Butyrate Prevents the Pathogenic Anemia-Inflammation Circuit by Facilitating Macrophage Iron Export.

Peng Xiao, Xuechun Cai, Zhou Zhang, Ke Guo, Yuehai Ke, Ziwei Hu, Zhangfa Song, Yuening Zhao, Lingya Yao, Manlu Shen, Jingyun Li, Youling Huang, Lingna Ye, Lingjie Huang, Yu Zhang, Rongbei Liu, Mengque Xu, Xutao Xu, Yuan Zhao, Qian Cao.

  Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron-mediated, pathogenic anemia-inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short-chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis-induced anemia but also reduces TNF-α production in macrophages. Consistently, macrophage-conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti-TNF-α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation.

Keywords:  anemia; butyrate; ferroportin; inflammatory bowel disease; macrophages

DOI:  https://doi.org/10.1002/advs.202306571
Cardiovasc Drugs Ther. 2024 Jan 18.

Metabolism Serves as a Bridge Between Cardiomyocytes and Immune Cells in Cardiovascular Diseases.

Lixiao Hang, Ying Zhang, Zheng Zhang, Haiqiang Jiang, Lin Xia.

  Metabolic disorders of cardiomyocytes play an important role in the progression of various cardiovascular diseases. Metabolic reprogramming can provide ATP to cardiomyocytes and protect them during diseases, but this transformation also leads to adverse consequences such as oxidative stress, mitochondrial dysfunction, and eventually aggravates myocardial injury. Moreover, abnormal accumulation of metabolites induced by metabolic reprogramming of cardiomyocytes alters the cardiac microenvironment and affects the metabolism of immune cells. Immunometabolism, as a research hotspot, is involved in regulating the phenotype and function of immune cells. After myocardial injury, both cardiac resident immune cells and heart-infiltrating immune cells significantly contribute to the inflammation, repair and remodeling of the heart. In addition, metabolites generated by the metabolic reprogramming of immune cells can further affect the microenvironment, thereby affecting the function of cardiomyocytes and other immune cells. Therefore, metabolic reprogramming and abnormal metabolite levels may serve as a bridge between cardiomyocytes and immune cells, leading to the development of cardiovascular diseases. Herein, we summarize the metabolic relationship between cardiomyocytes and immune cells in cardiovascular diseases, and the effect on cardiac injury, which could be therapeutic strategy for cardiovascular diseases, especially in drug research.

Keywords:  Cardiomyocytes; Cardiovascular diseases; Immune cells; Metabolism

DOI:  https://doi.org/10.1007/s10557-024-07545-5
APMIS. 2024 Jan 18.

Metabolic drives affecting Th17/Treg gene expression changes and differentiation: impact on immune-microenvironment regulation.

Carolina Brescia, Salvatore Audia, Alessia Pugliano, Federica Scaglione, Rodolfo Iuliano, Francesco Trapasso, Nicola Perrotti, Emanuela Chiarella, Rosario Amato.

  The CD4+ T-cell population plays a vital role in the adaptive immune system by coordinating the immune response against different pathogens. A significant transformation occurs in CD4+ cells during an immune response, as they shift from a dormant state to an active state. This transformation leads to extensive proliferation, differentiation, and cytokine production, which contribute to regulating and coordinating the immune response. Th17 and Treg cells are among the most intriguing CD4+ T-cell subpopulations in terms of genetics and metabolism. Gene expression modulation processes rely on and are linked to metabolic changes in cells. Lactylation is a new model that combines metabolism and gene modulation to drive Th17/Treg differentiation and functional processes. The focus of this review is on the metabolic pathways that impact lymphocyte gene modulation in a functionally relevant manner.

Keywords:  RANBP1; SGK1; Th17; Treg; glycolysis; immuno-regulation; immunogenetics; lactate; mTOR; metabolism

DOI:  https://doi.org/10.1111/apm.13378
Proc Natl Acad Sci U S A. 2024 Jan 23. 121(4): e2320602121

Adipose-tissue regulatory T cells are a consortium of subtypes that evolves with age and diet.

Andrés R Muñoz-Rojas, Gang Wang, Christophe Benoist, Diane Mathis.

