bims-traimu Biomed News
on Trained immunity
Issue of 2023‒01‒15
six papers selected by
Yantong Wan
Southern Medical University
  1. C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells.
  2. Memory Macrophages.
  3. Manganese potentiates lipopolysaccharide-induced innate immune responses and septic shock.
  4. TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy.
  5. Self-Adjuvanting Protein Vaccine Conjugated with a Novel Synthetic TLR4 Agonist on Virus-Like Liposome Induces Potent Immunity against SARS-CoV-2.
  6. Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.
  1. Cell Stem Cell. 2023 Jan 05. pii: S1934-5909(22)00489-1. [Epub ahead of print]30(1): 112
    C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells.
    Bérengère de Laval, Julien Maurizio, Prashanth K Kandalla, Gabriel Brisou, Louise Simonnet, Caroline Huber, Gregory Gimenez, Orit Matcovitch-Natan, Susanne Reinhardt, Eyal David, Alexander Mildner, Achim Leutz, Bertrand Nadel, Christophe Bordi, Ido Amit, Sandrine Sarrazin, Michael H Sieweke.
      
    DOI:  https://doi.org/10.1016/j.stem.2022.12.005
  2. Int J Mol Sci. 2022 Dec 20. pii: 38. [Epub ahead of print]24(1):
    Memory Macrophages.
    Malgorzata Kloc, Jacek Z Kubiak, Robert Zdanowski, Rafik M Ghobrial.
      Immunological memory is a crucial part of the immune defense that allows organisms to respond against previously encountered pathogens or other harmful factors. Immunological memory is based on the establishment of epigenetic modifications of the genome. The ability to memorize encounters with pathogens and other harmful factors and mount enhanced defense upon subsequent encounters is an evolutionarily ancient mechanism operating in all animals and plants. However, the term immunological memory is usually restricted to the organisms (invertebrates and vertebrates) possessing the immune system. The mammalian immune system, with innate and adaptive branches, is the most sophisticated among vertebrates. The concept of innate memory and memory macrophages is relatively new and thus understudied. We introduce the concept of immunological memory and describe types of memory in different species and their evolutionary status. We discuss why the traditional view of innate immune cells as the first-line defenders is too restrictive and how the innate immune cells can accumulate and retain immunologic memory. We describe how the initial priming leads to chromatin remodeling and epigenetic changes, which allow memory macrophage formation. We also summarize what is currently known about the mechanisms underlying development of memory macrophages; their molecular and metabolic signature and surface markers; and how they may contribute to immune defense, diseases, and organ transplantation.
    Keywords:  epigenetic modifications; innate immunological memory; macrophage; trained immunity; transplantation
    DOI:  https://doi.org/10.3390/ijms24010038
  3. Int J Biol Macromol. 2023 Jan 10. pii: S0141-8130(23)00076-4. [Epub ahead of print] 123202
    Manganese potentiates lipopolysaccharide-induced innate immune responses and septic shock.
    Yanchao Gu, Jingjing Tang, Fuhua Zhang, Yichen Qu, Min Zhao, Mengyuan Li, Zhen Xie, Xiao Wang, Li Song, Zhengfan Jiang, Yao Wang, Xihui Shen, Lei Xu.
      Divalent metal ions such as magnesium (Mg2+), manganese (Mn2+), and zinc (Zn2+) play important roles in regulating innate immune responses. Lipopolysaccharide stimulation led to increased intracellular Mn and Zn in macrophages. However, the effect of those metal ions in regulating lipopolysaccharide-induced innate immune responses remains unclear. Here, we uncovered that both Mn2+ and Zn2+ have immunostimulatory effects, which could potentiate the lipopolysaccharide-induced expression of interferon-stimulated genes (ISGs), cytokines and pro-inflammatory genes in a dose-dependent manner. Enhancement of lipopolysaccharide-induced innate immune gene expression by Mn2+ varies between 10 % and 900 %. Conversely, the chelating of Mn2+ almost totally diminished Mn2+-enhanced lipopolysaccharide-induced gene expression. In addition, Mn2+ exerted its ability to potentiate LPS-induced innate immune gene expression regardless of slight pH changes. Importantly, we found that Mn2+ potentiates lipopolysaccharide-induced immune responses independent of TLR4 but partially relies on cGAS-STING pathway. Further in vivo study showed that colloidal Mn2+ salt (Mn jelly [MnJ]) pretreatment exacerbated lipopolysaccharide-induced septic shock and mice death. In conclusion, we demonstrated that Mn2+ plays an essential role in boosting lipopolysaccharide-induced innate immune responses. These findings greatly expand the current understanding of the immunomodulatory potential of divalent metal Mn2+ and may provide a potential therapeutic target to prevent excessive immune responses.
