bims-traimu Biomed News
on Trained immunity
Issue of 2024‒10‒27
thirteen papers selected by
Yantong Wan, Southern Medical University
  1. [Current progress on trained immunity-based vaccines].
  2. Knowledge mapping of trained immunity/innate immune memory: Insights from two decades of studies.
  3. Impact of cooperative or competitive dynamics between the yeast Saccharomyces cerevisiae and lactobacilli on the immune response of the host.
  4. Understanding the role of innate immune training in prevention of respiratory infections.
  5. From periphery to center stage: 50 years of advancements in innate immunity.
  6. Decoding the multiple functions of ZBP1 in the mechanism of sepsis-induced acute lung injury.
  7. Long-term reprogramming of primed microglia after moderate inhibition of CSF1R signaling.
  8. Targeting Unc5b in macrophages drives atherosclerosis regression and pro-resolving immune cell function.
  9. CENCAT enables immunometabolic profiling by measuring protein synthesis via bioorthogonal noncanonical amino acid tagging.
  10. The contribution of neutrophils to bacteriophage clearance and pharmacokinetics in vivo.
  11. Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification.
  12. The STAT3/SETDB2 axis dictates NF-κB-mediated inflammation in macrophages during wound repair.
  13. Macrophage variants in laboratory research: most are well done, but some are RAW.
  1. Zhonghua Yu Fang Yi Xue Za Zhi. 2024 Oct 06. 58(10): 1598-1603
    [Current progress on trained immunity-based vaccines].
    C Y Xiang, N Wang, Y Shi.
      Trained immunity-based vaccines (TIbV) is an emerging vaccine strategy in the field of vaccine research, referring to vaccines designed based on the principles of trained immunity (TI). TI involves the enhanced immune response of innate immune cells upon re-stimulation after being trained. TIbV, built on the concept of TI, aims to enhance resistance to various infectious pathogens by training the host's innate immune system to acquire natural immune memory. This approach is designed to bolster immunity against a wide range of infectious agents, including those not covered by conventional vaccines. This article reviews the concepts, mechanisms, application areas, and future prospects of TIbV, intending to offer a new perspective for vaccine development and design.
    DOI:  https://doi.org/10.3760/cma.j.cn112150-20231121-00360
  2. Hum Vaccin Immunother. 2024 Dec 31. 20(1): 2415823
    Knowledge mapping of trained immunity/innate immune memory: Insights from two decades of studies.
    Jiacheng He, Hongxia Cui, Guoqian Jiang, Lijun Fang, Jianlei Hao.
      This study employs knowledge mapping and bibliometric techniques to analyze the research landscape of trained immunity over the past 20 years and to identify current research hotspots and future development directions. The literature related to trained immunity was searched from the Web of Science Core Collection database, spanning 2004 to 2023. VOSViewer, CiteSpace and Bibliometrix were used for the knowledge mapping analysis. The foremost research institutions are Radboud University Nijmegen, University of Bonn, and Harvard University. Professor Netea MG of Radboud University Nijmegen has published the greatest number of articles. The current research focus encompasses immune memory, nonspecific effects, epigenetics, metabolic reprogramming, BCG vaccine, and the development of trained immunity-based vaccines. It is likely that research on trained immunity-based vaccines will become a major focus in the development of new vaccines in the future. It would be advantageous to observe a greater number of prospective clinical studies with robust evidence.
    Keywords:  Bibliometrix; CiteSpace; Trained immunity; Vosviewer; innate immune memories; visual analysis
    DOI:  https://doi.org/10.1080/21645515.2024.2415823
  3. Front Immunol. 2024 ;15 1399842
    Impact of cooperative or competitive dynamics between the yeast Saccharomyces cerevisiae and lactobacilli on the immune response of the host.
    Stefano Nenciarini, Damariz Rivero, Alessia Ciccione, Roberta Amoriello, Benedetta Cerasuolo, Marco Pallecchi, Gian Luca Bartolucci, Clara Ballerini, Duccio Cavalieri.