  Foxp3+CD4+ regulatory T (Treg) cells found within tissues regulate local immunity, inflammation, and homeostasis. Tregs in epididymal visceral adipose tissue (eVAT) are critical regulators of local and systemic inflammation and metabolism. During aging and under obesogenic conditions, eVAT Tregs undergo transcriptional and phenotypic changes and are important for containing inflammation and normalizing metabolic indices. We have employed single-cell RNA sequencing, single-cell Tra and Trb sequencing, adoptive transfers, photoconvertible mice, cellular interaction analyses, and in vitro cultures to dissect the evolving heterogeneity of eVAT Tregs with aging and obesity. Distinct Treg subtypes with distinguishable gene expression profiles and functional roles were enriched at differing ages and with differing diets. Like those in lean mice, eVAT Tregs in obese mice were not primarily recruited from the circulation but instead underwent local expansion and had a distinct and diversified T cell receptor repertoire. The different eVAT-Treg subtypes were specialized in different functions; for example, the subtypes enriched in lean, but not obese, mice suppressed adipogenesis. The existence of functionally divergent eVAT-Treg subtypes in response to obesogenic conditions presents possibilities for precision therapeutics in the context of obesity.

Keywords:  T cell receptor; adipose tissue; obesity; regulatory T cells; single-cell

DOI:  https://doi.org/10.1073/pnas.2320602121
J Neuroinflammation. 2024 Jan 20. 21(1): 28

Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis.

Peng-Fei Wang, Fei Jiang, Qiu-Ming Zeng, Wei-Fan Yin, Yue-Zi Hu, Qiao Li, Zhao-Lan Hu.

  Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the infiltration of inflammatory cells and demyelination of nerves. Mitochondrial dysfunction has been implicated in the pathogenesis of MS, as studies have shown abnormalities in mitochondrial activities, metabolism, mitochondrial DNA (mtDNA) levels, and mitochondrial morphology in immune cells of individuals with MS. The presence of mitochondrial dysfunctions in immune cells contributes to immunological dysregulation and neurodegeneration in MS. This review provided a comprehensive overview of mitochondrial dysfunction in immune cells associated with MS, focusing on the potential consequences of mitochondrial metabolic reprogramming on immune function. Current challenges and future directions in the field of immune-metabolic MS and its potential as a therapeutic target were also discussed.

Keywords:  Immune cells; Immune-metabolic; MS; Mitochondrion

DOI:  https://doi.org/10.1186/s12974-024-03016-8
Cell Metab. 2024 Jan 04. pii: S1550-4131(23)00470-9. [Epub ahead of print]

Niche-specific control of tissue function by regulatory T cells-Current challenges and perspectives for targeting metabolic disease.

Maike Becker, Sandra M Dirschl, Martin G Scherm, Isabelle Serr, Carolin Daniel.

  Tissue regulatory T cells (Tregs) exert pivotal functions in both immune and metabolic regulation, maintaining local tissue homeostasis, integrity, and function. Accordingly, Tregs play a crucial role in controlling obesity-induced inflammation and supporting efficient muscle function and repair. Depending on the tissue context, Tregs are characterized by unique transcriptomes, growth, and survival factors and T cell receptor (TCR) repertoires. This functional specialization offers the potential to selectively target context-specific Treg populations, tailoring therapeutic strategies to specific niches, thereby minimizing potential side effects. Here, we discuss challenges and perspectives for niche-specific Treg targeting, which holds promise for highly efficient and precise medical interventions to combat metabolic disease.

Keywords:  ADCs; CAR Tregs; T2D; Treg engineering; antibody-drug conjugates; bispecific antibodies; bsAbs; immunometabolism; personalized medicines; therapeutic Treg targeting; tissue Treg; tissue Treg targeting in distinct niches; type 2 diabetes

DOI:  https://doi.org/10.1016/j.cmet.2023.12.019
Int Immunopharmacol. 2024 Jan 17. pii: S1567-5769(24)00064-X. [Epub ahead of print]128 111546

Protein 4.1R regulates M1 macrophages polarization via glycolysis, alleviating sepsis-induced liver injury in mice.

Si-Yao Sang, Yuan-Jiao Wang, Taotao Liang, Yan Liu, Jiao-Jiao Liu, Hui Li, Xin Liu, Qiao-Zhen Kang, Ting Wang.

