bims-traimu Biomed News
on Trained immunity
Issue of 2024‒01‒07
fourteen papers selected by
Yantong Wan, Southern Medical University
  1. Rice-derived arabinoxylan fibers are particle size-dependent inducers of trained immunity in a human macrophage-intestinal epithelial cell co-culture model.
  2. Polysaccharide of Asparagus cochinchinensis (Lour.) Merr regulates macrophage immune response and epigenetic memory through TLR4-JNK/p38/ERK signaling pathway and histone modification.
  3. BCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination.
  4. Improved bladder cancer antitumor efficacy with a recombinant BCG that releases a STING agonist.
  5. BCG-mediated viral protection goes biphasic.
  6. Borrelia burgdorferi initiates early transcriptional re-programming in macrophages that supports long-term suppression of inflammation.
  7. Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection.
  8. Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis.
  9. TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53.
  10. TRAM deletion attenuates monocyte exhaustion and alleviates sepsis severity.
  11. ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis.
  12. TLR agonists as vaccine adjuvants in the prevention of viral infections: an overview.
  13. ADAR1 protects pulmonary macrophages from sepsis-induced pyroptosis and lung injury through miR-21/A20 signaling.
  14. ROS-induced metabolic reprogramming to one-carbon metabolism and S-adenosylmethionine-mediated epigenetic modification in IL-10-producing B cells for the resolution of pneumonia.
  1. Curr Res Food Sci. 2024 ;8 100666
    Rice-derived arabinoxylan fibers are particle size-dependent inducers of trained immunity in a human macrophage-intestinal epithelial cell co-culture model.
    Bart G J Moerings, Suzanne Abbring, Monic M M Tomassen, Henk A Schols, Renger F Witkamp, Klaske van Norren, Coen Govers, Jeroen van Bergenhenegouwen, Jurriaan J Mes.
      Arabinoxylans have been identified for a wide range of purported health-promoting applications, primarily attributed to its immunomodulatory effects. Previously, we have reported the ability of arabinoxylans to induce non-specific memory in innate immune cells, commonly referred to as "trained innate immunity". In the present study, we investigated the effect of particle size on innate immune training and resilience in primary human macrophages as well as in a more physiologically relevant macrophage-intestinal epithelial cell co-culture model. We demonstrated that smaller (>45 & < 90 μm) compared to larger (>90 μm) particle size fractions of rice bran-derived arabinoxylan preparations have a higher enhancing effect on training and resilience in both models. Smaller particle size fractions elevated TNF-α production in primary macrophages and enhanced Dectin-1 receptor activation in reporter cell lines compared to larger particles. Responses were arabinoxylan source specific as only the rice-derived arabinoxylans showed these immune-supportive effects. This particle size-dependent induction of trained immunity was confirmed in the established co-culture model. These findings demonstrate the influence of particle size on the immunomodulatory potential of arabinoxylans, provide further insight into the structure-activity relationship, and offer new opportunities to optimize the immune-enhancing effects of these dietary fibers.
    Keywords:  Arabinoxylan; Co-culture model; Dectin-1; Particle size; Trained immunity
    DOI:  https://doi.org/10.1016/j.crfs.2023.100666
  2. Phytomedicine. 2023 Dec 17. pii: S0944-7113(23)00652-9. [Epub ahead of print]124 155294
    Polysaccharide of Asparagus cochinchinensis (Lour.) Merr regulates macrophage immune response and epigenetic memory through TLR4-JNK/p38/ERK signaling pathway and histone modification.
    Xiao-Dong Xie, Min Tang, Shou-Li Yi, Ying He, Si-Yu Chen, Yi Zhao, Qi Chen, Mi-Xia Cao, Mei-Ling Yu, Ying-Yi Wei, Wei-Hua Yu, Ting-Jun Hu.
      BACKGROUND: Innate immune memory of macrophages is closely linked to histone modifications. While various studies have demonstrated that the polysaccharide of Asparagus cochinchinensis (Lour.) Merr (ACMP), extracted through alcohol-alkali extraction, enhances macrophages' non-specific immune function; no literature currently addresses whether ACMP's regulatory effect is related to innate immune memory and histone modification.PURPOSE: This study aims to investigate if ACMP induces innate immune memory emergence in macrophages via pattern recognition receptor (PRR).
