bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒05‒22
twenty-two papers selected by
Dylan Ryan
University of Cambridge
  1. CTH exacerbates Helicobacter pylori immunopathogenesis by promoting macrophage metabolic remodeling and activation.
  2. Immunometabolism shapes B cell fate and functions.
  3. Metabolites: Fuelling the Immune Response.
  4. The metabolic characteristic of decidual immune cells and their unique properties in pregnancy loss.
  5. Depletion of CLL cells by venetoclax treatment reverses oxidative stress and impaired glycolysis in CD4 T cells.
  6. Mitochondrial metabolism mediated macrophage polarization in chronic lung diseases.
  7. Metabolic regulation of follicular helper T cell differentiation in a mouse model of lupus.
  8. The Metabolic Basis of ILC Plasticity.
  9. The ER-Mitochondria Interface as a Dynamic Hub for T Cell Efficacy in Solid Tumors.
  10. Targeting Metabolic Reprogramming of T-Cells for Enhanced Anti-Tumor Response.
  11. Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming.
  12. Sodium butyrate reverses lipopolysaccharide-induced mitochondrial dysfunction in lymphoblasts.
  13. The role of B cell metabolism in autoimmune diseases.
  14. Retinoic acid signaling acts as a rheostat to balance Treg function.
  15. Metabolic control of epigenetic rearrangements in B cell pathophysiology.
  16. Mycobacterium tuberculosis Induces Irg1 in Murine Macrophages by a Pathway Involving Both TLR-2 and STING/IFNAR Signaling and Requiring Bacterial Phagocytosis.
  17. IL-1R-IRAKM-Slc25a1 signaling axis reprograms lipogenesis in adipocytes to promote diet-induced obesity in mice.
  18. Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver.
  19. Dietary Cholesterol Causes Inflammatory Imbalance and Exacerbates Morbidity in Mice Infected with Influenza A Virus.
  20. Tetrandrine, an immunosuppressive alkaloid isolated from Steohania tetrandra S. Moore, induces the generation of Treg cells through enhancing fatty acid oxidation.
  21. Oxidized PUFAs Increase Susceptibility of Mice to Salmonella Infection by Diminishing Host's Innate Immune Responses.
  22. Arginase-1 Is Required for Macrophage-Mediated Renal Tubule Regeneration.
  1. JCI Insight. 2022 May 17. pii: e155338. [Epub ahead of print]
    CTH exacerbates Helicobacter pylori immunopathogenesis by promoting macrophage metabolic remodeling and activation.
    Yvonne L Latour, Johanna C Sierra, Jordan L Finley, Mohammad Asim, Daniel P Barry, Margaret M Allaman, Thaddeus M Smith, Kara M McNamara, Paula B Luis, Claus Schneider, Justin Jacobse, Jeremy A Goettel, M Wade Calcutt, Kristie L Rose, Kevin L Schey, Ginger L Milne, Alberto G Delgado, M Blanca Piazuelo, Bindu D Paul, Solomon Snyder, Alain P Gobert, Keith T Wilson.
      Macrophages play a crucial role in the inflammatory response to the human stomach pathogen Helicobacter pylori, which infects half of the world's population and causes gastric cancer. Recent studies have highlighted the importance of macrophage immunometabolism in their activation state and function. We have demonstrated that the cysteine-producing enzyme, cystathionine g-lyase (CTH), is upregulated in humans and mice with H. pylori infection. Here we show that induction of CTH in macrophages by H. pylori promotes persistent inflammation. Cth-/- mice have reduced macrophage and T-cell activation in H. pylori-infected tissues, an altered metabolome, and decreased enrichment of immune-associated gene networks, culminating in decreased H. pylori-induced-gastritis. CTH is downstream of the proposed anti-inflammatory molecule, S-adenosylmethionine (SAM). While Cth-/- mice exhibit gastric SAM accumulation, WT mice treated with SAM did not display protection against H. pylori-induced inflammation. Instead, we demonstrate that Cth-deficient macrophages exhibit alterations in the proteome, decreased NF-kB activation, diminished expression of macrophage activation markers, and impaired oxidative phosphorylation and glycolysis. Thus, through altering cellular respiration, CTH is a key enhancer of macrophage activation contributing to a pathogenic inflammatory response that is the universal precursor for the development of H. pylori-induced gastric disease.
    Keywords:  Amino acid metabolism; Gastroenterology; Immunology; Innate immunity; Macrophages
    DOI:  https://doi.org/10.1172/jci.insight.155338
  2. Immunology. 2022 May 15.
    Immunometabolism shapes B cell fate and functions.
    Ying Fu, Luman Wang, Baichao Yu, Damo Xu, Yiwei Chu.
