bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2021‒11‒28
nineteen papers selected by
Dylan Ryan
University of Cambridge
  1. ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation.
  2. The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with Mycobacterium tuberculosis.
  3. Fatty acid metabolism in adaptive immunity.
  4. ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice.
  5. Meta-Inflammation and Metabolic Reprogramming of Macrophages in Diabetes and Obesity: The Importance of Metabolites.
  6. Continuous Modeling of T CD4 Lymphocyte Activation and Function.
  7. Resolving macrophage polarization through distinct Ca2+ entry channel that maintains intracellular signaling and mitochondrial bioenergetics.
  8. Interleukin-4 and interleukin-13 induce different metabolic profiles in microglia and macrophages that relate with divergent outcomes after spinal cord injury.
  9. Immunometabolic Therapeutic Targets of Graft-versus-Host Disease (GvHD).
  10. Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.
  11. The Metabolic Control of Myeloid Cells in the Tumor Microenvironment.
  12. The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis.
  13. CD226 knockout alleviates high-fat diet induced obesity by suppressing proinflammatory macrophage phenotype.
  14. Immunological Mechanisms of Sickness Behavior in Viral Infection.
  15. Resident and migratory adipose immune cells control systemic metabolism and thermogenesis.
  16. Macrophages and Iron: A Special Relationship.
  17. Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness.
  18. Human gut bacterial metabolism drives Th17 activation and colitis.
  19. IL-27 signalling promotes adipocyte thermogenesis and energy expenditure.
  1. Cells. 2021 Oct 30. pii: 2962. [Epub ahead of print]10(11):
    ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation.
    Anna Santarsiero, Paolo Convertini, Simona Todisco, Ciro L Pierri, Anna De Grassi, Niamh C Williams, Dominga Iacobazzi, Giulio De Stefano, Luke A J O'Neill, Vittoria Infantino.
      Macrophage stimulation by pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS) or lipoteichoic acid (LTA) drives a proinflammatory phenotype and induces a metabolic reprogramming to sustain the cell's function. Nevertheless, the relationship between metabolic shifts and gene expression remains poorly explored. In this context, the metabolic enzyme ATP citrate lyase (ACLY), the producer of citrate-derived acetyl-coenzyme A (CoA), plays a critical role in supporting a proinflammatory response. Through immunocytochemistry and cytosol-nucleus fractionation, we found a short-term ACLY nuclear translocation. Protein immunoprecipitation unveiled the role of nuclear ACLY in NF-κB acetylation and in turn its full activation in human PBMC-derived macrophages. Notably, sepsis in the early hyperinflammatory phase triggers ACLY-mediated NF-κB acetylation. The ACLY/NF-κB axis increases the expression levels of proinflammatory genes, including SLC25A1-which encodes the mitochondrial citrate carrier-and ACLY, thus promoting the existence of a proinflammatory loop involving SLC25A1 and ACLY genes.
    Keywords:  ACLY; NF-κB; PAMPs; gene expression; immunometabolism; inflammation; macrophages; nuclear translocation; p65 acetylation; sepsis
    DOI:  https://doi.org/10.3390/cells10112962
  2. Int J Mol Sci. 2021 Nov 10. pii: 12189. [Epub ahead of print]22(22):
    The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with Mycobacterium tuberculosis.
    Christina Cahill, Dónal J Cox, Fiona O'Connell, Sharee A Basdeo, Karl M Gogan, Cilian Ó'Maoldomhnaigh, Jacintha O'Sullivan, Joseph Keane, James J Phelan.