    STUDY DESIGN: After co-incubating different doses of ACMP with RAW264.7 cells and BMDM cells, we observed changes in signaling pathways related to PRR and assessed the presence of innate immune memory phenomenon in the cells.
    METHODS: We observed the morphological characteristics of the ACMP using a scanning electron microscope, infrared spectrum, and HPLC pre-column derivatization method. We used q-PCR, Western blot, RNA-seq, and CUT&Tag-seq methods to examine ACMP's regulation of macrophage immune response and innate immune memory and explored its specific mechanism.
    RESULTS: ACMP, primarily composed of Man, GlcN, Rha, Fuc, GalA, Xyl, Glc, Gal, Ara, and, exhibited a molar ratio of each monosaccharide (1.41: 0.35: 0.49: 0.18: 1.00: 97.12: 0.36: 3.58: 1.14). ACMP regulated immunological function in macrophages through the TLR4-MAPK-JNK/p38/ERK pathway. ACMP induced elevated levels of chromosomal H3K4me1, enhancing TNF-α, IL-1β, and other genes' responsiveness, allowing macrophages to develop innate immune memory to ACMP stimulation.
    CONCLUSION: This study first time demonstrates that ACMP regulates immunological function through the TLR4-MAPK-JNK/ERK/p38 signaling pathway, distinct from prior reports. ACMP induces innate immune memory in macrophages in response to its immune stimulation by promoting increased H3K4me1 on chromosomes. This mechanism may be crucial in how plant polysaccharides regulate macrophages and the body's immune function.
    Keywords:  Asparagus cochinchinensis (lour.) Merr; H3K4me1; Innate immune memory; TLR4
    DOI:  https://doi.org/10.1016/j.phymed.2023.155294
  3. Nat Commun. 2024 Jan 02. 15(1): 114
    BCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination.
    Krista E van Meijgaarden, Wenchao Li, Simone J C F M Moorlag, Valerie A C M Koeken, Hans J P M Koenen, Leo A B Joosten, Annapurna Vyakarnam, Asma Ahmed, Srabanti Rakshit, Vasista Adiga, Tom H M Ottenhoff, Yang Li, Mihai G Netea, Simone A Joosten.
      Bacillus Calmette-Guèrin - vaccination induces not only protection in infants and young children against severe forms of tuberculosis, but also against non-tuberculosis related all-cause mortality. To delineate different factors influencing mycobacterial growth control, here we first investigate the effects of BCG-vaccination in healthy Dutch adults. About a quarter of individuals already control BCG-growth prior to vaccination, whereas a quarter of the vaccinees acquires the capacity to control BCG upon vaccination. This leaves half of the population incapable to control BCG-growth. Single cell RNA sequencing identifies multiple processes associated with mycobacterial growth control. These data suggest (i) that already controllers employ different mechanisms to control BCG-growth than acquired controllers, and (ii) that half of the individuals fail to develop measurable growth control irrespective of BCG-vaccination. These results shed important new light on the variable immune responses to mycobacteria in humans and may impact on improved vaccination against tuberculosis and other diseases.
    DOI:  https://doi.org/10.1038/s41467-023-44252-5
  4. bioRxiv. 2023 Dec 15. pii: 2023.12.15.571740. [Epub ahead of print]
    Improved bladder cancer antitumor efficacy with a recombinant BCG that releases a STING agonist.
    Peter K Um, Monali Praharaj, Kara A Lombardo, Takahiro Yoshida, Andres Matoso, Alex S Baras, Liang Zhao, Geetha Srikrishna, Joy Huang, Pankaj Prasad, Max Kates, David McConkey, Drew M Pardoll, William R Bishai, Trinity J Bivalacqua.