      B lymphocyte-mediated humoral immune response is essential for protection against infectious diseases. Deeper research in B cell biology, particularly metabolism is required for the better understanding of its properties in homeostasis and in diseases. Emerging immunometabolism, including anabolism and catabolism, has tremendously impacts on immune cells from development to function and markedly advances our view on immunoregulation. Growing evidence suggests that the ultimate effect of intracellular metabolism on immune cell functions is not only influenced by the external stimuli, but also by the balance of the different metabolic pathways. However, B cell immunometabolism is not deeply investigated like T cells. The complex development and differentiation processes of B cell subsets have left many untouched, but fundamental aspects in B cell metabolism. Available evidence demonstrated that the intracellular metabolism has the ubiquitous impact on B cell fate and function decisions at the transcriptional regulation and signal transduction processes. In this review, we update the recent development in the immunometabolism of B cells with the latest findings including the immune-metabolic steering on B cell development, differentiation, and function skewing, and emphasis on how immunometabolism landscape may shape B cell function in metabolic, autoimmune, and inflammatory disorders. The metabolic interaction of B cells with other immune cells in disease context will also be discussed. This article is protected by copyright. All rights reserved.
    Keywords:  B cells; Immunometabolism; development; differentiation; fate decisions
    DOI:  https://doi.org/10.1111/imm.13499
  3. Clin Exp Immunol. 2022 May 16. pii: uxac053. [Epub ahead of print]
    Metabolites: Fuelling the Immune Response.
    Corrado Mauro, Diana Moreira, Nicholas Jones.
      
    DOI:  https://doi.org/10.1093/cei/uxac053
  4. Immunol Rev. 2022 May 18.
    The metabolic characteristic of decidual immune cells and their unique properties in pregnancy loss.
    Tao Zhang, Hui-Hui Shen, Xue-Yun Qin, Ming-Qing Li.
      Maternal tolerance to semi- or fully allograft conceptus is a prerequisite for the maintenance of pregnancy. Once this homeostasis is disrupted, it may result in pregnancy loss. As a potential approach to prevent pregnancy loss, targeting decidual immune cells (DICs) at the maternal-fetal interface has been suggested. Although the phenotypic features and functions of DIC have been extensively profiled, the regulatory pathways for this unique immunological adaption have yet to be elucidated. In recent years, a pivotal mechanism has been highlighted in the area of immunometabolism, by which the changes in intracellular metabolic pathways in DIC and interaction with the adjacent metabolites in the microenvironment can alter their phenotypes and function. More inspiringly, the manipulation of metabolic profiling in DIC provides a novel avenue for the prevention and treatment of pregnancy loss. Herein, this review highlights the major metabolic programs (specifically, glycolysis, ATP-adenosine metabolism, lysophosphatidic acid metabolism, and amino acid metabolism) in multiple immune cells (including decidual NK cells, macrophages, and T cells) and their integrations with the metabolic microenvironment in normal pregnancy. Importantly, this perspective may help to provide a potential therapeutic strategy for reducing pregnancy loss via targeting this interplay.
    Keywords:  decidual Mφ; decidual NK cells; decidual T cells; glycolysis; immunometabolism; lysophosphatidic acid; pregnancy loss
    DOI:  https://doi.org/10.1111/imr.13085
  5. Blood Adv. 2022 May 17. pii: bloodadvances.2022007034. [Epub ahead of print]
    Depletion of CLL cells by venetoclax treatment reverses oxidative stress and impaired glycolysis in CD4 T cells.
    J A C van Bruggen, G J W van der Windt, Mels Hoogendoorn, J Dubois, Arnon P Kater, F S Peters.
      Acquired T-cell dysfunction is characteristic of CLL and is associated with reduced efficacy of T-cell based therapies. A recently described feature of dysfunctional CLL-derived CD8 T cells is reduced metabolic plasticity. To what extend CD4 T cells are affected, and if CD4 T-cell metabolism and function can be restored upon clinical depletion of CLL cells is currently unknown. Here we address these unresolved issues by a comprehensive phenotypic, metabolic, transcriptomic and functional analysis of CD4 T cells of untreated CLL patients, and by analyzing the effects of venetoclax + obinutuzumab on the CD4 population. Resting CD4 T cells derived from CLL patients expressed lower levels of GLUT-1, displayed deteriorated oxidative phosphorylation (OXPHOS) and overall reduced mitochondrial fitness. Upon T-cell stimulation, CLL T cells were unable to initiate glycolysis. Transcriptome analysis revealed that depletion of CLL cells in vitro resulted in upregulation of OXPHOS and glycolysis pathways and restored T-cell function in vitro. Analysis of CD4 T cells from CLL patients prior and after venetoclax + obinutuzumab treatment, which led to effective clearance of CLL in blood and bone marrow, revealed recovery of T-cell activation and restoration of the switch to glycolysis, as well as improved T-cell proliferation. Collectively these data demonstrate that CLL cells impose metabolic restrictions on CD4 T cells which lead to reduced CD4 T-cell functionality. This trial is registered in the Netherlands Trial Registry ID: NTR6043.
    DOI:  https://doi.org/10.1182/bloodadvances.2022007034
  6. Pharmacol Ther. 2022 May 12. pii: S0163-7258(22)00102-4. [Epub ahead of print] 108208
    Mitochondrial metabolism mediated macrophage polarization in chronic lung diseases.