      Fungi and bacteria can be found coexisting in a wide variety of environments. The combination of their physical and molecular interactions can result in a broad range of outcomes for each partner, from competition to cooperative relationships. Most of these interactions can also be found in the human gastrointestinal tract. The gut microbiota is essential for humans, helping the assimilation of food components as well as the prevention of pathogen invasions through host immune system modulation and the production of beneficial metabolites such as short-chain fatty acids (SCFAs). Several factors, including changes in diet habits due to the progressive Westernization of the lifestyle, are linked to the onset of dysbiosis statuses that impair the correct balance of the gut environment. It is therefore crucial to explore the interactions between commensal and diet-derived microorganisms and their influence on host health. Investigating these interactions through co-cultures between human- and fermented food-derived lactobacilli and yeasts led us to understand how the strains' growth yield and their metabolic products rely on the nature and concentration of the species involved, producing either cooperative or competitive dynamics. Moreover, single cultures of yeasts and lactobacilli proved to be ideal candidates for developing immune-enhancing products, given their ability to induce trained immunity in blood-derived human monocytes in vitro. Conversely, co-cultures as well as mixtures of yeasts and lactobacilli have been shown to induce an anti-inflammatory response on the same immune cells in terms of cytokine profiles and activation surface markers, opening new possibilities in the design of probiotic and dietary therapies.
    Keywords:  Saccharomyces cerevisiae; fermented food; host immune system modulation; lactobacilli; microbial ecology; short-chain fatty acids; trained immunity; yeasts
    DOI:  https://doi.org/10.3389/fimmu.2024.1399842
  4. Pediatr Pulmonol. 2024 Oct 22.
    Understanding the role of innate immune training in prevention of respiratory infections.
    Peter D Sly.
      
    Keywords:  child; immune maturation; infant; maternal gut mcrobiome; microbial exposure
    DOI:  https://doi.org/10.1002/ppul.27278
  5. Cell. 2024 Oct 18. pii: S0092-8674(24)01189-9. [Epub ahead of print]
    From periphery to center stage: 50 years of advancements in innate immunity.
    Susan Carpenter, Luke A J O'Neill.
      
    DOI:  https://doi.org/10.1016/j.cell.2024.10.013
  6. Commun Biol. 2024 Oct 21. 7(1): 1361
    Decoding the multiple functions of ZBP1 in the mechanism of sepsis-induced acute lung injury.
    Ting Gong, Yu Fu, Qingde Wang, Patricia A Loughran, Yuehua Li, Timothy R Billiar, Zongmei Wen, Youtan Liu, Jie Fan.
      Sepsis-induced acute lung injury (ALI), characterized by severe hypoxemia and pulmonary leakage, remains a leading cause of mortality in intensive care units. The exacerbation of ALI during sepsis is largely attributed to uncontrolled inflammatory responses and endothelial dysfunction. Emerging evidence suggests an important role of Z-DNA binding protein 1 (ZBP1) as a sensor in innate immune to drive inflammatory signaling and cell death during infections. However, the role of ZBP1 in sepsis-induced ALI has yet to be defined. We utilized ZBP1 knockout mice and combined single-cell RNA sequencing with experimental validation to investigate ZBP1's roles in the regulation of macrophages and lung endothelial cells during sepsis. We demonstrate that in sepsis, ZBP1 deficiency in macrophages reduces mitochondrial damage and inhibits glycolysis, thereby altering the metabolic status of macrophages. Consequently, this metabolic shift leads to a reduction in the differentiation of macrophages into pro-inflammatory states and decreases macrophage pyroptosis triggered by activation of the NLRP3 inflammasome. These changes significantly weaken the inflammatory signaling pathways between macrophages and endothelial cells and alleviate endothelial dysfunction and cellular damage. These findings reveal important roles for ZBP1 in mediating multiple pathological processes involved in sepsis-induced ALI by modulating the functional states of macrophages and endothelial cells, thereby highlighting its potential as a promising therapeutic target.
    DOI:  https://doi.org/10.1038/s42003-024-07072-x
  7. Glia. 2024 Oct 24.
    Long-term reprogramming of primed microglia after moderate inhibition of CSF1R signaling.
    Ana León-Rodríguez, Jesús M Grondona, Sonia Marín-Wong, Manuel F López-Aranda, María D López-Ávalos.