      Despite the introduction of several new agents for the treatment of bladder cancer (BC), intravesical BCG remains a first line agent for the management of non-muscle invasive bladder cancer. In this study we evaluated the antitumor efficacy in animal models of BC of a recombinant BCG known as BCG- disA -OE that releases the small molecule STING agonist c-di-AMP. We found that compared to wild-type BCG (BCG-WT), in both the orthotopic, carcinogen-induced rat MNU model and the heterotopic syngeneic mouse MB-49 model BCG- disA -OE afforded improved antitumor efficacy. A mouse safety evaluation further revealed that BCG- disA -OE proliferated to lesser degree than BCG-WT in BALB/c mice and displayed reduced lethality in SCID mice. To probe the mechanisms that may underlie these effects, we found that BCG- disA -OE was more potent than BCG-WT in eliciting IFN-β release by exposed macrophages, in reprogramming myeloid cell subsets towards an M1-like proinflammatory phenotypes, inducing epigenetic activation marks in proinflammatory cytokine promoters, and in shifting monocyte metabolomic profiles towards glycolysis. Many of the parameters elevated in cells exposed to BCG- disA -OE are associated with BCG-mediated trained innate immunity suggesting that STING agonist overexpression may enhance trained immunity. These results indicate that modifying BCG to release high levels of proinflammatory PAMP molecules such as the STING agonist c-di-AMP can enhance antitumor efficacy in bladder cancer.
    DOI:  https://doi.org/10.1101/2023.12.15.571740
  5. Nat Immunol. 2024 Jan;25(1): 13-14
    BCG-mediated viral protection goes biphasic.
    Maria Rescigno.
      
    DOI:  https://doi.org/10.1038/s41590-023-01713-9
  6. PLoS Pathog. 2023 Dec 29. 19(12): e1011886
    Borrelia burgdorferi initiates early transcriptional re-programming in macrophages that supports long-term suppression of inflammation.
    Tanja Petnicki-Ocwieja, Julie E McCarthy, Urmila Powale, P Kent Langston, Jennifer D Helble, Linden T Hu.
      Borrelia burgdorferi (Bb), the causative agent of Lyme disease, establishes a long-term infection and leads to disease manifestations that are the result of host immune responses to the pathogen. Inflammatory manifestations resolve spontaneously despite continued bacterial presence, suggesting inflammatory cells become less responsive over time. This is mimicked by in vitro repeated stimulations, resulting in tolerance, a phenotypic subset of innate immune memory. We performed comparative transcriptional analysis of macrophages in acute and memory states and identified sets of Tolerized, Hyper-Induced, Secondary-Induced and Hyper-Suppressed genes resulting from memory induction, revealing previously unexplored networks of genes affected by cellular re-programming. Tolerized gene families included inflammatory mediators and interferon related genes as would be predicted by the attenuation of inflammation over time. To better understand how cells mediate inflammatory hypo-responsiveness, we focused on genes that could mediate maintenance of suppression, such as Hyper-Induced genes which are up-regulated in memory states. These genes were notably enriched in stress pathways regulated by anti-inflammatory modulators. We examined one of the most highly expressed negative regulators of immune pathways during primary stimulation, Aconitate decarboxylase 1 (Acod1), and tested its effects during in vivo infection with Bb. As predicted by our in vitro model, we show its inflammation-suppressive downstream effects are sustained during in vivo long-term infection with Bb, with a specific role in Lyme carditis.
    DOI:  https://doi.org/10.1371/journal.ppat.1011886
  7. Immunity. 2023 Dec 22. pii: S1074-7613(23)00500-9. [Epub ahead of print]
    Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection.
    Tommaso Torcellan, Christin Friedrich, Rémi Doucet-Ladevèze, Thomas Ossner, Virgínia Visaconill Solé, Sofie Riedmann, Milas Ugur, Fabian Imdahl, Stephan P Rosshart, Sebastian J Arnold, Mercedes Gomez de Agüero, Nicola Gagliani, Richard A Flavell, Simone Backes, Wolfgang Kastenmüller, Georg Gasteiger.
      Natural killer (NK) cells are present in the circulation and can also be found residing in tissues, and these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigate whether circulating conventional NK (cNK) cells can develop into long-lived tissue-resident NK (trNK) cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1hiCD69hi trNK cells that share transcriptional similarity with CD56brightTCF1hi NK cells in human tissues. Skin trNK cells arose from interferon (IFN)-γ-producing effector cells and required restricted expression of the transcriptional regulator Blimp1 to optimize Tcf1-dependent trNK cell formation. Upon secondary infection, trNK cells rapidly gained effector function and mediated an accelerated NK cell response. Thus, cNK cells redistribute and permanently position at sites of previous infection via a mechanism promoting tissue residency that is distinct from Hobit-dependent developmental paths of NK cells and ILC1 seeding tissues during ontogeny.