      Tuberculosis (TB) remains a global health challenge. Patients with drug-sensitive and drug-resistant TB undergo long, arduous, and complex treatment regimens, often involving multiple antimicrobials. While these drugs were initially implemented based on their bactericidal effects, some studies show that TB antimicrobials can also directly affect cells of the immune system, altering their immune function. As use of these antimicrobials has been the mainstay of TB therapy for over fifty years now, it is more important than ever to understand how these antimicrobials affect key pathways of the immune system. One such central pathway, which underpins the immune response to a variety of infections, is immunometabolism, namely glycolysis and oxidative phosphorylation (OXPHOS). We hypothesise that in addition to their direct bactericidal effect on Mycobacterium tuberculosis (Mtb), current TB antimicrobials can modulate immunometabolic profiles and alter mitochondrial function in primary human macrophages. Human monocyte-derived macrophages (hMDMs) were differentiated from PBMCs isolated from healthy blood donors, and treated with four first-line and six second-line TB antimicrobials three hours post stimulation with either iH37Rv-Mtb or lipopolysaccharide (LPS). 24 h post stimulation, baseline metabolism and mitochondrial function were determined using the Seahorse Extracellular Flux Analyser. The effect of these antimicrobials on cytokine and chemokine production was also assayed using Meso Scale Discovery Multi-Array technology. We show that some of the TB antimicrobials tested can significantly alter OXPHOS and glycolysis in uninfected, iH37Rv-Mtb, and LPS-stimulated hMDMs. We also demonstrate how these antimicrobial-induced immunometabolic effects are linked with alterations in mitochondrial function. Our results show that TB antimicrobials, specifically clofazimine, can modify host immunometabolism and mitochondrial function. Moreover, clofazimine significantly increased the production of IL-6 in human macrophages that were stimulated with iH37Rv-Mtb. This provides further insight into the use of some of these TB antimicrobials as potential host-directed therapies in patients with early and active disease, which could help to inform TB treatment strategies in the future.
    Keywords:  antimicrobials; bioenergetics; drug-resistant tuberculosis; glycolysis; host-directed therapy; lipopolysaccharide; mitochondrial function; oxidative phosphorylation; tuberculosis
    DOI:  https://doi.org/10.3390/ijms222212189
  3. FEBS J. 2021 Nov 25.
    Fatty acid metabolism in adaptive immunity.
    Xian Zhou, Xingxing Zhu, Hu Zeng.
      Fatty acids not only are a key component of cellular membrane structure, but also have diverse functions in biological processes. Recent years have seen great advances in understanding of how fatty acid metabolism contributes to adaptive immune response. Here, we review 3 key processes, fatty acid biosynthesis, fatty acid oxidation and fatty acid uptake, and how they direct T and B cell functions during immune challenges. Then we will focus on the relationship between microbiota derived fatty acids, short-chain fatty acids, and adaptive immunity. Along the way, we will also discuss the outstanding controversies and challenges in the field.
    Keywords:  B cells; Fatty acid; T cells; Treg; germinal center; memory; mitochondrial; oxidation
    DOI:  https://doi.org/10.1111/febs.16296
  4. J Exp Med. 2021 Dec 06. pii: e20210639. [Epub ahead of print]218(12):
    ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice.
    Takahiro Nakajima, Toshio Kanno, Satoru Yokoyama, Shigemi Sasamoto, Hikari K Asou, Damon J Tumes, Osamu Ohara, Toshinori Nakayama, Yusuke Endo.
      T cells possess distinguishing effector functions and drive inflammatory disorders. We have previously identified IL-5-producing Th2 cells as the pathogenic population predominantly involved in the pathology of allergic inflammation. However, the cell-intrinsic signaling pathways that control the pathogenic Th2 cell function are still unclear. We herein report the high expression of acetyl-CoA carboxylase 1 (ACC1) in the pathogenic CD4+ T cell population in the lung and skin. The genetic deletion of CD4+ T cell-intrinsic ACC1 dampened eosinophilic and basophilic inflammation in the lung and skin by constraining IL-5 or IL-3 production. Mechanistically, ACC1-dependent fatty acid biosynthesis induces the pathogenic cytokine production of CD4+ T cells via metabolic reprogramming and the availability of acetyl-CoA for epigenetic regulation. We thus identified a distinct phenotype of the pathogenic T cell population in the lung and skin, and ACC1 was shown to be an essential regulator controlling the pathogenic function of these populations to promote type 2 inflammation.