  Acute liver injury (ALI) is a common clinical disease caused by sepsis, metabolic syndrome, hepatitis virus. Macrophage plays an important role in the development of ALI, which is characterized by polarization and inflammatory regulation. The polarization process of macrophages is related to membrane binding proteins and adaptors. Protein 4.1R acts as an adaptor, linking membrane proteins to the cytoskeleton, and is involved in cell activation and cytokine secretion. However, whether protein 4.1R is involved in regulating macrophage polarization and inflammation-induced liver injury remains unknown. In this study, protein 4.1R is identified with the special effect on macrophage M1 polarization. And it is further demonstrated that protein 4.1R deficiency significantly enhance glycolytic metabolism. Mechanistically, the regulation of protein 4.1R on pyruvate kinase M2 (PKM2) plays a key role in glycolysis metabolism. In addition, we found that protein 4.1R directly interacts with toll-like receptor 4 (TLR4), inhibits the activation of the AKT/HIF-1α signaling pathway. In conclusion, protein 4.1R targets HIF-1α mediated glycolysis regulates M1 macrophage polarization, indicating that protein 4.1R is a candidate for regulating macrophage mediated inflammatory response. In conclusion, we have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy. We have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy.

Keywords:  AKT/HIF-1α signal pathway; Acute liver injury; Glycolysis; M1 macrophage polarization; Protein 4.1R

DOI:  https://doi.org/10.1016/j.intimp.2024.111546
Arthritis Res Ther. 2024 Jan 13. 26(1): 21

Impaired immune tolerance mediated by reduced Tfr cells in rheumatoid arthritis linked to gut microbiota dysbiosis and altered metabolites.

Ruihe Wu, Dongming Wang, Liyun Cheng, Rui Su, Baochen Li, Chunxue Fan, Chong Gao, Caihong Wang.

  BACKGROUND: Patients with rheumatoid arthritis (RA) showed impaired immune tolerance characterized by reduced follicular regulatory T (Tfr) cells, and they also exhibited altered gut microbiotas and their metabolites in RA. However, the association of gut microbiotas and their metabolites with the immune tolerance mediated by Tfr cells in RA remains unclear.METHODS: Peripheral blood and stool samples were collected from 32 new-onset RA patients and 17 healthy controls (HCs) in the Second Hospital of Shanxi Medical University between January 2022 and June 2022. The peripheral blood was used to detect the circulating regulatory T (Treg), helper T(Th)17, Tfr, and follicular helper T (Tfh) cells by modified flow cytometry. The stool samples were used to analyze the gut microbiotas and their metabolites via 16S rDNA sequencing and metabolomic profiling. We aimed to characterize the gut microbiotas and their metabolites in RA and identified their association with Tfr cell-mediated immune tolerance.
RESULTS: The new-onset RA demonstrated reduced Treg and Tfr cells, associated with the disease activity and autoantibodies. There were significant differences in gut microbiotas between the two groups as the results of β diversity analysis (P = 0.039) including 21 differential gut microbiotas from the phylum to genus levels. In which, Ruminococcus 2 was associated with the disease activity and autoantibodies of RA, and it was identified as the potential biomarker of RA [area under curve (AUC) = 0.782, 95% confidence interval (CI) = 0.636-0.929, P = 0.001]. Eleven differential metabolites were identified and participated in four main pathways related to RA. Arachidonic acid might be the potential biomarker of RA (AUC = 0.724, 95% CI = 0.595-0.909, P = 0.038), and it was the core metabolite as the positive association with six gut microbiotas enriched in RA. The reduced Tfr cells were associated with the altered gut microbiotas and their metabolites including the Ruminococcus 2, the arachidonic acid involved in the biosynthesis of unsaturated fatty acid pathway and the 3-methyldioxyindole involved in the tryptophan metabolism pathway.
CONCLUSION: The breakdown of immune tolerance mediated by reduced Tfr cells was associated with the altered gut microbiotas and their metabolites implying the possible mechanism of RA pathogenesis from the perspective of microecology-metabolism-immune.

Keywords:  Follicular regulatory T cells; Gut microbiota; Gut-joint axis; Immune tolerance; Metabolites; Rheumatoid arthritis

DOI:  https://doi.org/10.1186/s13075-023-03260-y
Redox Biol. 2024 Jan 05. pii: S2213-2317(23)00422-6. [Epub ahead of print]70 103021

Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthma.

Yanhong Wang, Yanqing Le, Jie Wu, Wenqu Zhao, Qian Zhang, Guiling Xu, Zhaoqian Gong, Maosheng Xu, Yanyan Ma, Changhui Yu, Shaoxi Cai, Haijin Zhao.