    Keywords:  Staphylococcus aureus; infection; innate immune memory; innate lymphoid cells; natural killer cells; tissue immunity; tissue-resident lymphocytes; trained immunity; vaccination; vaccinia virus
    DOI:  https://doi.org/10.1016/j.immuni.2023.11.018
  8. Nat Commun. 2024 Jan 02. 15(1): 145
    Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis.
    Yinan Yang, Huijing Zhou, Xiawei Huang, Chengfang Wu, Kewei Zheng, Jingrong Deng, Yonggang Zheng, Jiahui Wang, Xiaofeng Chi, Xianjue Ma, Huimin Pan, Rui Shen, Duojia Pan, Bo Liu.
      The Hippo pathway controls developmental, homeostatic and regenerative tissue growth, and is frequently dysregulated in various diseases. Although this pathway can be activated by innate immune/inflammatory stimuli, the underlying mechanism is not fully understood. Here, we identify a conserved signaling cascade that leads to Hippo pathway activation by innate immune/inflammatory signals. We show that Tak1, a key kinase in innate immune/inflammatory signaling, activates the Hippo pathway by inducing the lysosomal degradation of Cka, an essential subunit of the STRIPAK PP2A complex that suppresses Hippo signaling. Suppression of STRIPAK results in the activation of Hippo pathway through Tao-Hpo signaling. We further show that Tak1-mediated Hippo signaling is involved in processes ranging from cell death to phagocytosis and innate immune memory. Our findings thus reveal a molecular connection between innate immune/inflammatory signaling and the evolutionally conserved Hippo pathway, thus contributing to our understanding of infectious, inflammatory and malignant diseases.
    DOI:  https://doi.org/10.1038/s41467-023-44542-y
  9. Cell Death Differ. 2024 Jan 05.
    TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53.
    Shiyu Gong, Ming Zhai, Jiayun Shi, Guanye Yu, Zhijun Lei, Yefei Shi, Yanxi Zeng, Peinan Ju, Na Yang, Zhuo Zhang, Donghui Zhang, Jianhui Zhuang, Qing Yu, Xumin Zhang, Weixia Jian, Wei Wang, Wenhui Peng.
      Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis and metabolism, but how it modulates myocardial infarction remains unclear. In this study, we showed that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Using RNA-seq, protein and molecular docking, and Targeted Metabolomics (LC-MS), our data demonstrated that macrophages expressing TREM2 exhibited decreased SLC25A53 transcription through the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD+ transport into mitochondria, downregulated SLC25A53 thereby causing the breakpoint in the TCA cycle and subsequently increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2+ macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages could improve cardiac function. In summary, our study reveals a novel role for macrophage-specific TREM2 in MI, connecting efferocytosis to immune metabolism during cardiac repair.
    DOI:  https://doi.org/10.1038/s41418-023-01252-8
  10. Front Immunol. 2023 ;14 1297329
    TRAM deletion attenuates monocyte exhaustion and alleviates sepsis severity.
    Jing Wang, Yajun Wu, RuiCi Lin, Yao Zhang, Liwu Li.
      Monocyte exhaustion characterized by immune-suppressive features can develop during sepsis and contribute to adverse patient outcomes. However, molecular mechanisms responsible for the establishment of immune-suppressive monocytes with reduced expression of immune-enhancing mediators such as CD86 during sepsis are not well understood. In this study, we identified that the TLR4 intracellular adaptor TRAM plays a key role in mediating the sustained reduction of CD86 expression on exhausted monocytes and generating an immune-suppressive monocyte state. TRAM contributes to the prolonged suppression of CD86 through inducing TAX1BP1 as well as SARM1, collectively inhibiting Akt and NFκB. TRAM deficient mice are protected from cecal slurry-induced experimental sepsis and retain immune-competent monocytes with CD86 expression. Our data reveal a key molecular circuitry responsible for monocyte exhaustion and provide a viable target for rejuvenating functional monocytes and treating sepsis.
    Keywords:  TRAM; intervention; monocyte exhaustion; sepsis; signaling
    DOI:  https://doi.org/10.3389/fimmu.2023.1297329
  11. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00465-5. [Epub ahead of print]
    ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis.
