bims-traimu Biomed News
on Trained immunity
Issue of 2025–07–13
eleven papers selected by
Yantong Wan, Southern Medical University



  1. Adv Exp Med Biol. 2025 ;1476 275-296
      Recent research has increasingly highlighted the adaptive characteristics of the innate immune system, revealing its capacity for a heterologous memory of previous infections. Allergen-specific immunotherapy (AIT) has demonstrated that innate immune cells, such as monocytes, macrophages, and natural killer (NK) cells, can provide protection against specific diseases even in the absence of lymphocyte support. The mechanisms underlying innate host defense and the immunological memory of adaptive immunity differ significantly in terms of cellular populations and molecular pathways. Prototypical innate immune cells, including NK cells and monocytes/macrophages, contribute to the sustained heightened state of innate immunity known as "trained immunity," which enhances resistance to secondary infections. Trained immunity is typically initiated through the engagement of pattern recognition receptors (PRRs) by microbial structures, suggesting that vaccines designed to induce trained immunity should incorporate appropriate PRR ligands. This approach not only offers protection against reinfection in a manner independent of T and B cells but also promotes nonspecific epigenetic reprogramming that enhances immune responses. For instance, Bacillus Calmette-Guérin (BCG) vaccination has been linked to long-lasting immune modifications associated with a non-specific immune response to various infections, characterized by heterologous T helper 1 (Th1) and Th17 responses. Emerging evidence indicates that heat-killed Mycobacterium manresensis can induce trained immunity in vitro, although its effectiveness in vivo remains to be fully established. This highlights the potential of novel strategies in vaccine development, particularly through the lens of trained immunity. The concept of trained immunity-based vaccines (TIbV) presents a paradigm shift in immunization strategies, as these vaccines can elicit broad-spectrum protection against a variety of pathogens. By leveraging the principles of trained immunity, TIbV can enhance both innate and adaptive immune responses, potentially improving the efficacy of conventional vaccines and offering new avenues for immunotherapy.The integration of trained innate immunity into vaccine development holds significant promise for enhancing immune protection against infectious diseases. By harnessing the principles of trained immunity, these innovative vaccines can enhance innate immune responses, potentially improving protection against a wide range of infectious diseases and contributing to better public health outcomes.
    DOI:  https://doi.org/10.1007/978-3-031-85340-1_11
  2. Elife. 2025 Jul 08. pii: RP102068. [Epub ahead of print]13
      Alveolar macrophages (AMs) reside in the lower airways and play a crucial role in lung health and response to sterile inflammation and infections. AMs possess remarkable adaptability to different environmental challenges that can persist through their memory capacity (trained immunity). β-Glucan has been characterized as a potent inducer of central trained immunity by reprogramming haematopoietic stem cells in the bone marrow. In the present study, we show that systemic administration of β-glucan in mice induces peripheral trained immunity by reprogramming AMs in the lungs, in a Dectin1-independent manner. We furthermore demonstrate that AM reprogramming at both the transcriptional and metabolic levels exacerbate lung injury following bacterial (lipopolysaccharide) or viral (polyI:C) challenges via a neutrophil/IFN-γ-dependent manner. These findings identify an additional facet of β-glucan in trained immunity involving AM reprogramming and shed light on the potential detrimental effects of trained immunity.
    Keywords:  acute lung injury; immunology; inflammation; mouse; trained immunity; β-glucan
    DOI:  https://doi.org/10.7554/eLife.102068
  3. Dev Cell. 2025 Jul 07. pii: S1534-5807(25)00259-X. [Epub ahead of print]60(13): 1813-1815
      In this issue of Developmental Cell, Haacke et al. demonstrate that osteoclasts undergo innate immune training, resulting in increased bone resorption and exacerbation of arthritis. These data highlight the complexity of inflammatory osteoclast precursors and costimulatory pathways in arthritis and open new research avenues in the ever-growing field of osteoimmunology.
    DOI:  https://doi.org/10.1016/j.devcel.2025.04.021
  4. Genome Biol. 2025 Jul 09. 26(1): 180
       BACKGROUND: Epigenetic reprogramming shapes immune memory in both innate (trained immunity) and adaptive immune cells following Bacillus Calmette-Guérin (BCG) vaccination. However, the role of dynamic DNA methylation changes in post-vaccination immune responses remains unclear.