    DOI:  https://doi.org/10.1084/jem.20210639
  5. Front Immunol. 2021 ;12 746151
    Meta-Inflammation and Metabolic Reprogramming of Macrophages in Diabetes and Obesity: The Importance of Metabolites.
    Sara Russo, Marcel Kwiatkowski, Natalia Govorukhina, Rainer Bischoff, Barbro N Melgert.
      Diabetes mellitus type II and obesity are two important causes of death in modern society. They are characterized by low-grade chronic inflammation and metabolic dysfunction (meta-inflammation), which is observed in all tissues involved in energy homeostasis. A substantial body of evidence has established an important role for macrophages in these tissues during the development of diabetes mellitus type II and obesity. Macrophages can activate into specialized subsets by cues from their microenvironment to handle a variety of tasks. Many different subsets have been described and in diabetes/obesity literature two main classifications are widely used that are also defined by differential metabolic reprogramming taking place to fuel their main functions. Classically activated, pro-inflammatory macrophages (often referred to as M1) favor glycolysis, produce lactate instead of metabolizing pyruvate to acetyl-CoA, and have a tricarboxylic acid cycle that is interrupted at two points. Alternatively activated macrophages (often referred to as M2) mainly use beta-oxidation of fatty acids and oxidative phosphorylation to create energy-rich molecules such as ATP and are involved in tissue repair and downregulation of inflammation. Since diabetes type II and obesity are characterized by metabolic alterations at the organism level, these alterations may also induce changes in macrophage metabolism resulting in unique macrophage activation patterns in diabetes and obesity. This review describes the interactions between metabolic reprogramming of macrophages and conditions of metabolic dysfunction like diabetes and obesity. We also focus on different possibilities of measuring a range of metabolites intra-and extracellularly in a precise and comprehensive manner to better identify the subsets of polarized macrophages that are unique to diabetes and obesity. Advantages and disadvantages of the currently most widely used metabolite analysis approaches are highlighted. We further describe how their combined use may serve to provide a comprehensive overview of the metabolic changes that take place intracellularly during macrophage activation in conditions like diabetes and obesity.
    Keywords:  DMTII; M1; M2; MS; alternatively activated macrophage; classically activated macrophage; metabolic syndrome; metabolite analysis
    DOI:  https://doi.org/10.3389/fimmu.2021.746151
  6. Front Immunol. 2021 ;12 743559
    Continuous Modeling of T CD4 Lymphocyte Activation and Function.
    David Martínez-Méndez, Luis Mendoza, Carlos Villarreal, Leonor Huerta.
      T CD4+ cells are central to the adaptive immune response against pathogens. Their activation is induced by the engagement of the T-cell receptor by antigens, and of co-stimulatory receptors by molecules also expressed on antigen presenting cells. Then, a complex network of intracellular events reinforce, diversify and regulate the initial signals, including dynamic metabolic processes that strongly influence both the activation state and the differentiation to effector cell phenotypes. The regulation of cell metabolism is controlled by the nutrient sensor adenosine monophosphate-activated protein kinase (AMPK), which drives the balance between oxidative phosphorylation (OXPHOS) and glycolysis. Herein, we put forward a 51-node continuous mathematical model that describes the temporal evolution of the early events of activation, integrating a circuit of metabolic regulation into the main routes of signaling. The model simulates the induction of anergy due to defective co-stimulation, the CTLA-4 checkpoint blockade, and the differentiation to effector phenotypes induced by external cytokines. It also describes the adjustment of the OXPHOS-glycolysis equilibrium by the action of AMPK as the effector function of the T cell develops. The development of a transient phase of increased OXPHOS before induction of a sustained glycolytic phase during differentiation to the Th1, Th2 and Th17 phenotypes is shown. In contrast, during Treg differentiation, glycolysis is subsequently reduced as cell metabolism is predominantly polarized towards OXPHOS. These observations are in agreement with experimental data suggesting that OXPHOS produces an ATP reservoir before glycolysis boosts the production of metabolites needed for protein synthesis, cell function, and growth.