    Chao Chen, Zhenxing Zhang, Caiyun Liu, Pengkai Sun, Ping Liu, Xinjian Li.
      Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections.
    Keywords:  ABCG2; TFEB; exporter; innate immunity; itaconate; lysosomal biogenesis; macrophages
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.015
  12. Front Microbiol. 2023 ;14 1249718
    TLR agonists as vaccine adjuvants in the prevention of viral infections: an overview.
    Mohammad Enamul Hoque Kayesh, Michinori Kohara, Kyoko Tsukiyama-Kohara.
      Tol-like receptor (TLR) agonists, as potent adjuvants, have gained attention in vaccine research for their ability to enhance immune responses. This study focuses on their application in improving vaccine efficacy against key viral infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), SARS-CoV-2, influenza virus, and flaviviruses, including West Nile virus, dengue virus, and chikungunya virus. Vaccines are crucial in preventing microbial infections, including viruses, and adjuvants play a vital role in modulating immune responses. However, there are still many diseases for which effective vaccines are lacking or have limited immune response, posing significant threats to human health. The use of TLR agonists as adjuvants in viral vaccine formulations holds promise in improving vaccine effectiveness. By tailoring adjuvants to specific pathogens, such as HBV, HCV, HIV, SARS-CoV-2, influenza virus, and flavivirus, protective immunity against chronic and emerging infectious disease can be elicited.
    Keywords:  HIV; SARS-CoV-2; TLR; hepatitis virus; influenza virus
    DOI:  https://doi.org/10.3389/fmicb.2023.1249718
  13. Int J Biol Sci. 2024 ;20(2): 464-485
    ADAR1 protects pulmonary macrophages from sepsis-induced pyroptosis and lung injury through miR-21/A20 signaling.
    Xiaojun Zhao, Jiangang Xie, Chujun Duan, Linxiao Wang, Yi Si, Shanshou Liu, Qianmei Wang, Dan Wu, Yifan Wang, Wen Yin, Ran Zhuang, Junjie Li.
      Acute lung injury is a serious complication of sepsis with high morbidity and mortality. Pyroptosis is a proinflammatory form of programmed cell death that leads to immune dysregulation and organ dysfunction during sepsis. We previously found that adenosine deaminase acting on double-stranded RNA 1 (ADAR1) plays regulatory roles in the pathology of sepsis, but the mechanism of ADAR1 in sepsis-induced pyroptosis and lung injury remains unclear. Here, we mainly investigated the regulatory effects and underlying mechanism of ADAR1 in sepsis-induced lung injury and pyroptosis of pulmonary macrophages through RNA sequencing of clinical samples, caecal ligation and puncture (CLP)-induced septic mouse models, and in vitro cellular experiments using RAW264.7 cells with lipopolysaccharide (LPS) stimulation. The results showed that pyroptosis was activated in peripheral blood mononuclear cells (PBMCs) from patients with sepsis. In the CLP-induced septic mouse model, pyroptosis was mainly activated in pulmonary macrophages. LPS-stimulated RAW264.7 cells showed significantly increased activation of the NLRP3 inflammasome. ADAR1 was downregulated in PMBCs of patients with sepsis, and overexpression of ADAR1 alleviated CLP-induced lung injury and NLRP3 inflammasome activation. Mechanistically, the regulatory effects of ADAR1 on macrophage pyroptosis were mediated by the miR-21/A20/NLRP3 signalling cascade. ADAR1 attenuated sepsis-induced lung injury and hindered the activation of pyroptosis in pulmonary macrophages in sepsis through the miR-21/A20/NLRP3 axis. Our study highlights the role of ADAR1 in protecting pulmonary macrophages against pyroptosis and suggests targeting ADAR1/miR-21 signalling as a therapeutic opportunity in sepsis-related lung injury.
    Keywords:  A20; ADAR1; lung injury; macrophage; pyroptosis; sepsis
    DOI:  https://doi.org/10.7150/ijbs.86424
  14. Cell Mol Immunol. 2024 Jan 04.
    ROS-induced metabolic reprogramming to one-carbon metabolism and S-adenosylmethionine-mediated epigenetic modification in IL-10-producing B cells for the resolution of pneumonia.
    Sujin Lee, Tae Jin Kim.
      
    DOI:  https://doi.org/10.1038/s41423-023-01117-7
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