    Keywords:  Innate immunity; Interferon (IFN); Interferon-stimulated gene (ISG); Lipopolysaccharide (LPS); Manganese; Toll-like receptor 4 (TLR4); cGAS-STING
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.123202
  4. Commun Biol. 2023 Jan 12. 6(1): 31
    TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy.
    Caleb Gonzalez, Sarah Williamson, Seth T Gammon, Sarah Glazer, Joon Haeng Rhee, David Piwnica-Worms.
      Primary and adaptive resistance to immune checkpoint therapies (ICT) represent a considerable obstacle to achieving enhanced overall survival. Innate immune activators have been actively pursued for their antitumor potential. Herein we report that a syngeneic 4T1 mammary carcinoma murine model for established highly-refractory triple negative breast cancer showed enhanced survival when treated intra-tumorally with either the TLR5 agonist flagellin or CBLB502, a flagellin derivative, in combination with antibodies targeting CTLA-4 and PD-1. Long-term survivor mice showed immunologic memory upon tumor re-challenge and a distinctive immune activating cytokine profile that engaged both innate and adaptive immunity. Low serum levels of G-CSF and CXCL5 (as well as high IL-15) were candidate predictive biomarkers correlating with enhanced survival. CBLB502-induced enhancement of ICT was also observed in poorly immunogenic B16-F10 melanoma tumors. Combination immune checkpoint therapy plus TLR5 agonists may offer a new therapeutic strategy to treat ICT-refractory solid tumors.
    DOI:  https://doi.org/10.1038/s42003-022-04403-8
  5. J Med Chem. 2023 Jan 10.
    Self-Adjuvanting Protein Vaccine Conjugated with a Novel Synthetic TLR4 Agonist on Virus-Like Liposome Induces Potent Immunity against SARS-CoV-2.
    Dong Ding, Yu Wen, Chun-Miao Liao, Xu-Guang Yin, Ru-Yan Zhang, Jian Wang, Shi-Hao Zhou, Zhi-Ming Zhang, Yong-Ke Zou, Xiao-Fei Gao, Hua-Wei Wei, Guang-Fu Yang, Jun Guo.
      Exploring potent adjuvants and new vaccine strategies is crucial for the development of protein vaccines. In this work, we synthesized a new TLR4 agonist, structurally simplified lipid A analogue GAP112, as a potent built-in adjuvant to improve the immunogenicity of SARS-CoV-2 spike RBD protein. The new TLR4 agonist GAP112 was site-selectively conjugated on the N-terminus of RBD to construct an adjuvant-protein conjugate vaccine in a liposomal formulation. It is the first time that a TLR4 agonist is site-specifically and quantitatively conjugated to a protein antigen. Compared with an unconjugated mixture of GAP112/RBD, a two-dose immunization of the GAP112-RBD conjugate vaccine strongly activated innate immune cells, elicited a 223-fold increase in RBD-specific antibodies, and markedly enhanced T-cell responses. Antibodies induced by GAP112-RBD also effectively cross-neutralized SARS-CoV-2 variants (Delta/B.1.617.2 and Omicron/B.1.1.529). This conjugate strategy provides an effective method to greatly enhance the immunogenicity of antigen in protein vaccines against SARS-CoV-2 and other diseases.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c01642
  6. Cell Rep. 2023 Jan 09. pii: S2211-1247(22)01842-3. [Epub ahead of print]42(1): 111941
    Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.
    Allison K Meyers, Zhan Wang, Wenzheng Han, Qingxia Zhao, Manal Zabalawi, Likun Duan, Juan Liu, Qianyi Zhang, Rajesh K Manne, Felipe Lorenzo, Matthew A Quinn, Qianqian Song, Daping Fan, Hui-Kuan Lin, Cristina M Furdui, Jason W Locasale, Charles E McCall, Xuewei Zhu.
      Activating the macrophage NLRP3 inflammasome can promote excessive inflammation with severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages and septic mice by lowering caspase-1 cleavage and interleukin-1β (IL-1β) secretion. Inhibiting PDHK reverses NLRP3 inflammasome-induced metabolic reprogramming, enhances autophagy, promotes mitochondrial fusion over fission, preserves crista ultrastructure, and attenuates mitochondrial reactive oxygen species (ROS) production. The suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of its canonical role as a pyruvate dehydrogenase regulator. Our study suggestsa non-canonical role of mitochondrial PDHK in promoting mitochondrial stress and supporting NLRP3 inflammasome activation during acute inflammation.
    Keywords:  CP: Immunology; NLRP3 inflammasome; autophagy; cristae; immunometabolism; macrophages; metabolic flux; mitochondria; mitochondrial fission and fusion; pyruvate dehydrogenase kinase; sepsis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111941
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