    Keywords:  CTLA-4; T CD4 cells; T cell receptor; lymphocyte activation; mTOR; mathematical model; metabolism; regulatory network
    DOI:  https://doi.org/10.3389/fimmu.2021.743559
  7. iScience. 2021 Nov 19. 24(11): 103339
    Resolving macrophage polarization through distinct Ca2+ entry channel that maintains intracellular signaling and mitochondrial bioenergetics.
    Viviane Nascimento Da Conceicao, Yuyang Sun, Karthik Ramachandran, Arun Chauhan, Amritha Raveendran, Manigandan Venkatesan, Bony DeKumar, Soumya Maity, Neelanjan Vishnu, George A Kotsakis, Paul F Worley, Donald L Gill, Bibhuti B Mishra, Muniswamy Madesh, Brij B Singh.
      Transformation of naive macrophages into classically (M1) or alternatively (M2) activated macrophages regulates the inflammatory response. Here, we identified that distinct Ca2+ entry channels determine the IFNγ-induced M1 or IL-4-induced M2 transition. Naive or M2 macrophages exhibit a robust Ca2+ entry that was dependent on Orai1 channels, whereas the M1 phenotype showed a non-selective TRPC1 current. Blockade of Ca2+ entry suppresses pNF-κB/pJNK/STAT1 or STAT6 signaling events and consequently lowers cytokine production that is essential for M1 or M2 functions. Of importance, LPS stimulation shifted M2 cells from Orai1 toward TRPC1-mediated Ca2+ entry and TRPC1-/- mice exhibited transcriptional changes that suppress pro-inflammatory cytokines. In contrast, Orai1-/- macrophages showed a decrease in anti-inflammatory cytokines and exhibited a suppression of mitochondrial oxygen consumption rate and inhibited mitochondrial shape transition specifically in the M2 cells. Finally, alterations in TRPC1 or Orai1 expression determine macrophage polarization suggesting a distinct role of Ca2+ channels in modulating macrophage transformation.
    Keywords:  Immune system; Molecular biology; Molecular network
    DOI:  https://doi.org/10.1016/j.isci.2021.103339
  8. Theranostics. 2021 ;11(20): 9805-9820
    Interleukin-4 and interleukin-13 induce different metabolic profiles in microglia and macrophages that relate with divergent outcomes after spinal cord injury.
    Jesus Amo-Aparicio, Joana Garcia-Garcia, Isaac Francos-Quijorna, Andrea Urpi, Anna Esteve-Codina, Marta Gut, Albert Quintana, Ruben Lopez-Vales.
      Background: Microglia and macrophages adopt a pro-inflammatory phenotype after spinal cord injury (SCI), what is thought to contribute to secondary tissue degeneration. We previously reported that this is due, in part, to the low levels of anti-inflammatory cytokines, such as IL-4. Since IL-13 and IL-4 share receptors and both cytokines drive microglia and macrophages towards an anti-inflammatory phenotype in vitro, here we studied whether administration of IL-13 and IL-4 after SCI leads to beneficial effects. Methods: We injected mice with recombinant IL-13 or IL-4 at 48 h after SCI and assessed their effects on microglia and macrophage phenotype and functional outcomes. We also performed RNA sequencing analysis of macrophages and microglia sorted from the injured spinal cords of mice treated with IL-13 or IL-4 and evaluated the metabolic state of these cells by using Seahorse technology. Results: We observed that IL-13 induced the expression of anti-inflammatory markers in microglia and macrophages after SCI but, in contrast to IL-4, it failed to mediate functional recovery. We found that these two cytokines induced different gene signatures in microglia and macrophages after SCI and that IL-4, in contrast to IL-13, shifted microglia and macrophage metabolism from glycolytic to oxidative phosphorylation. These findings were further confirmed by measuring the metabolic profile of these cells. Importantly, we also revealed that macrophages stimulated with IL-4 or IL-13 are not deleterious to neurons, but they become cytotoxic when oxidative metabolism is blocked. This suggests that the metabolic shift, from glycolysis to oxidative phosphorylation, is required to minimize the cytotoxic responses of microglia and macrophages. Conclusions: These results reveal that the metabolic fitness of microglia and macrophages after SCI contributes to secondary damage and that strategies aimed at boosting oxidative phosphorylation might be a novel approach to minimize the deleterious actions of microglia and macrophages in neurotrauma.
