bims-traimu Biomed News
on Trained immunity
Issue of 2024‒06‒23
thirteen papers selected by
Yantong Wan, Southern Medical University

  1. J Allergy Clin Immunol. 2024 Jun 10. pii: S0091-6749(24)00605-5. [Epub ahead of print]
    Keywords:  Trained immunity; epigenetic inheritance; immune memory; maternal immune transfer; microbiota; offspring; transgenerational immunity
  2. J Allergy Clin Immunol. 2024 Jun 10. pii: S0091-6749(24)00604-3. [Epub ahead of print]
    Keywords:  Innate immune memory; chronic inflammation; hematopoietic stem and progenitor cells; myelopoiesis; trained immunity
  3. Int J Mol Sci. 2024 May 28. pii: 5856. [Epub ahead of print]25(11):
      Trained immunity is a concept in immunology in which innate immune cells, such as monocytes and macrophages, exhibit enhanced responsiveness and memory-like characteristics following initial contact with a pathogenic stimulus that may promote a more effective immune defense following subsequent contact with the same pathogen. Helicobacter pylori, a bacterium that colonizes the stomach lining, is etiologically associated with various gastrointestinal diseases, including gastritis, peptic ulcer, gastric adenocarcinoma, MALT lymphoma, and extra gastric disorders. It has been demonstrated that repeated exposure to H. pylori can induce trained immunity in the innate immune cells of the gastric mucosa, which become more responsive and better able to respond to subsequent H. pylori infections. However, interactions between H. pylori and trained immunity are intricate and produce both beneficial and detrimental effects. H. pylori infection is characterized histologically as the presence of both an acute and chronic inflammatory response called acute-on-chronic inflammation, or gastritis. The clinical outcomes of ongoing inflammation include intestinal metaplasia, gastric atrophy, and dysplasia. These same mechanisms may also reduce immunotolerance and trigger autoimmune pathologies in the host. This review focuses on the relationship between trained immunity and H. pylori and underscores the dynamic interplay between the immune system and the pathogen in the context of gastric colonization and inflammation.
    Keywords:  Helicobacter pylori; gastritis; immunocompetent cells; trained immunity
  4. Mol Med Rep. 2024 Aug;pii: 145. [Epub ahead of print]30(2):
      Atherosclerosis (AS) is a chronic inflammatory disease caused by the deposition of lipoproteins and sequent immune responses. Within the atherosclerotic plaque, macrophages are the most abundant immune cells and play a great part as protagonists and promoters of AS. In the past decade, the concept of 'trained immunity' has emerged, which highlights the memory characteristics of innate immunity, thus opening up a new avenue of research. Evidence suggests that trained immunity may regulate the onset and progression of AS with trained macrophages playing an important and dynamic role in atherogenesis. The present review provided a summary of concepts related to trained immunity and its relationship with AS. Furthermore, different phenotypes of macrophages responding to various stimuli within the atherosclerotic plaque were presented, along with the complex mechanisms of metabolic and epigenetic reprogramming in the cells. Finally, several promising therapeutic approaches for AS cardiovascular disease were discussed, which may shed light on new clinical strategies.
    Keywords:  atherosclerosis; epigenetics; innate immunity; macrophage; metabolism; trained immunity
  5. Int J Mol Sci. 2024 May 29. pii: 5951. [Epub ahead of print]25(11):
      Maternal obesity and over/undernutrition can have a long-lasting impact on offspring health during critical periods in the first 1000 days of life. Children born to mothers with obesity have reduced immune responses to stimuli which increase susceptibility to infections. Recently, maternal western-style diets (WSDs), high in fat and simple sugars, have been associated with skewing neonatal immune cell development, and recent evidence suggests that dysregulation of innate immunity in early life has long-term consequences on metabolic diseases and behavioral disorders in later life. Several factors contribute to abnormal innate immune tolerance or trained immunity, including changes in gut microbiota, metabolites, and epigenetic modifications. Critical knowledge gaps remain regarding the mechanisms whereby these factors impact fetal and postnatal immune cell development, especially in precursor stem cells in bone marrow and fetal liver. Components of the maternal microbiota that are transferred from mothers consuming a WSD to their offspring are understudied and identifying cause and effect on neonatal innate and adaptive immune development needs to be refined. Tools including single-cell RNA-sequencing, epigenetic analysis, and spatial location of specific immune cells in liver and bone marrow are critical for understanding immune system programming. Considering the vital role immune function plays in offspring health, it will be important to understand how maternal diets can control developmental programming of innate and adaptive immunity.