      In acute neuroinflammation, microglia activate transiently, and return to a resting state later on. However, they may retain immune memory of such event, namely priming. Primed microglia are more sensitive to new stimuli and develop exacerbated responses, representing a risk factor for neurological disorders with an inflammatory component. Strategies to control the hyperactivation of microglia are, hence, of great interest. The receptor for colony stimulating factor 1 (CSF1R), expressed in myeloid cells, is essential for microglia viability, so its blockade with specific inhibitors (e.g. PLX5622) results in significant depletion of microglial population. Interestingly, upon inhibitor withdrawal, new naïve microglia repopulate the brain. Depletion-repopulation has been proposed as a strategy to reprogram microglia. However, substantial elimination of microglia is inadvisable in human therapy. To overcome such drawback, we aimed to reprogram long-term primed microglia by CSF1R partial inhibition. Microglial priming was induced in mice by acute neuroinflammation, provoked by intracerebroventricular injection of neuraminidase. After 3-weeks recovery, low-dose PLX5622 treatment was administrated for 12 days, followed by a withdrawal period of 7 weeks. Twelve hours before euthanasia, mice received a peripheral lipopolysaccharide (LPS) immune challenge, and the subsequent microglial inflammatory response was evaluated. PLX5622 provoked a 40%-50% decrease in microglial population, but basal levels were restored 7 weeks later. In the brain regions studied, hippocampus and hypothalamus, LPS induced enhanced microgliosis and inflammatory activation in neuraminidase-injected mice, while PLX5622 treatment prevented these changes. Our results suggest that PLX5622 used at low doses reverts microglial priming and, remarkably, prevents broad microglial depletion.
    Keywords:  CSF1R; PLX5622; microglia; neuroinflammation; priming
    DOI:  https://doi.org/10.1002/glia.24627
  8. Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2412690121
    Targeting Unc5b in macrophages drives atherosclerosis regression and pro-resolving immune cell function.
    Martin Schlegel, Yannick Cyr, Alexandra A C Newman, Korbinian Schreyer, José Gabriel Barcia Durán, Monika Sharma, Fazli K Bozal, Morgane Gourvest, Maxwell La Forest, Milessa S Afonso, Coen van Solingen, Edward A Fisher, Kathryn J Moore.
      Atherosclerosis results from lipid-driven inflammation of the arterial wall that fails to resolve. Imbalances in macrophage accumulation and function, including diminished migratory capacity and defective efferocytosis, fuel maladaptive inflammation and plaque progression. The neuroimmune guidance cue netrin-1 has dichotomous roles in inflammation partly due to its multiple receptors; in atherosclerosis, netrin-1 promotes macrophage survival and retention via its receptor Unc5b. To minimize the pleiotropic effects of targeting netrin-1, we tested the therapeutic potential of deleting Unc5b in mice with advanced atherosclerosis. We generated Unc5bfl/flCx3cr1creERT2/WT mice, which allowed conditional deletion of Un5b (∆Unc5bMØ) in monocytes and macrophages by tamoxifen injection. After inducing advanced atherosclerosis by hepatic PCSK9 overexpression and western diet feeding for 20 wk, Unc5b was deleted and hypercholesterolemia was normalized to simulate clinical lipid management. Deletion of myeloid Unc5b led to a 40% decrease in atherosclerotic plaque burden and reduced plaque complexity compared to Unc5bfl/flCx3cr1WT/WT littermate controls (CtrlMØ). Consistently, plaque macrophage content was reduced by 50% in ∆Unc5bMØ mice due to reduced plaque Ly6Chi monocyte recruitment and macrophage retention. Compared to CtrlMØ mice, plaques in ∆Unc5bMØ mice had reduced necrotic area and fewer apoptotic cells, which correlated with improved efferocytotic capacity by Unc5b-deficient macrophages in vivo and in vitro. Beneficial changes in macrophage dynamics in the plaque upon Unc5b deletion were accompanied by an increase in atheroprotective T cell populations, including T-regulatory and Th2 cells. Our data identify Unc5b in advanced atherosclerosis as a therapeutic target to induce pro-resolving restructuring of the plaque immune cells and to promote atherosclerosis regression.