    Keywords:  immune metabolism; interleukin 13; interleukin 4; polarization; spinal cord injury
    DOI:  https://doi.org/10.7150/thno.65203
  9. Metabolites. 2021 Oct 27. pii: 736. [Epub ahead of print]11(11):
    Immunometabolic Therapeutic Targets of Graft-versus-Host Disease (GvHD).
    Kudakwashe Mhandire, Komalpreet Saggu, Nataliya Prokopenko Buxbaum.
      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option in the treatment of aggressive malignant and non-malignant blood disorders. However, the benefits of allo-HSCT can be compromised by graft-versus-host disease (GvHD), a prevalent and morbid complication of allo-HSCT. GvHD occurs when donor immune cells mount an alloreactive response against host antigens due to histocompatibility differences between the donor and host, which may result in extensive tissue injury. The reprogramming of cellular metabolism is a feature of GvHD that is associated with the differentiation of donor CD4+ cells into the pathogenic Th1 and Th17 subsets along with the dysfunction of the immune-suppressive protective T regulatory cells (Tregs). The activation of glycolysis and glutaminolysis with concomitant changes in fatty acid oxidation metabolism fuel the anabolic activities of the proliferative alloreactive microenvironment characteristic of GvHD. Thus, metabolic therapies such as glycolytic enzyme inhibitors and fatty acid metabolism modulators are a promising therapeutic strategy for GvHD. We comprehensively review the role of cellular metabolism in GvHD pathogenesis, identify candidate therapeutic targets, and describe potential strategies for augmenting immunometabolism to ameliorate GvHD.
    Keywords:  GvHD; T cells; fatty acid oxidation; glycolysis; metabolism; therapeutic targets
    DOI:  https://doi.org/10.3390/metabo11110736
  10. Nat Immunol. 2021 Nov 22.
    Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.
    Bowen Wu, Tuantuan V Zhao, Ke Jin, Zhaolan Hu, Matthew P Abdel, Ken J Warrington, Jörg J Goronzy, Cornelia M Weyand.
      Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.
    DOI:  https://doi.org/10.1038/s41590-021-01065-2
  11. Cells. 2021 Oct 30. pii: 2960. [Epub ahead of print]10(11):
    The Metabolic Control of Myeloid Cells in the Tumor Microenvironment.
    Eloise Ramel, Sebastian Lillo, Boutaina Daher, Marina Fioleau, Thomas Daubon, Maya Saleh.
      Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new immunotherapies. The recent use of high-dimensional single-cell approaches, e.g., mass cytometry and single-cell RNA-sequencing (scRNA-seq) has reinforced the predominance of myeloid cells in the tumor microenvironment and uncovered their phenotypic diversity in different cancers. The cancerous metabolic environment has emerged as a critical modulator of myeloid cell functions in anti-tumor immunity versus immune suppression and immune evasion. Here, we discuss mechanisms of immune-metabolic crosstalk in tumorigenesis, with a particular focus on the tumor-associated myeloid cell's metabolic programs. We highlight the impact of several metabolic pathways on the pro-tumoral functions of tumor-associated macrophages and myeloid-derived suppressor cells and discuss the potential myeloid cell metabolic checkpoints for cancer immunotherapy, either as monotherapies or in combination with other immunotherapies.
    Keywords:  cancer; cellular metabolism; immunometabolism; immunotherapy; macrophages; myeloid cells; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells10112960
  12. Front Immunol. 2021 ;12 776879
    The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis.
    Sara Fuentelsaz-Romero, Celia Barrio-Alonso, Raquel García Campos, Mónica Torres Torresano, Ittai B Muller, Ana Triguero-Martínez, Laura Nuño, Alejandro Villalba, Rosario García-Vicuña, Gerrit Jansen, María-Eugenia Miranda-Carús, Isidoro González-Álvaro, Amaya Puig-Kröger.