    RESULTS: We established a cohort of 284 healthy Dutch individuals, profiling genome-wide DNA methylation and cytokine responses to ex vivo stimulation at baseline, 14 days, and 90 days post-BCG vaccination. We identified distinct patterns of DNA methylation alternations in the short- and long-term following BCG vaccination. Moreover, we established that baseline DNA methylation profiles exert influence on the change in interferon-γ (IFN-γ) production upon heterologous (Staphylococcus aureus) stimulation before and after BCG vaccination. Specifically, we identified the regulation of kisspeptin as a novel pathway implicated in the modulation of IFN-γ production, and this finding has been substantiated through experimental validation. We also observed associations between BCG-induced DNA methylation changes and increased IFN-γ and interleukin-1 β (IL-1β) production upon S. aureus stimulation. Interestingly, by integrating with genetic, epigenetic, and cytokine response data from the same individuals, mediation analysis demonstrated that most of the identified DNA methylation changes played a mediating role between genetic variants and cytokine responses; for example, the changes of cg21375332 near SLC12 A3 gene mediated the regulation of genetic variants on IFN-γ changes after BCG vaccination. Sex-specific effects were observed in DNA methylation and cytokine responses, highlighting the importance of considering sex in immune studies.
    CONCLUSIONS: These findings provide deeper insights into immune response mechanisms, crucial for developing effective epigenetic-based medical interventions for personalized medicine.
    Keywords:  BCG vaccination; Cytokines response; DNA methylation; Systems biology; Trained immunity
    DOI:  https://doi.org/10.1186/s13059-025-03611-9
  5. Pharmacol Rev. 2025 Jun 12. pii: S0031-6997(25)07482-4. [Epub ahead of print]77(5): 100074
      Myeloid innate immune cells, including macrophages, neutrophils, myeloid-derived suppressor cells, and dendritic cells, represent major components of the tumor microenvironment (TME), exhibiting remarkable plasticity and dual roles in cancer progression and immune regulation. In recent years, microbial-induced innate immune memory, also termed "trained immunity" (TRIM), has emerged as a novel strategy to reprogram myeloid cells into an immunostimulatory, antitumor state. In this review, we explore the intricate landscape of myeloid cells in cancer and examine how microbial ligands, such as the Bacillus Calmette-Guérin vaccine and β-glucan, reprogram both bone marrow progenitors and tissue-resident myeloid cells to enhance inflammatory and antitumor responses. Notable findings include the hematopoietic stem and progenitor cell reprogramming by Bacillus Calmette-Guérin for sustained anticancer immunity, and the enhanced granulopoiesis and neutrophil-mediated tumor killing mediated by β-glucan-induced TRIM. These mechanisms synergize with immunotherapies, such as immune checkpoint inhibitors, by reshaping the immunosuppressive TME and enhancing adaptive immunity. However, challenges remain, including the structural complexity of microbial products, the lack of predictive biomarkers, and the need for optimized dosing and delivery strategies. Addressing these gaps by introducing precise characterization of microbial-derived ligands, biomarker-driven patient selection through large-scale clinical trials, as well as the development of novel approaches for targeted therapy will be essential to harness the full potential of microbial-induced TRIM, ultimately paving the way for more effective and durable cancer immunotherapies. SIGNIFICANCE STATEMENT: Tumor-promoting myeloid cells within the tumor microenvironment remain a major barrier to effective cancer immunotherapy. Microbial-induced trained immunity offers a novel strategy to reprogram myeloid cells into an antitumor state. This review provides a comprehensive overview of myeloid cell populations in cancer and the mechanisms underlying microbial-induced trained immunity. It also highlights preclinical and clinical evidence demonstrating the efficacy of microbial-based strategies in overcoming immunosuppression and synergizing with existing immunotherapies, offering a promising approach to improve cancer treatment outcomes.