    Keywords:  epigenetics; fetal–maternal health; innate immune regulation; maternal obesity; metabolites; microbiome; multi-omics
  6. Front Immunol. 2024 ;15 1386578
      The immune memory is one of the defensive strategies developed by both unicellular and multicellular organisms for ensuring their integrity and functionality. While the immune memory of the vertebrate adaptive immune system (based on somatic recombination) is antigen-specific, encompassing the generation of memory T and B cells that only recognize/react to a specific antigen epitope, the capacity of vertebrate innate cells to remember past events is a mostly non-specific mechanism of adaptation. This "innate memory" can be considered as germline-encoded because its effector tools (such as innate receptors) do not need somatic recombination for being active. Also, in several organisms the memory-related information is integrated in the genome of germline cells and can be transmitted to the progeny for several generations, but it can also be erased depending on the environmental conditions. Overall, depending on the organism, its environment and its living habits, innate immune memory appears to be a mechanism for achieving better protection and survival against repeated exposure to microbes/stressful agents present in the same environment or occurring in the same anatomical district, able to adapt to changes in the environmental cues. The anatomical and functional complexity of the organism and its lifespan drive the generation of different immune memory mechanisms, for optimal adaptation to changes in the living/environmental conditions. The concept of innate immunity being non-specific needs to be revisited, as a wealth of evidence suggests a significant degree of specificity both in the primary immune reaction and in the ensuing memory-like responses. This is clearly evident in invertebrate metazoans, in which distinct scenarios can be observed, with both non-specific (immune enhancement) or specific (immune priming) memory-like responses. In the case of mammals, there is evidence that some degree of specificity can be attained in different situations, for instance as organ-specific protection rather than microorganism-specific reaction. Thus, depending on the challenges and conditions, innate memory can be non-specific or specific, can be integrated in the germline and transmitted to the progeny or be short-lived, thereby representing an exceptionally plastic mechanism of defensive adaptation for ensuring individual and species survival.
    Keywords:  adaptation; innate immunity; innate memory; specificity; survival
  7. Front Cell Infect Microbiol. 2024 ;14 1394070
      Mycobacterium avium subsp. paratuberculosis (Map) is the etiological agent of paratuberculosis (PTB), a chronic intestinal inflammatory disease that causes high economical losses in dairy livestock worldwide. Due to the absence of widely available preventive or therapeutical treatments, new alternative therapies are needed. In this study, the effect of a probiotic alone or in combination with a commercial vaccine has been evaluated in a rabbit model. Vaccination enhanced the humoral response, exerted a training effect of peripheral polymorphonuclear neutrophils (PMNs) against homologous and heterologous stimuli, stimulated the release of pro-inflammatory cytokines by gut-associated lymphoid tissue (GALT) macrophages, and reduced the bacterial burden in GALT as well. However, the administration of the probiotic after vaccination did not affect the PMN activity, increased metabolic demand, and supressed pro-inflammatory cytokines, although humoral response and bacterial burden decrease in GALT was maintained similar to vaccination alone. The administration of the probiotic alone did not enhance the humoral response or PMN activity, and the bacterial burden in GALT was further increased compared to the only challenged group. In conclusion, the probiotic was able to modulate the immune response hampering the clearance of the infection and was also able to affect the response of innate immune cells after vaccination. This study shows that the administration of a probiotic can modulate the immune response pathways triggered by vaccination and/or infection and even exacerbate the outcome of the disease, bringing forward the importance of verifying treatment combinations in the context of each particular infectious agent.