      The identification of "trained immunity/tolerance" in myeloid cells has changed our perception of the performance of monocytes and macrophages during inflammatory and immune responses. Pemetrexed (PMX) and methotrexate (MTX) are blockers of the one-carbon metabolism (OCM) and commonly used therapeutic agents in cancer and rheumatoid arthritis (RA). We have previously showed that MTX promotes trained immunity in human macrophages. In the present manuscript, we have assessed the anti-inflammatory effects of PMX and MTX and found that OCM blockers alter the functional and gene expression profile of human macrophages and that OCM blockade reprograms macrophages towards a state of lipopolysaccharide (LPS) tolerance at the signaling and functional levels. Moreover, OCM blockade reduced macrophage LPS responsiveness by impairing the expression of membrane-bound and soluble CD14 (sCD14). The therapeutic relevance of these results was later confirmed in early RA patients, as MTX-responder RA patients exhibit lower sCD14 serum levels, with baseline sCD14 levels predicting MTX response. As a whole, our results demonstrate that OCM is a metabolic circuit that critically mediates the acquisition of innate immune tolerance and positions sCD14 as a valuable tool to predict MTX response in RA patients.
    Keywords:  macrophages; methotrexate; pemetrexed; predictor biomarker; sCD14
    DOI:  https://doi.org/10.3389/fimmu.2021.776879
  13. J Transl Med. 2021 Nov 25. 19(1): 477
    CD226 knockout alleviates high-fat diet induced obesity by suppressing proinflammatory macrophage phenotype.
    Jingchang Ma, Wei Hu, Dongliang Zhang, Jiangang Xie, Chujun Duan, Yitian Liu, Yuling Wang, Xuexue Xu, Kun Cheng, Boquan Jin, Yuan Zhang, Ran Zhuang.
      Obesity is associated with chronic low-grade inflammation, contributing to an increasing prevalence of chronic metabolic diseases, such as insulin resistance, non-alcoholic fatty liver disease (NALFD), and steatohepatitis. Macrophages are the predominant immune cells in adipose tissues. Adipose tissue macrophages (ATMs) would switch to pro-inflammatory M1 state during obesity, causing local and systemic inflammation. However, the regulatory mechanism of ATMs has not yet been well described within this process. Using a high-fat diet (HFD)-induced mouse obesity model, we found that the costimulatory molecule CD226 was highly expressed on ATMs and knockout (KO) of CD226 alleviated obesity caused by HFD. Loss of CD226 reduced the accumulation of ATMs and hindered macrophage M1 polarization, with lower serum proinflammatory cytokine levels. Furthermore, deficiency of CD226 on ATMs decreased the phosphorylation levels of VAV1, AKT, and FOXO1 and thereby upregulated PPAR-γ. Further administration of PPAR-γ inhibitor restored M1 phenotype in CD226KO ATMs. In summary, loss of CD226 alleviates the HFD-induced obesity and systemic inflammation through inhibition of the accumulation and M1 polarization of ATMs in which PPAR-γ-dependent signaling pathway is involved, suggesting that CD226 may be identified as a potential molecular target for the clinical treatment of obesity.
    Keywords:  CD226; HFD; Macrophage; Obesity; Polarization
    DOI:  https://doi.org/10.1186/s12967-021-03150-4
  14. Viruses. 2021 Nov 08. pii: 2245. [Epub ahead of print]13(11):
    Immunological Mechanisms of Sickness Behavior in Viral Infection.
    Mia Krapić, Inga Kavazović, Felix M Wensveen.