    Ting Dong, Xinyi Chen, Haochuan Xu, Yaxin Song, Huirui Wang, Yinghui Gao, Jingcheng Wang, Ruiqing Du, Hongxiang Lou, Ting Dong.
      As the first line of defence in the lung, alveolar macrophage contributes to maintaining lung immune homoeostasis. Characterized by the heterogeneity and plasticity, macrophages polarize into two pro-inflammatory and anti-inflammatory phenotypes regarding the biological and pathological environment. In the past decade, numerous studies have revolutionized the relationship between cellular metabolism and macrophage functions. Mitochondria dysfunctions, which results in altered cellular metabolic profile, were observed in the alveolar macrophages during chronic lung diseases. In addition, alveolar macrophages adapt metabolic reprogramming to produce an immune response against the pathogens. Here, we outline the role of mitochondria in the development of macrophage phenotypes and functions and highlight the mitochondrial dysfunction in the setting of chronic lung diseases. Lastly, we emphasize the therapeutic relevance of targeting metabolic pathways in alveolar macrophages, which may shed light on developing novel strategies against chronic lung diseases.
    Keywords:  Chronic lung disease; Macrophage; Macrophage polarization; Metabolic reprogramming; Mitochondria metabolism
    DOI:  https://doi.org/10.1016/j.pharmthera.2022.108208
  7. Immunol Lett. 2022 May 11. pii: S0165-2478(22)00054-2. [Epub ahead of print]
    Metabolic regulation of follicular helper T cell differentiation in a mouse model of lupus.
    Xueyang Zou, Seung-Chul Choi, Leilani Zeumer-Spataro, Yogesh Scindia, Emily K Moser, Laurence Morel.
      Follicular helper T (TFH) cells are expanded in systemic lupus erythematosus (SLE), where they are required for production of high affinity autoantibodies. A better understanding of the mechanisms that regulate the differentiation of TFH cells is critical. Naïve T cells from lupus-prone B6.NZM2410.Sle1.Sle2.Sle3 (TC) mice showed an intrinsic higher capacity to differentiate into TFH cells. Metabolic reprogramming is a vital regulatory mechanism for T cell differentiation, but how metabolic pathways contribute to TFH cell expansion in SLE remains elusive. Here we show that glycolysis, mTOR signaling, FAO, and the activity of complex V of the electron transport chain support TFH lineage commitment. Blocking complex I uniquely decreased the expansion of TFH cells from lupus-prone mice, and inhibition of some pathways had a greater effect in lupus-prone than control TFH cells. However, blocking glutaminolysis, complex III and ADP/ATP translocase did not affect TFH cell expansion. Together, our results identified novel intrinsic metabolic requirements for TFH cell differentiation, and further defined the differential metabolic pathways that support the expansion of TFH cells in lupus-prone mice. Together, our data indicates the crucial but distinct roles for metabolic pathways in TFH cell differentiation and provide a comprehensive experimental basis for fully understanding the precise roles of distant metabolic signaling in regulating the TFH cell differentiation.
    Keywords:  Follicular helper T cells; Metabolic pathways; SLE
    DOI:  https://doi.org/10.1016/j.imlet.2022.03.008
  8. Front Immunol. 2022 ;13 858051
    The Metabolic Basis of ILC Plasticity.
    Abigaelle Pelletier, Christian Stockmann.
      Innate Lymphoid Cells (ILCs) are the innate counterpart of adaptive lymphoid T cells. They are key players in the regulation of tissues homeostasis and early inflammatory host responses. ILCs are divided into three groups, and further subdivided into five subsets, that are characterised by distinct transcription factors, surface markers and their cytokine expression profiles. Group 1 ILCs, including natural killer (NK) cells and non-NK cell ILC1s, express T-bet and produce IFN-γ. Group 2 ILCs depend on GATA3 and produce IL-4, IL-5 and IL-13. Group 3 ILCs, composed of ILC3s and Lymphoid Tissue Inducer (LTi) cells, express RORγt and produce IL-17 and IL-22. Even though, the phenotype of each subset is well defined, environmental signals can trigger the interconversion of phenotypes and the plasticity of ILCs, in both mice and humans. Several extrinsic and intrinsic drivers of ILC plasticity have been described. However, the changes in cellular metabolism that underlie ILC plasticity remain largely unexplored. Given that metabolic changes critically affect fate and effector function of several immune cell types, we, here, review recent findings on ILC metabolism and discuss the implications for ILC plasticity.
    Keywords:  Innate Lymphoid Cells (ILCs); OxPhos; cytokines; glycolysis; metabolism; plasticity
    DOI:  https://doi.org/10.3389/fimmu.2022.858051
  9. Front Cell Dev Biol. 2022 ;10 867341
    The ER-Mitochondria Interface as a Dynamic Hub for T Cell Efficacy in Solid Tumors.
    Elizabeth G Hunt, Alex M Andrews, Sydney R Larsen, Jessica E Thaxton.