    Keywords:  macrophage polarization; neutrophils; paratuberculosis; phagocytes; probiotic; reactive oxygen species; trained immunity; vaccine
  8. Proc Natl Acad Sci U S A. 2024 Jun 25. 121(26): e2319623121
      Solid organ transplantation mobilizes myeloid cells, including monocytes and macrophages, which are central protagonists of allograft rejection. However, myeloid cells can also be functionally reprogrammed by perioperative costimulatory blockade to promote a state of transplantation tolerance. Transplantation tolerance holds promise to reduce complications from chronic immunosuppression and promote long-term survival in transplant recipients. We sought to identify different mediators of transplantation tolerance by performing single-cell RNA sequencing of acute rejecting or tolerized cardiac allografts. This led to the unbiased identification of the transcription factor, hypoxia inducible factor (HIF)-2α, in a subset of tolerogenic monocytes. Using flow cytometric analyses and mice with conditional loss or gain of function, we uncovered that myeloid cell expression of HIF-2α was required for costimulatory blockade-induced transplantation tolerance. While HIF-2α was dispensable for mobilization of tolerogenic monocytes, which were sourced in part from the spleen, it promoted the expression of colony stimulating factor 1 receptor (CSF1R). CSF1R mediates monocyte differentiation into tolerogenic macrophages and was found to be a direct transcriptional target of HIF-2α in splenic monocytes. Administration of the HIF stabilizer, roxadustat, within micelles to target myeloid cells, increased HIF-2α in splenic monocytes, which was associated with increased CSF1R expression and enhanced cardiac allograft survival. These data support further exploration of HIF-2α activation in myeloid cells as a therapeutic strategy for transplantation tolerance.
    Keywords:  macrophage; tolerance; transplant
  9. Am J Transl Res. 2024 ;16(5): 1643-1659
      OBJECTIVES: To elucidate the transcriptome of macrophages in an inflammation model induced by lipopolysaccharide (LPS), providing insight into the molecular basis of inflammation.METHODS: We utilized RNA sequencing (RNA-seq) to analyze dynamic changes in gene expression in RAW264.7 macrophages treated with LPS at multiple time points. Differentially expressed genes (DEGs) were identified using the edgeR package. Short Time-series Expression Miner (STEM) and KEGG pathway enrichment analyses were conducted to determine temporal expression patterns during inflammation.
    RESULTS: We identified 2,512 DEGs, with initial inflammatory responses occurring in two distinct phases at 1 h and 3 h. Venn diagram analysis revealed 78 consistently dysregulated genes throughout the inflammatory process. A key module of 18 dysregulated genes was identified, including Irg1, which may exert an inhibitory effect on inflammation. Further, a second metabolic shift in activated macrophages was observed at the late middle stage (12 h). Multi-omics analysis highlighted the ribosome's potential regulatory role in the inflammatory response.
    CONCLUSIONS: This study provides a detailed view of the molecular mechanisms underlying inflammation in macrophages and reveals a dynamic genetic landscape crucial for further research. Our findings underscore the complex interaction between gene expression, metabolic shifts, and ribosomal functions in response to LPS-induced inflammation.
    Keywords:  Macrophage; inflammation; metabolism; transcriptome
  10. Immunity. 2024 Jun 19. pii: S1074-7613(24)00305-4. [Epub ahead of print]
      Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2'3'-cyclic GMP-AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation.