      Sickness behavior is the common denominator for a plethora of changes in normal behavioral routines and systemic metabolism during an infection. Typical symptoms include temperature, muscle weakness, and loss of appetite. Whereas we experience these changes as a pathology, in fact they are a carefully orchestrated response mediated by the immune system. Its purpose is to optimize immune cell functionality against pathogens whilst minimizing viral replication in infected cells. Sickness behavior is controlled at several levels, most notably by the central nervous system, but also by other organs that mediate systemic homeostasis, such as the liver and adipose tissue. Nevertheless, the changes mediated by these organs are ultimately initiated by immune cells, usually through local or systemic secretion of cytokines. The nature of infection determines which cytokine profile is induced by immune cells and therefore which sickness behavior ensues. In context of infection, sickness behavior is typically beneficial. However, inappropriate activation of the immune system may induce adverse aspects of sickness behavior. For example, tissue stress caused by obesity may result in chronic activation of the immune system, leading to lasting changes in systemic metabolism. Concurrently, metabolic disease prevents induction of appropriate sickness behavior following viral infection, thus impairing the normal immune response. In this article, we will revisit recent literature that elucidates both the benefits and the negative aspects of sickness behavior in context of viral infection.
    Keywords:  T cells; anorexia; appetite; coronavirus; cytokines; cytomegalovirus; diabetes; infection; metabolic disease; metabolism; nausea; sickness behavior
    DOI:  https://doi.org/10.3390/v13112245
  15. Cell Mol Immunol. 2021 Nov 26.
    Resident and migratory adipose immune cells control systemic metabolism and thermogenesis.
    Kevin Man, Axel Kallies, Ajithkumar Vasanthakumar.
      Glucose is a vital source of energy for all mammals. The balance between glucose uptake, metabolism and storage determines the energy status of an individual, and perturbations in this balance can lead to metabolic diseases. The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues, including adipose tissue, which is an endocrine and energy storage organ that is critical for the regulation of systemic metabolism. Adipose tissue consists of an array of different cell types, including specialized adipocytes and stromal and endothelial cells. In addition, adipose tissue harbors a wide range of immune cells that play vital roles in adipose tissue homeostasis and function. These cells contribute to the regulation of systemic metabolism by modulating the inflammatory tone of adipose tissue, which is directly linked to insulin sensitivity and signaling. Furthermore, these cells affect the control of thermogenesis. While lean adipose tissue is rich in type 2 and anti-inflammatory cytokines such as IL-10, obesity tips the balance in favor of a proinflammatory milieu, leading to the development of insulin resistance and the dysregulation of systemic metabolism. Notably, anti-inflammatory immune cells, including regulatory T cells and innate lymphocytes, protect against insulin resistance and have the characteristics of tissue-resident cells, while proinflammatory immune cells are recruited from the circulation to obese adipose tissue. Here, we review the key findings that have shaped our understanding of how immune cells regulate adipose tissue homeostasis to control organismal metabolism.
    Keywords:  adipose tissue; immune cells; metabolism
    DOI:  https://doi.org/10.1038/s41423-021-00804-7
  16. Biomedicines. 2021 Oct 30. pii: 1585. [Epub ahead of print]9(11):
    Macrophages and Iron: A Special Relationship.
    Stefania Recalcati, Gaetano Cairo.
      Macrophages perform a variety of different biological functions and are known for their essential role in the immune response. In this context, a principal function is phagocytic clearance of pathogens, apoptotic and senescent cells. However, the major targets of homeostatic phagocytosis by macrophages are old/damaged red blood cells. As such, macrophages play a crucial role in iron trafficking, as they recycle the large quantity of iron obtained by hemoglobin degradation. They also seem particularly adapted to handle and store amounts of iron that would be toxic to other cell types. Here, we examine the specific and peculiar iron metabolism of macrophages.
    Keywords:  ferroptosis; iron; macrophage
    DOI:  https://doi.org/10.3390/biomedicines9111585
  17. Front Immunol. 2021 ;12 722469
    Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness.
    Laryssa C Manigat, Mitchell E Granade, Suchet Taori, Charlotte Anne Miller, Luke R Vass, Xiao-Ping Zhong, Thurl E Harris, Benjamin W Purow.