    Keywords:  Treg; atherosclerosis; efferocytosis; inflammation; regression
    DOI:  https://doi.org/10.1073/pnas.2412690121
  9. Cell Rep Methods. 2024 Oct 21. pii: S2667-2375(24)00266-2. [Epub ahead of print]4(10): 100883
    CENCAT enables immunometabolic profiling by measuring protein synthesis via bioorthogonal noncanonical amino acid tagging.
    Frank Vrieling, Hendrik J P van der Zande, Britta Naus, Lisa Smeehuijzen, Julia I P van Heck, Bob J Ignacio, Kimberly M Bonger, Jan Van den Bossche, Sander Kersten, Rinke Stienstra.
      Cellular energy metabolism significantly contributes to immune cell function. To further advance immunometabolic research, novel methods to study the metabolism of immune cells in complex samples are required. Here, we introduce CENCAT (cellular energetics through noncanonical amino acid tagging). This technique utilizes click labeling of alkyne-bearing noncanonical amino acids to measure protein synthesis inhibition as a proxy for metabolic activity. CENCAT successfully reproduced known metabolic signatures of lipopolysaccharide (LPS)/interferon (IFN)γ and interleukin (IL)-4 activation in human primary macrophages. Application of CENCAT in peripheral blood mononuclear cells revealed diverse metabolic rewiring upon stimulation with different activators. Finally, CENCAT was used to analyze the cellular metabolism of murine tissue-resident immune cells from various organs. Tissue-specific clustering was observed based on metabolic profiles, likely driven by microenvironmental priming. In conclusion, CENCAT offers valuable insights into immune cell metabolic responses, presenting a powerful platform for studying cellular metabolism in complex samples and tissues in both humans and mice.
    Keywords:  CP: Immunology; CP: Metabolism; OXPHOS; SCENITH; energy metabolism; glycolysis; immunometabolism
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100883
  10. JCI Insight. 2024 Oct 22. pii: e181309. [Epub ahead of print]9(20):
    The contribution of neutrophils to bacteriophage clearance and pharmacokinetics in vivo.
    Arne Echterhof, Tejas Dharmaraj, Arya Khosravi, Robert McBride, Lynn Miesel, Ju-Hsin Chia, Patrick M Blankenberg, Kun-Yuan Lin, Chien-Chang Shen, Yu-Ling Lee, Yu-Chuan Yeh, Wei Ting Liao, Francis G Blankenberg, Krystyna Dąbrowska, Derek F Amanatullah, Adam R Frymoyer, Paul L Bollyky.
      With the increasing prevalence of antimicrobial-resistant bacterial infections, there is interest in using bacteriophages (phages) to treat such infections. However, the factors that govern bacteriophage pharmacokinetics in vivo remain poorly understood. Here, we have examined the contribution of neutrophils, the most abundant phagocytes in the body, to the pharmacokinetics of i.v. administered bacteriophage in uninfected mice. A single dose of LPS-5, a bacteriophage recently used in human clinical trials to treat drug-resistant Pseudomonas aeruginosa, was administered i.v. to both immunocompetent BALB/c and neutropenic CD1 mice. Phage concentrations were assessed in peripheral blood and spleen at 0.25, 1, 2, 4, 8, 12, and 24 hours after administration by plaque assay and qPCR. We observed that the phage clearance was only minimally affected by neutropenia. Indeed, the half-lives of phages in blood in BALB/c and CD1 mice were 3.45 and 3.66 hours, respectively. These data suggest that neutrophil-mediated phagocytosis is not a major determinant of phage clearance. Conversely, we observed a substantial discrepancy in circulating phage levels over time when measured by qPCR versus plaque assay, suggesting that significant inactivation of circulating phages occurs over time. These data indicate that alternative factors, but not neutrophils, inactivate i.v. administered phages.
    Keywords:  Bacterial infections; Infectious disease
    DOI:  https://doi.org/10.1172/jci.insight.181309
  11. Nat Genet. 2024 Oct 23.
    Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification.