    Keywords:  IL-18; SLC12A3; bistable circuit; cGAMP; fatty acid oxidation; immunometabolism; intestinal tolerance; macrophage; metabolic reprogramming; metabolic switch
  11. Cells. 2024 May 26. pii: 916. [Epub ahead of print]13(11):
      Acute inflammation is a rapid and dynamic process involving the recruitment and activation of multiple cell types in a coordinated and precise manner. Here, we investigate the origin and transcriptional reprogramming of monocytes using a model of acute inflammation, zymosan-induced peritonitis. Monocyte trafficking and adoptive transfer experiments confirmed that monocytes undergo rapid phenotypic change as they exit the blood and give rise to monocyte-derived macrophages that persist during the resolution of inflammation. Single-cell transcriptomics revealed significant heterogeneity within the surface marker-defined CD11b+Ly6G-Ly6Chi monocyte populations within the blood and at the site of inflammation. We show that two major transcriptional reprogramming events occur during the initial six hours of Ly6Chi monocyte mobilisation, one in the blood priming monocytes for migration and a second at the site of inflammation. Pathway analysis revealed an important role for oxidative phosphorylation (OxPhos) during both these reprogramming events. Experimentally, we demonstrate that OxPhos via the intact mitochondrial electron transport chain is essential for murine and human monocyte chemotaxis. Moreover, OxPhos is needed for monocyte-to-macrophage differentiation and macrophage M(IL-4) polarisation. These new findings from transcriptional profiling open up the possibility that shifting monocyte metabolic capacity towards OxPhos could facilitate enhanced macrophage M2-like polarisation to aid inflammation resolution and tissue repair.
    Keywords:  Ly6Chi monocytes; OxPhos; chemotaxis; single cell transcriptomics
  12. Shock. 2024 Jun 18.
      ABSTRACT: Mitochondrial dysfunction is a recognized feature of sepsis, characterized by ultrastructural damage, diminished oxidative phosphorylation, and depletion of mitochondrial antioxidant capacity observed in deceased septic patients. Lipopolysaccharide (LPS) tolerance induces a controlled response to sepsis. This study aimed to evaluate the function of tolerant mitochondria after cecal ligation and puncture (CLP)-induced sepsis. Mytochondrial oxygen consumption was determined using polarography. Extraction and quantification of RNA for the expression of Tfam, Nrf-1 and Ppargc-1α; and Respiratory complex activity were measured. CLP-tolerant animals presented preserved respiratory rates of S3 and S4 and a ratio of respiratory control (RCR) compared to CLP non-tolerant animals with reduced oxidative phosphorylation and increased uncoupled respiration. Complex I Vmax was reduced in septic animals; however, CLP animals sustained normal Vmax. Mitochondrial biogenesis was preserved in CLP-tolerant animals compared to the CLP-nontolerant group, likely due to increased TFAM expression. LPS tolerance protected septic animals from mitochondrial dysfunction, favoring mitochondrial biogenesis and preserving mitochondrial respiration and respiratory complex I activity.
  13. Immunology. 2024 Jun 12.
      The cross-regulation of immunity and metabolism is currently a research hotspot in life sciences and immunology. Metabolic immunology plays an important role in cutting-edge fields such as metabolic regulatory mechanisms in immune cell development and function, and metabolic targets and immune-related disease pathways. Protein post-translational modification (PTM) is a key epigenetic mechanism that regulates various biological processes and highlights metabolite functions. Currently, more than 400 PTM types have been identified to affect the functions of several proteins. Among these, metabolic PTMs, particularly various newly identified histone or non-histone acylation modifications, can effectively regulate various functions, processes and diseases of the immune system, as well as immune-related diseases. Thus, drugs aimed at targeted acylation modification can have substantial therapeutic potential in regulating immunity, indicating a new direction for further clinical translational research. This review summarises the characteristics and functions of seven novel lysine acylation modifications, including succinylation, S-palmitoylation, lactylation, crotonylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation and malonylation, and their association with immunity, thereby providing valuable references for the diagnosis and treatment of immune disorders associated with new acylation modifications.
    Keywords:  S‐palmitoylation; acylation; immunity; lactylation; succinylation