  BACKGROUND: Extracellular high mobility group box 1 (HMGB1) is a key mediator in driving allergic airway inflammation and contributes to asthma. Yet, mechanism of HMGB1 secretion in asthma is poorly defined. Pulmonary metabolic dysfunction is recently recognized as a driver of respiratory pathology. However, the altered metabolic signatures and the roles of metabolic to allergic airway inflammation remain unclear.METHODS: Male C57BL/6 J mice were sensitized and challenged with toluene diisocyanate (TDI) to generate a chemically induced asthma model. Pulmonary untargeted metabolomics was employed. According to results, mice were orally administered allopurinol, a xanthine oxidase (XO) inhibitor. Human bronchial epithelial cells (16HBE) were stimulated by TDI-human serum albumin (HSA).
RESULTS: We identified the purine metabolism was the most enriched pathway in TDI-exposed lungs, corresponding to the increase of xanthine and uric acid, products of purine degradation mediated by XO. Inhibition of XO by allopurinol ameliorates TDI-induced oxidative stress and DNA damage, mixed granulocytic airway inflammation and Th1, Th2 and Th17 immunology as well as HMGB1 acetylation and secretion. Mechanistically, HMGB1 acetylation was caused by decreased activation of the NAD+-sirtuin 1 (SIRT1) axis triggered by hyperactivation of the DNA damage sensor poly (ADP-ribose)-polymerase 1 (PARP-1). This was rescued by allopurinol, PARP-1 inhibitor or supplementation with NAD+ precursor in a SIRT1-dependent manner. Meanwhile, allopurinol attenuated Nrf2 defect due to SIRT1 inactivation to help ROS scavenge.
CONCLUSIONS: We demonstrated a novel regulation of HMGB1 acetylation and secretion by purine metabolism that is critical for asthma onset. Allopurinol may have therapeutic potential in patients with asthma.

Keywords:  Allopurinol; Asthma; HMGB1; Purine metabolism; SIRT1

DOI:  https://doi.org/10.1016/j.redox.2023.103021
J Rheumatol. 2024 Jan 15. pii: jrheum.2023-0833. [Epub ahead of print]

The link between dysregulated immunometabolism and vascular damage: Implications for the development of atherosclerosis in SLE and other rheumatic diseases.

Anjali S Yennemadi, Natasha Jordan, Sophie Diong, Joseph Keane, Gina Leisching.

A bimodal pattern of mortality in Systemic Lupus Erythematosus (SLE) exists. Early-stage deaths are predominantly caused by infection, while later-stage deaths are caused mainly by atherosclerotic disease. Further, while SLE-related mortality has reduced considerably in recent years, cardiovascular events remain one of the leading causes of death in people with SLE. Accelerated atherosclerosis in SLE is attributed both to an increase in traditional cardiovascular risk factors and the inflammatory effects of SLE itself. Many of these changes occur within the microenvironment of the vascular-immune interface, the site of atherosclerotic plaque development. Here, an intimate interaction between endothelial cells, vascular smooth muscle cells, and immune cells, dictates physiological versus pathological responses to a chronic type 1 interferon environment. Low-density neutrophils (LDNs) have also been implicated in eliciting vasculature-damaging effects at such lesion sites. These changes are thought to be governed by dysfunctional metabolism of immune cells in this niche due, at least in part, to the chronic induction of type 1 interferons. Understanding of these novel pathophysiological mechanisms and metabolic pathways may unveil potential innovative pharmacological targets and therapeutic opportunities for atherosclerosis, as well as shed light on the development of premature atherosclerosis in SLE patients who develop cardiovascular events.

DOI: https://doi.org/10.3899/jrheum.2023-0833
Cell Mol Biol Lett. 2024 Jan 16. 29(1): 14

Mechanistic role of quercetin as inhibitor for adenosine deaminase enzyme in rheumatoid arthritis: systematic review.

Amira Atta, Maha M Salem, Karim Samy El-Said, Tarek M Mohamed.

  Rheumatoid arthritis (RA) is an autoimmune disease involving T and B lymphocytes. Autoantibodies contribute to joint deterioration and worsening symptoms. Adenosine deaminase (ADA), an enzyme in purine metabolism, influences adenosine levels and joint inflammation. Inhibiting ADA could impact RA progression. Intracellular ATP breakdown generates adenosine, which increases in hypoxic and inflammatory conditions. Lymphocytes with ADA play a role in RA. Inhibiting lymphocytic ADA activity has an immune-regulatory effect. Synovial fluid levels of ADA are closely associated with the disease's systemic activity, making it a useful parameter for evaluating joint inflammation. Flavonoids, such as quercetin (QUE), are natural substances that can inhibit ADA activity. QUE demonstrates immune-regulatory effects and restores T-cell homeostasis, making it a promising candidate for RA therapy. In this review, we will explore the impact of QUE in suppressing ADA and reducing produced the inflammation in RA, including preclinical investigations and clinical trials.