      The endoplasmic reticulum (ER) is a large continuous membranous organelle that plays a central role as the hub of protein and lipid synthesis while the mitochondria is the principal location for energy production. T cells are an immune subset exhibiting robust dependence on ER and mitochondrial function based on the need for protein synthesis and secretion and metabolic dexterity associated with foreign antigen recognition and cytotoxic effector response. Intimate connections exist at mitochondrial-ER contact sites (MERCs) that serve as the structural and biochemical platforms for cellular metabolic homeostasis through regulation of fission and fusion as well as glucose, Ca2+, and lipid exchange. Work in the tumor immunotherapy field indicates that the complex interplay of nutrient deprivation and tumor antigen stimulation in the tumor microenvironment places stress on the ER and mitochondria, causing dysfunction in organellar structure and loss of metabolic homeostasis. Here, we assess prior literature that establishes how the structural interface of these two organelles is impacted by the stress of solid tumors along with recent advances in the manipulation of organelle homeostasis at MERCs in T cells. These findings provide strong evidence for increased tumor immunity using unique therapeutic avenues that recharge cellular metabolic homeostasis in T cells.
    Keywords:  ER stress; MERCs; T cell; cancer immunotherapy; endoplasmic recticulum (ER); metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2022.867341
  10. Biologics. 2022 ;16 35-45
    Targeting Metabolic Reprogramming of T-Cells for Enhanced Anti-Tumor Response.
    Yosef Tsegaye Dabi, Henok Andualem, Sisay Teka Degechisa, Solomon Tebeje Gizaw.
      Cancer immunotherapy is an effective treatment option against cancer. One of the approaches of cancer immunotherapy is the modification of T cell-based anti-tumor immune responses. T-cells, a type of adaptive immune response cells responsible for cell-mediated immunity, have long been recognized as key regulators of immune-mediated anti-tumor immunity. T-cell activities have been reported to be suppressed or enhanced by changes in cell metabolism. Moreover, metabolic reprogramming during activation of T cells is required for the development of distinct differentiation profiles of these cells, which may allow the development of long-term cell-mediated anti-tumor immunity. However, T cells have been shown to undergo metabolic exhaustion in tumor microenvironment (TME) as it poses several obstacles to their function. Applications of several mechanistic solutions to improve the efficacy of T cell-based therapies including chimeric antigen receptor (CAR) T cell therapy are yet to be determined. Modifying the metabolic properties of these cells and employing them in cancer immunotherapy is a potential strategy for improving their anti-tumor activity and therapeutic efficacy. To give an insight, in this review paper, we endeavoured to cover metabolic reprogramming in cancer and T cells, signalling mechanisms involved in immuno-metabolic regulation, the effects of the TME on T cell metabolic fitness, and targeting metabolic reprogramming of T cells for an enhanced anti-tumor response.
    Keywords:  T-cell; cancer; immunotherapy; metabolic reprogramming
    DOI:  https://doi.org/10.2147/BTT.S365490
  11. Cell Mol Life Sci. 2022 May 19. 79(6): 301
    Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming.
    Sadiq Umar, Karol Palasiewicz, Anja Meyer, Prabhakaran Kumar, Bellur S Prabhakar, Michael V Volin, Rani Rahat, Mina Al-Awqati, Huan J Chang, Ryan K Zomorrodi, Jalees Rehman, Shiva Shahrara.
      Escalated innate immunity plays a critical role in SARS-CoV-2 pathology; however, the molecular mechanism is incompletely understood. Thus, we aim to characterize the molecular mechanism by which SARS-CoV-2 Spike protein advances human macrophage (Mϴ) inflammatory and glycolytic phenotypes and uncover novel therapeutic strategies. We found that human Mϴs exposed to Spike protein activate IRAK4 phosphorylation. Blockade of IRAK4 in Spike protein-stimulated Mϴs nullifies signaling of IRAK4, AKT, and baseline p38 without affecting ERK and NF-κB activation. Intriguingly, IRAK4 inhibitor (IRAK4i) rescues the SARS-CoV-2-induced cytotoxic effect in ACE2+HEK 293 cells. Moreover, the inflammatory reprogramming of Mϴs by Spike protein was blunted by IRAK4i through IRF5 and IRF7, along with the reduction of monokines, IL-6, IL-8, TNFα, and CCL2. Notably, in Spike protein-stimulated Mϴs, suppression of the inflammatory markers by IRAK4i was coupled with the rebalancing of oxidative phosphorylation over metabolic activity. This metabolic adaptation promoted by IRAK4i in Spike protein-activated Mϴs was shown to be in part through constraining PFKBF3, HIF1α, cMYC, LDHA, lactate expression, and reversal of citrate and succinate buildup. IRAK4 knockdown could comparably impair Spike protein-enhanced inflammatory and metabolic imprints in human Mϴs as those treated with ACE2, TLR2, and TLR7 siRNA. Extending these results, in murine models, where human SARS-CoV-2 Spike protein was not recognized by mouse ACE2, TLRs were responsible for the inflammatory and glycolytic responses instigated by Spike protein and were dysregulated by IRAK4i therapy. In conclusion, IRAK4i may be a promising strategy for severe COVID-19 patients by counter-regulating ACE2 and TLR-mediated Mϴ hyperactivation. IRAK4i therapy counteracts Mϴ inflammatory and glycolytic reprogramming triggered by Spike protein. This study illustrates that SARS-CoV-2 Spike protein activates IRAK4 signaling via ACE2 as well as TLR2 and TLR7 sensing in human Mϴs. Remarkably, IRAK4i treatment can dysregulate both ACE-dependent and independent (via TLR sensing) SARS-CoV-2 Spike protein-activated inflammatory and metabolic imprints.