      The diacylglycerol kinases (DGKs) are a family of enzymes responsible for the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). In addition to their primary function in lipid metabolism, DGKs have recently been identified as potential therapeutic targets in multiple cancers, including glioblastoma (GBM) and melanoma. Aside from its tumorigenic properties, DGKα is also a known promoter of T-cell anergy, supporting a role as a recently-recognized T cell checkpoint. In fact, the only significant phenotype previously observed in Dgka knockout (KO) mice is the enhancement of T-cell activity. Herein we reveal a novel, macrophage-specific, immune-regulatory function of DGKα. In bone marrow-derived macrophages (BMDMs) cultured from wild-type (WT) and KO mice, we observed increased responsiveness of KO macrophages to diverse stimuli that yield different phenotypes, including LPS, IL-4, and the chemoattractant MCP-1. Knockdown (KD) of Dgka in a murine macrophage cell line resulted in similar increased responsiveness. Demonstrating in vivo relevance, we observed significantly smaller wounds in Dgka-/- mice with full-thickness cutaneous burns, a complex wound healing process in which macrophages play a key role. The burned area also demonstrated increased numbers of macrophages. In a cortical stab wound model, Dgka-/- brains show increased Iba1+ cell numbers at the needle track versus that in WT brains. Taken together, these findings identify a novel immune-regulatory checkpoint function of DGKα in macrophages with potential implications for wound healing, cancer therapy, and other settings.
    Keywords:  BMDM; DGKα; diacylglycerol kinase; immune regulation; macrophage; wound healing
    DOI:  https://doi.org/10.3389/fimmu.2021.722469
  18. Cell Host Microbe. 2021 Nov 18. pii: S1931-3128(21)00507-2. [Epub ahead of print]
    Human gut bacterial metabolism drives Th17 activation and colitis.
    Margaret Alexander, Qi Yan Ang, Renuka R Nayak, Annamarie E Bustion, Moriah Sandy, Bing Zhang, Vaibhav Upadhyay, Katherine S Pollard, Susan V Lynch, Peter J Turnbaugh.
      Bacterial activation of T helper 17 (Th17) cells exacerbates mouse models of autoimmunity, but how human-associated bacteria impact Th17-driven disease remains elusive. We show that human gut Actinobacterium Eggerthella lenta induces intestinal Th17 activation by lifting inhibition of the Th17 transcription factor Rorγt through cell- and antigen-independent mechanisms. E. lenta is enriched in inflammatory bowel disease (IBD) patients and worsens colitis in a Rorc-dependent manner in mice. Th17 activation varies across E. lenta strains, which is attributable to the cardiac glycoside reductase 2 (Cgr2) enzyme. Cgr2 is sufficient to induce interleukin (IL)-17a, a major Th17 cytokine. cgr2+ E. lenta deplete putative steroidal glycosides in pure culture; related compounds are negatively associated with human IBD severity. Finally, leveraging the sensitivity of Cgr2 to dietary arginine, we prevented E. lenta-induced intestinal inflammation in mice. Together, these results support a role for human gut bacterial metabolism in driving Th17-dependent autoimmunity.
    Keywords:  T helper 17 cells; autoimmune disease; dietary supplementation; human gut microbiome; inflammatory bowel disease; microbial metabolism
    DOI:  https://doi.org/10.1016/j.chom.2021.11.001
  19. Nature. 2021 Nov 24.
    IL-27 signalling promotes adipocyte thermogenesis and energy expenditure.
    Qian Wang, Dehai Li, Guangchao Cao, Qiping Shi, Jing Zhu, Mingyue Zhang, Hao Cheng, Qiong Wen, Hao Xu, Leqing Zhu, Hua Zhang, Rachel J Perry, Olga Spadaro, Yunfan Yang, Shengqi He, Yong Chen, Baocheng Wang, Guangqiang Li, Zonghua Liu, Caixian Yang, Xiaoli Wu, Libing Zhou, Qinghua Zhou, Zhenyu Ju, Hongyun Lu, Yongjie Xin, Xiaoyong Yang, Cunchuan Wang, Yong Liu, Gerald I Shulman, Vishwa Deep Dixit, Ligong Lu, Hengwen Yang, Richard A Flavell, Zhinan Yin.
      Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3-6. Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-021-04127-5
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