Keywords:  Adenosine deaminase; Flavonoid; Quercetin; Rheumatoid arthritis; Synovial fluid

DOI:  https://doi.org/10.1186/s11658-024-00531-7
Cancer Res. 2024 Jan 19.

Nutrient sensing in macrophages linked to reorganized tumor vasculature.

Hilda L Chan, Xiang H-F Zhang.

Macrophages are plastic immune cells that have varying functions dependent on stimulation from their environment. In a recent issue of Immunity, Do and colleagues demonstrated that activating mechanistic target of rapamycin complex 1 signaling in tumor macrophages alters their metabolism, localization, and function. Specifically, these tumor macrophages promote vascular remodeling that develops a hypoxic environment toxic to cancer cells. This culminates in a tangible reduction in tumor burden in a murine model of breast cancer. Their findings reveal a unique strategy to promote vascular remodeling through macrophage polarization and thereby highlight the intimate connections between macrophage metabolism and function. Additionally, their model highlights parallels between tumor progression and wound healing contexts while emphasizing the amplified effect of small perturbations to a tumor ecosystem.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0201
Proc Natl Acad Sci U S A. 2024 Jan 23. 121(4): e2311630121

Copper regulates the host innate immune response against bacterial infection via activation of ALPK1 kinase.

Jing Lu, Xue Liu, Xinghua Li, Hongyan Li, Liwa Shi, Xin Xia, Bai-Liang He, Thomas F Meyer, Xiaofeng Li, Hongzhe Sun, Xinming Yang.

  Copper is an essential trace element for the human body, and its requirement for optimistic immune functions has been recognized for decades. How copper is involved in the innate immune pathway, however, remains to be clarified. Here, we report that copper serves as a signal molecule to regulate the kinase activity of alpha-kinase 1 (ALPK1), a cytosolic pattern-recognition receptor (PRR), and therefore promotes host cell defense against bacterial infection. We show that in response to infection, host cells actively accumulate copper in the cytosol, and the accumulated cytosolic copper enhances host cell defense against evading pathogens, including intracellular and, unexpectedly, extracellular bacteria. Subsequently, we demonstrate that copper activates the innate immune pathway of host cells in an ALPK1-dependent manner. Further mechanistic studies reveal that copper binds to ALPK1 directly and is essential for the kinase activity of this cytosolic PRR. Moreover, the binding of copper to ALPK1 enhances the sensitivity of ALPK1 to the bacterial metabolite ADP-heptose and eventually prompts host cells to elicit an enhanced immune response during bacterial infection. Finally, using a zebrafish in vivo model, we show that a copper-treated host shows an increased production of proinflammatory cytokines, enhanced recruitment of phagosome cells, and promoted bacterial clearance. Our findings uncover a previously unrecognized role of copper in the modulation of host innate immune response against bacterial pathogens and advance our knowledge on the cross talk between cytosolic copper homeostasis and immune system.

Keywords:  ALPK1; bacterial infection; copper; innate immunity; metalloprotein

DOI:  https://doi.org/10.1073/pnas.2311630121
Free Radic Biol Med. 2024 Jan 17. pii: S0891-5849(24)00026-1. [Epub ahead of print]

Reduced mitochondrial-encoded NADH dehydrogenase 6 gene expression drives inflammatory CD4+T cells in patients with systemic lupus erythematosus.

Miheraiy Abdukiyum, Xiaojun Tang, Nan Zhao, Yiyuan Cui, Jingjing Zhang, Tohtihan Alim, Yuanyuan Zheng, Wenjing Li, Mengxi Huang, Xuxue Feng, Honghong Yu, Xuebing Feng.