    Keywords:  Glycolysis; IRAK4 inhibitor; Macrophages; Mitochondrial oxidative phosphorylation; SARS-COV-2 Spike protein; TLRs
    DOI:  https://doi.org/10.1007/s00018-022-04329-8
  12. J Cell Mol Med. 2022 May 19.
    Sodium butyrate reverses lipopolysaccharide-induced mitochondrial dysfunction in lymphoblasts.
    Scott L Weiss, Donglan Zhang, Sumera Farooqi, Douglas C Wallace.
      Butyrate is a short-chain fatty acid that is produced by commensal microbes within the intestinal microbiome through fermentation of dietary fibre. Microbial-derived butyrate has been shown to promote immunologic and metabolic homeostasis, in part through its beneficial effects on mitochondrial function, and thus has been proposed as a possible anti-inflammatory therapy. We tested the hypothesis that butyrate could mitigate the decrease in mitochondrial respiration in immune cells under septic conditions as a preliminary step towards better understanding the potential for butyrate as a novel therapy in sepsis. Mitochondrial respiration and content (measured as citrate synthase activity) were compared within four Epstein-Barr virus-transformed lymphoblast (LB) cell lines exposed to either control media or lipopolysaccharide (LPS) 100 ng/ml. Both co-incubation of LBs with LPS + butyrate and treatment with butyrate after LPS stimulation reversed the decrease in mitochondrial respiration observed in LBs exposed to LPS without butyrate. Neither LPS nor butyrate led to significant changes in citrate synthase activity. The preliminary findings support further investigation of a potential mitochondrial-based mechanism through which butyrate may help to mitigate the immuno-inflammatory response in sepsis.
    Keywords:  human immunology; immunometabolism; metabolism; mitochondria; sepsis
    DOI:  https://doi.org/10.1111/jcmm.17342
  13. Autoimmun Rev. 2022 May 17. pii: S1568-9972(22)00086-6. [Epub ahead of print] 103116
    The role of B cell metabolism in autoimmune diseases.
    Raeda Mubariki, Zahava Vadasz.
      B cells are major players in immune responses being the source of protective antibodies and antigen presenting cells. When self-tolerance fails, auto reactive B cells produce autoantibodies and pro-inflammatory cytokines leading to the development of autoimmune diseases. Many recent studies have assessed importance of metabolic pathways in B cells, demonstrating their role in controlling autoimmunity and maintaining immune homeostasis. Alterations in B cell functions in autoimmune diseases are closely associated with abnormal metabolic shifts, allowing auto reactive B cells to escape tolerogenic checkpoints. Understanding the metabolic changes in B cells, opens up new possibilities for targeting metabolic pathways and manipulating metabolic avenues as a therapeutic strategy for the treatment of autoimmune diseases.
    Keywords:  Autoimmune diseases; B cell metabolism
    DOI:  https://doi.org/10.1016/j.autrev.2022.103116
  14. Cell Mol Immunol. 2022 May 17.
    Retinoic acid signaling acts as a rheostat to balance Treg function.
    Govindarajan Thangavelu, Gabriela Andrejeva, Sara Bolivar-Wagers, Sujeong Jin, Michael C Zaiken, Michael Loschi, Ethan G Aguilar, Scott N Furlan, Chrysothemis C Brown, Yu-Chi Lee, Cameron McDonald Hyman, Colby J Feser, Angela Panoskaltsis-Mortari, Keli L Hippen, Kelli P MacDonald, William J Murphy, Ivan Maillard, Geoffrey R Hill, David H Munn, Robert Zeiser, Leslie S Kean, Jeffrey C Rathmell, Hongbo Chi, Randolph J Noelle, Bruce R Blazar.
      Regulatory T cells (Tregs) promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses. Under certain inflammatory conditions, Tregs can lose their lineage stability and function. Previous studies have reported that ex vivo exposure to retinoic acid (RA) enhances Treg function and stability. However, it is unknown how RA receptor signaling in Tregs influences these processes in vivo. Herein, we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor (DN) RARα in all T cells. Despite the fact that DNRARα conventional T cells are hypofunctional, Tregs had increased CD25 expression, STAT5 pathway activation, mTORC1 signaling and supersuppressor function. Furthermore, DNRARα Tregs had increased inhibitory molecule expression, amino acid transporter expression, and metabolic fitness and decreased antiapoptotic proteins. Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist. Unexpectedly, Treg-specific expression of DNRARα resulted in distinct phenotypes, such that a single allele of DNRARα in Tregs heightened their suppressive function, and biallelic expression led to loss of suppression and autoimmunity. The loss of Treg function was not cell intrinsic, as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARα and wild-type bone marrow maintained the enhanced suppressive capacity. Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling. Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.