    Simone M Haag, Shiqi Xie, Celine Eidenschenk, Jean-Philippe Fortin, Marinella Callow, Mike Costa, Aaron Lun, Chris Cox, Sunny Z Wu, Rachana N Pradhan, Jaclyn Lock, Julia A Kuhn, Loryn Holokai, Minh Thai, Emily Freund, Ariane Nissenbaum, Mary Keir, Christopher J Bohlen, Scott Martin, Kathryn Geiger-Schuller, Hussein A Hejase, Brian L Yaspan, Sandra Melo Carlos, Shannon J Turley, Aditya Murthy.
      Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory 'states' that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states. This process identifies regulators of five distinct states associated with key features of macrophage function. Among these regulators, loss of the N6-methyladenosine (m6A) writer components abolishes m6A modification of TNF transcripts, thereby enhancing mRNA stability and TNF production associated with multiple inflammatory pathologies. Thus, phenotypic characterization of primary murine and human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.
    DOI:  https://doi.org/10.1038/s41588-024-01962-w
  12. JCI Insight. 2024 Oct 22. pii: e179017. [Epub ahead of print]9(20):
    The STAT3/SETDB2 axis dictates NF-κB-mediated inflammation in macrophages during wound repair.
    Kevin D Mangum, Aaron denDekker, Qinmengge Li, Lam C Tsoi, Amrita D Joshi, William J Melvin, Sonya J Wolf, Jadie Y Moon, Christopher O Audu, James Shadiow, Andrea T Obi, Rachael Wasikowski, Emily C Barrett, Tyler M Bauer, Kylie Boyer, Zara Ahmed, Frank M Davis, Johann Gudjonsson, Katherine A Gallagher.
      Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified that the histone methyltransferase SETDB2 in macrophages drives tissue repair by repressing NF-κB-mediated inflammation. Complementary ATAC-Seq and RNA-Seq of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NF-κB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages, yet paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NF-κB component, RELA, leading to increased RELA/NF-κB-mediated inflammatory gene expression. Furthermore, RNA-Seq in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally coregulate overlapping genes. Finally, in diabetic wound macrophages, STAT3 expression and STAT3/SETDB2 binding were increased. We have identified what we believe to be a novel STAT3/SETDB2 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.
    Keywords:  Inflammation; Transcription
    DOI:  https://doi.org/10.1172/jci.insight.179017
  13. Front Cell Infect Microbiol. 2024 ;14 1457323
    Macrophage variants in laboratory research: most are well done, but some are RAW.
    Marc Herb, Valentin Schatz, Karina Hadrian, Deniz Hos, Bohdan Holoborodko, Jonathan Jantsch, Natascha Brigo.
      Macrophages play a pivotal role in the innate immune response. While their most characteristic function is phagocytosis, it is important not to solely characterize macrophages by this activity. Their crucial roles in body development, homeostasis, repair, and immune responses against pathogens necessitate a broader understanding. Macrophages exhibit remarkable plasticity, allowing them to modify their functional characteristics in response to the tissue microenvironment (tissue type, presence of pathogens or inflammation, and specific signals from neighboring cells) swiftly. While there is no single defined "macrophage" entity, there is a diverse array of macrophage types because macrophage ontogeny involves the differentiation of progenitor cells into tissue-resident macrophages, as well as the recruitment and differentiation of circulating monocytes in response to tissue-specific cues. In addition, macrophages continuously sense and respond to environmental cues and tissue conditions, adjusting their functional and metabolic states accordingly. Consequently, it is of paramount importance to comprehend the heterogeneous origins and functions of macrophages employed in in vitro studies, as each available in vitro macrophage model is associated with specific sets of strengths and limitations. This review centers its attention on a comprehensive comparison between immortalized mouse macrophage cell lines and primary mouse macrophages. It provides a detailed analysis of the strengths and weaknesses inherent in these in vitro models. Finally, it explores the subtle distinctions between diverse macrophage cell lines, offering insights into numerous factors beyond the model type that can profoundly influence macrophage function.
    Keywords:  immunity; macrophage polarization (MP); macrophage types; macrophage-like cell lines; primary macrophages
    DOI:  https://doi.org/10.3389/fcimb.2024.1457323
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