  Abnormal mitochondrial function has been implicated in the progression of systemic lupus erythematosus (SLE), the prototypical autoimmune disease, yet the underlying cause remains unclear. In this study, mitochondrial-encoded NADH dehydrogenase 6 gene (MT-ND6) was identified as having increased m6A methylation and decreased expression in peripheral blood mononuclear cells of SLE patients by MeRIP-seq analysis. MT-ND6 expression was negatively correlated with SLE disease activity index score and 24-hour urine protein level, and lower in patients with positive anti-Sm or anti-dsDNA antibodies. With the reduction of MT-ND6 levels, CD4+ T cells in SLE patients exhibited mitochondrial dysfunction, as evidenced by increased levels of reactive oxygen species (ROS) and mitochondrial ROS and insufficient ATP production. Accordingly, in vitro MT-ND6 silencing induced abnormalities in the above mitochondrial indicators in CD4+ T cells, and promoted the development of both transcription and inflammatory factors in these cells. In contrast, treatment with targeted mitochondrial antioxidants largely counteracted the silencing effect of MT-MD6. Thus, reduced MT-ND6 in SLE patients may lead to mitochondrial dysfunction through ROS overproduction, thereby promoting inflammatory CD4+ T cells.

Keywords:  CD4(+) T cells; Mitochondrial function; NADH-Dehydrogenase 6; Systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.026
Cancer Discov. 2024 Jan 19.

EGFR-driven lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth.

Alexandra Kuhlmann-Hogan, Thekla Cordes, Ziyan Xu, Ramya S Kuna, Kacie A Traina, Camila Robles-Oteiza, Deborah Ayeni, Elizabeth M Kwong, Stellar Levy, Anna-Maria Globig, Matthew M Nobari, George Z Cheng, Sandra L Leibel, Robert J Homer, Reuben J Shaw, Christian M Metallo, Katerina Politi, Susan M Kaech.

The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0434
Nat Microbiol. 2024 Jan 15.

Host-derived organic acids enable gut colonization of the honey bee symbiont Snodgrassella alvi.

Andrew Quinn, Yassine El Chazli, Stéphane Escrig, Jean Daraspe, Nicolas Neuschwander, Aoife McNally, Christel Genoud, Anders Meibom, Philipp Engel.

Diverse bacteria can colonize the animal gut using dietary nutrients or by engaging in microbial crossfeeding interactions. Less is known about the role of host-derived nutrients in enabling gut bacterial colonization. Here we examined metabolic interactions within the evolutionary ancient symbiosis between the honey bee (Apis mellifera) and the core gut microbiota member Snodgrassella alvi. This betaproteobacterium is incapable of metabolizing saccharides, yet colonizes the honey bee gut in the presence of a sugar-only diet. Using comparative metabolomics, 13C-tracers and nanoscale secondary ion mass spectrometry (NanoSIMS), we show in vivo that S. alvi grows on host-derived organic acids, including citrate, glycerate and 3-hydroxy-3-methylglutarate, which are actively secreted by the host into the gut lumen. S. alvi also modulates tryptophan metabolism in the gut by converting kynurenine to anthranilate. These results suggest that S. alvi is adapted to a specific metabolic niche in the honey bee gut that depends on host-derived nutritional resources.

DOI: https://doi.org/10.1038/s41564-023-01572-y
Front Immunol. 2023 ;14 1332386

PRDM16 regulates γδT17 cell differentiation via controlling type 17 program and lipid-dependent cell fitness.

Jinwoo Nah, Youngjin Lee, Rho H Seong.

  γδT17 cells are a subset of γδT cells producing IL-17, which is crucial for protection against bacterial and fungal infections. It has recently been shown that γδT17 cells have enriched lipid storage and lipid metabolism. However, the regulation of γδT17 cell function and differentiation with respect to lipids remains unknown. Here, we report that PRDM16 is a critical regulator of γδT17 cell differentiation, controlling type 17 immunity gene expression program and lipid-dependent cell fitness. We demonstrated that γδT17 cells have higher lipid-dependent cell fitness, which is negatively correlated with the expression of Prdm16. Loss of Prdm16 enhances the function and differentiation of γδT17 cells, and increases their fitness in lipid-rich environments. Specifically, loss of Prdm16 exacerbates development of psoriasis in the skin, a lipid-rich organ, and Prdm16 controls lipid-mediated differentiation of Vγ4+ γδT17 cells, which are the major source of IL-17 during the onset of psoriasis. Our study highlights the potential impact of PRDM16 on lipid-dependent fitness and protective immune function of γδT cells and also on the immunotherapy of psoriasis and inflammatory diseases.

Keywords:  PRDM16; lipid; lipid-dependent cell fitness; psoriasis; γδT17 cell

DOI:  https://doi.org/10.3389/fimmu.2023.1332386