    Keywords:  Autoimmunity; Metabolism; Retinoic acid; STAT5; Tregulatory cells; mTORC1
    DOI:  https://doi.org/10.1038/s41423-022-00869-y
  15. Open Biol. 2022 May;12(5): 220038
    Metabolic control of epigenetic rearrangements in B cell pathophysiology.
    Beatrice Calciolari, Greta Scarpinello, Laura Quotti Tubi, Francesco Piazza, Alessandro Carrer.
      Both epigenetic and metabolic reprogramming guide lymphocyte differentiation and can be linked, in that metabolic inputs can be integrated into the epigenome to inform cell fate decisions. This framework has been thoroughly investigated in several pathophysiological contexts, including haematopoietic cell differentiation. In fact, metabolite availability dictates chromatin architecture and lymphocyte specification, a multi-step process where haematopoietic stem cells become terminally differentiated lymphocytes (effector or memory) to mount the adaptive immune response. B and T cell precursors reprogram their cellular metabolism across developmental stages, not only to meet ever-changing energetic demands but to impose chromatin accessibility and regulate the function of master transcription factors. Metabolic control of the epigenome has been extensively investigated in T lymphocytes, but how this impacts type-B life cycle remains poorly appreciated. This assay will review our current understanding of the connection between cell metabolism and epigenetics at crucial steps of B cell maturation and how its dysregulation contributes to malignant transformation.
    Keywords:  B cell; epigenetics; lymphoma; metabolism
    DOI:  https://doi.org/10.1098/rsob.220038
  16. Front Cell Infect Microbiol. 2022 ;12 862582
    Mycobacterium tuberculosis Induces Irg1 in Murine Macrophages by a Pathway Involving Both TLR-2 and STING/IFNAR Signaling and Requiring Bacterial Phagocytosis.
    Caio C B Bomfim, Logan Fisher, Eduardo P Amaral, Lara Mittereder, Katelyn McCann, André A S Correa, Sivaranjani Namasivayam, Muthulekha Swamydas, Mahtab Moayeri, Jonathan M Weiss, Raj Chari, Daniel W McVicar, Diego L Costa, Maria R D'Império Lima, Alan Sher.
      Irg1 is an enzyme that generates itaconate, a metabolite that plays a key role in the regulation of inflammatory responses. Previous studies have implicated Irg1 as an important mediator in preventing excessive inflammation and tissue damage in Mycobacterium tuberculosis (Mtb) infection. Here, we investigated the pattern recognition receptors and signaling pathways by which Mtb triggers Irg1 gene expression by comparing the responses of control and genetically deficient BMDMs. Using this approach, we demonstrated partial roles for TLR-2 (but not TLR-4 or -9), MyD88 and NFκB signaling in Irg1 induction by Mtb bacilli. In addition, drug inhibition studies revealed major requirements for phagocytosis and endosomal acidification in Irg1 expression triggered by Mtb but not LPS or PAM3CSK4. Importantly, the Mtb-induced Irg1 response was highly dependent on the presence of the bacterial ESX-1 secretion system, as well as host STING and Type I IFN receptor (IFNAR) signaling with Type II IFN (IFN-γ) signaling playing only a minimal role. Based on these findings we hypothesize that Mtb induces Irg1 expression in macrophages via the combination of two independent triggers both dependent on bacterial phagocytosis: 1) a major signal stimulated by phagocytized Mtb products released by an ESX-1-dependent mechanism into the cytosol where they activate the STING pathway leading to Type I-IFN production, and 2) a secondary TLR-2, MyD88 and NFκB dependent signal that enhances Irg1 production independently of Type I IFN induction.
    Keywords:  ESAT-6; ESX-1 system; IFN; Irg1; Mycobacterium tuberculosis; STING; TLR-2; macrophages
    DOI:  https://doi.org/10.3389/fcimb.2022.862582
  17. Nat Commun. 2022 May 18. 13(1): 2748
    IL-1R-IRAKM-Slc25a1 signaling axis reprograms lipogenesis in adipocytes to promote diet-induced obesity in mice.
    Weiwei Liu, Hao Zhou, Han Wang, Quanri Zhang, Renliang Zhang, Belinda Willard, Caini Liu, Zizhen Kang, Xiao Li, Xiaoxia Li.
      Toll-like receptors/Interleukin-1 receptor signaling plays an important role in high-fat diet-induced adipose tissue dysfunction contributing to obesity-associated metabolic syndromes. Here, we show an unconventional IL-1R-IRAKM-Slc25a1 signaling axis in adipocytes that reprograms lipogenesis to promote diet-induced obesity. Adipocyte-specific deficiency of IRAKM reduces high-fat diet-induced body weight gain, increases whole body energy expenditure and improves insulin resistance, associated with decreased lipid accumulation and adipocyte cell sizes. IL-1β stimulation induces the translocation of IRAKM Myddosome to mitochondria to promote de novo lipogenesis in adipocytes. Mechanistically, IRAKM interacts with and phosphorylates mitochondrial citrate carrier Slc25a1 to promote IL-1β-induced mitochondrial citrate transport to cytosol and de novo lipogenesis. Moreover, IRAKM-Slc25a1 axis mediates IL-1β induced Pgc1a acetylation to regulate thermogenic gene expression in adipocytes. IRAKM kinase-inactivation also attenuates high-fat diet-induced obesity. Taken together, our study suggests that the IL-1R-IRAKM-Slc25a1 signaling axis tightly links inflammation and adipocyte metabolism, indicating a potential therapeutic target for obesity.
    DOI:  https://doi.org/10.1038/s41467-022-30470-w
  18. Cell Mol Immunol. 2022 May 20.
    Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver.
    Wenshu Tang, Jingying Zhou, Weiqin Yang, Yu Feng, Haoran Wu, Myth T S Mok, Lingyun Zhang, Zhixian Liang, Xiaoyu Liu, Zhewen Xiong, Xuezhen Zeng, Jing Wang, Jiahuan Lu, Jingqing Li, Hanyong Sun, Xiaoyu Tian, Philip Chun Yeung, Yong Hou, Heung Man Lee, Candice C H Lam, Howard H W Leung, Anthony W H Chan, Ka Fai To, John Wong, Paul B S Lai, Kelvin K C Ng, Simon K H Wong, Vincent W S Wong, Alice P S Kong, Joseph J Y Sung, Alfred S L Cheng.
      Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8+ T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.
    Keywords:  HCC; NAFLD; NKT cells; cholesterol; mTOR
    DOI:  https://doi.org/10.1038/s41423-022-00872-3
  19. J Immunol. 2022 Jun 01. 208(11): 2523-2539
    Dietary Cholesterol Causes Inflammatory Imbalance and Exacerbates Morbidity in Mice Infected with Influenza A Virus.
    Allison Y Louie, Joseph Tingling, Evan Dray, Jamal Hussain, Daniel B McKim, Kelly S Swanson, Andrew J Steelman.
      Influenza is a common cause of pneumonia-induced hospitalization and death, but how host factors function to influence disease susceptibility or severity has not been fully elucidated. Cellular cholesterol levels may affect the pathogenesis of influenza infection, as cholesterol is crucial for viral entry and replication, as well as immune cell proliferation and function. However, there is still conflicting evidence on the extent to which dietary cholesterol influences cholesterol metabolism. In this study, we examined the effects of a high-cholesterol diet in modulating the immune response to influenza A virus (IAV) infection in mice. Mice were fed a standard or a high-cholesterol diet for 5 wk before inoculation with mouse-adapted human IAV (Puerto Rico/8/1934), and tissues were collected at days 0, 4, 8, and 16 postinfection. Cholesterol-fed mice exhibited dyslipidemia characterized by increased levels of total serum cholesterol prior to infection and decreased triglycerides postinfection. Cholesterol-fed mice also displayed increased morbidity compared with control-fed mice, which was neither a result of immunosuppression nor changes in viral load. Instead, transcriptomic analysis of the lungs revealed that dietary cholesterol caused upregulation of genes involved in viral-response pathways and leukocyte trafficking, which coincided with increased numbers of cytokine-producing CD4+ and CD8+ T cells and infiltrating dendritic cells. Morbidity as determined by percent weight loss was highly correlated with numbers of cytokine-producing CD4+ and CD8+ T cells as well as granulocytes. Taken together, dietary cholesterol promoted IAV morbidity via exaggerated cellular immune responses that were independent of viral load.
    DOI:  https://doi.org/10.4049/jimmunol.2100927
  20. Immunology. 2022 May 15.
    Tetrandrine, an immunosuppressive alkaloid isolated from Steohania tetrandra S. Moore, induces the generation of Treg cells through enhancing fatty acid oxidation.
    Yulai Fang, Qin Zhang, Xusheng Yuan, Changjun Lv, Jing Zhang, Yanrong Zhu, Zhifeng Wei, Yufeng Xia, Yue Dai.
      BACKGROUND: Our previous studies have demonstrated that tetrandrine can induce the generation of regulatory T (Treg) cells in vitro and in vivo. But, the underlying mechanism of tetrandrine remains obscure.METHODS: Naïve CD4+ T cells are isolated from the mesenteric lymph nodes of mice for the differentiation of Treg cells. Flow cytometry is used to detect the frequencies of Treg cells. Non-targeted metabolomics analysis based on UHPLC-QTOF/MS is performed to assess the intracellular metabolic profiles. ChIP-PCR analysis is conducted to detect the level of H3K27ac at Foxp3 promoter and CNS regions.
    RESULTS: Tetrandrine treatment alters the metabolic profile of Treg cells, and pathway enrichment of differential metabolites mainly involves fatty acid oxidation (FAO). Tetrandrine promotes the mRNA expression of carnitine palmitoyl transferase-1, and increases the level of acetyl coenzyme A (acetyl-CoA) and the intracellular oxygen consumption rate. Either CPT1 inhibitor (etomoxir) or siRNA markedly diminishes the promotion of tetrandrine on Treg cell differentiation. Furthermore, tetrandrine enhances the acetylation of H3K27 in the promoter and CNS1 regions of Foxp3 through the acetyl-CoA derived from FAO. In the mice with collagen-induced arthritis, tetrandrine also induces Treg cell generation through FAO pathway. In addition, tetrandrine enhances the immunosuppressive function of Treg cells both in vitro and in vivo.
    CONCLUSION: The findings indicate that tetrandrine promotes Treg cell differentiation by enhancing FAO-mediated Foxp3 acetylation, and the CPT1-mediated FAO can serve as the target for the discovery of novel inducers of Treg cell generation. This article is protected by copyright. All rights reserved.
    Keywords:  Treg cells; acetylation; fatty acid oxidation; tetrandrine
    DOI:  https://doi.org/10.1111/imm.13500
  21. J Agric Food Chem. 2022 May 19.
    Oxidized PUFAs Increase Susceptibility of Mice to Salmonella Infection by Diminishing Host's Innate Immune Responses.
    Yuandong Wang, Jiaxiu Liu, Huanhuan Liu, Lingzhi Liu, Xingchen Gao, Yuqin Tong, Shuang Song, Chunhong Yan.
      Dietary ω-3 PUFAs are highly prone to oxidation, and this may potentially limit their application in the health-promoting field. Here, we sought to investigate whether and how oxidized PUFAs modulate the susceptibility of mice to Salmonella typhimurium (S. Tm) infection. Algae oil (AO) and oxidized algae oil (ox-AO) were administered to the C57BL/6 mice prior to S. Tm infection. Compared to the S. Tm group, ox-AO increased bacterial burden in systemic and intestinal tissues, downregulated host anti-infection responses, and developed worse colitis. In macrophages, ox-AO decreased both phagocytosis of S. Tm and clearance of intracellular bacteria and dampened the activation of mitogen-activated protein kinase (MAPK), NF-κB, and autophagy pathways. Furthermore, ox-AO diminished LPS-induced inflammatory cytokine production and S. Tm induced NLRC4 inflammasome activation. This study reveals that oxidized PUFAs may contribute to the development of enteric infections and regular monitoring of the oxidation status in commercial PUFA supplements to prevent their potential adverse impact on human health.
    Keywords:  Salmonella; algae oil; immunity; inflammasome; murine; oxidized PUFAs
    DOI:  https://doi.org/10.1021/acs.jafc.2c00099
  22. J Am Soc Nephrol. 2022 May 16. pii: ASN.2021121548. [Epub ahead of print]
    Arginase-1 Is Required for Macrophage-Mediated Renal Tubule Regeneration.
    Naomi S Shin, Arnaud Marlier, Leyuan Xu, Natnael Doilicho, Daniel Linberg, Jiankan Guo, Lloyd G Cantley.
      BACKGROUND: After kidney injury, macrophages transition from initial proinflammatory activation to a proreparative phenotype characterized by expression of arginase-1 (Arg1), mannose receptor 1 (Mrc1), and macrophage scavenger receptor 1 (Msr1). The mechanism by which these alternatively activated macrophages promote repair is unknown.METHODS: We characterized the macrophage and renal responses after ischemia-reperfusion injury with contralateral nephrectomy in LysM-Cre;Arg1fl/fl mice and littermate controls and used in vitro coculture of macrophages and tubular cells to determine how macrophage-expressed arginase-1 promotes kidney repair.
    RESULTS: After ischemia-reperfusion injury with contralateral nephrectomy, Arg1-expressing macrophages were almost exclusively located in the outer stripe of the medulla adjacent to injured S3 tubule segments containing luminal debris or casts. Macrophage Arg1 expression was reduced by more than 90% in injured LysM-Cre;Arg1fl/fl mice, resulting in decreased mouse survival, decreased renal tubular cell proliferation and decreased renal repair compared with littermate controls. In vitro studies demonstrate that tubular cells exposed apically to dead cell debris secrete high levels of GM-CSF and induce reparative macrophage activation, with those macrophages in turn secreting Arg1-dependent factor(s) that directly stimulate tubular cell proliferation.
    CONCLUSIONS: GM-CSF-induced, proreparative macrophages express arginase-1, which is required for the S3 tubular cell proliferative response that promotes renal repair after ischemia-reperfusion injury.
    Keywords:  arginase-1; kidney repair; kidney tubules; macrophage; regeneration
    DOI:  https://doi.org/10.1681/ASN.2021121548
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