    DOI:  https://doi.org/10.1016/j.pharmr.2025.100074
  6. Avian Dis. 2025 Jun;69(2): 183-199
      Bacterial infections such as Escherichia coli and necrotic enteritis (NE) caused by Clostridium perfringens (CP) are responsible for significant economic losses in the broiler chicken industry. Our previous studies have involved trying to develop alternatives to antimicrobials and immunoprotective agents to such pathogens. Previously, we demonstrated that delivery of a single dose of oligodeoxynucleotides containing unmethylated cytosine-phosphodiester-guanine motifs (CpG-ODN) can promote antimicrobial immunity against yolk sac infections caused by E. coli and Salmonella by enriching immune compartments and activating immune cells. Recently, we have demonstrated delivery of CpG-ODN twice by the intramuscular (IM) route in neonatal broiler chickens at Days 1 and 4 of age to induce trained immunity and protect against lethal E. coli septicemia later in the grow-out period. The objectives of this study were to explore the ability of CpG-ODN to induce trained immunity in broiler chickens (1) by administering CpG-ODN by the in ovo route and intrapulmonary (IPL) route at hatch and (2) by administering CpG-ODN by the in ovo route and IPL delivery of a CP vaccine at hatch to protect against E. coli infections. Intramuscular (IM) delivery of CpG-ODN twice at Days 1 and 4 of age in neonatal broiler chickens induced trained immunity to protect against NE. Induction of trained immunity in broiler chickens led to a switch in cellular energy metabolism of immune cells from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) following two administrations of CpG-ODN. We have also demonstrated that delivery of CpG-ODN by the in ovo route followed by delivery of a live CP vaccine by the IPL route at hatch induced trained immunity and significantly (P < 0.0001) protected birds against E. coli septicemia at 27 days of age. Trained immunity was induced in broiler chickens only with administrations of CpG-ODN by the in ovo route followed by the IPL route at hatch or in ovo delivery of CpG-ODN followed by IPL delivery of a live CP vaccine at hatch. These birds were significantly (P < 0.0001) protected against lethal E. coli septicemia and NE later in the production cycle, demonstrating the utility of CpG-ODN for induction of trained immunity and broad-spectrum protection of broiler chickens against common lethal bacterial infections.
    Keywords:  Clostridium perfringens; Escherichia coli; broiler chickens; in ovo CpG-ODN; intrapulmonary vaccine delivery; necrotic enteritis; trained immunity
    DOI:  https://doi.org/10.1637/aviandiseases-D-24-00093
  7. Immunometabolism (Cobham). 2025 Jul;7(3): e00065
      The intricate interplay between cellular metabolism and immune function has emerged as a pivotal area of research in immunology. Macrophages, as central players in the innate immune system, exhibit remarkable metabolic flexibility that influences their activation states and functional outputs, with important implications for the pathophysiology of inflammatory diseases and cancer. A recent study by Zotta and colleagues provides new insights into the role of mitochondrial complex III (CIII) in regulating the anti-inflammatory cytokine interleukin-10 (IL-10) and its implications for tumor immunity.
    Keywords:  IL-10; ROS; immune evasion; inflammation; metabolism; mitochondria
    DOI:  https://doi.org/10.1097/IN9.0000000000000065
  8. J Lipid Res. 2025 Jul 04. pii: S0022-2275(25)00120-8. [Epub ahead of print] 100858
      Sepsis is the dysregulated immune response to an infection and is a leading cause of mortality. Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of death from sepsis, and increasing levels of HDL by inhibition of cholesteryl ester transfer protein (CETP) has been shown to decrease mortality in mouse models of sepsis. The objective of this study was to investigate the cellular mechanisms by which CETP inhibition and HDL lead to improved survival during sepsis. We found that HDL inhibits lipopolysaccharide (LPS)-induced activation of IL-1β in a mouse model of sepsis. The activation of IL-1β was dependent on the activity of scavenger receptor class B type 1 (SR-B1), and knockdown of SR-B1 significantly attenuated LPS-induced production of IL-1β in macrophages. Additionally, we found that LPS-induced SR-B1 internalization occurs through the endosome-lysosome pathway, which is also likely responsible for LPS degradation in the macrophages. Furthermore, we revealed that raising HDL by CETP inhibition markedly enhanced HDL-mediated anti-inflammatory effects in response to LPS stimulation, and these effects were not due to CETP itself but rather HDL-dependent. Finally, we show that pharmacological inhibition of CETP significantly improved endotoxemia-induced mortality by inhibiting IL-1β production in the liver and circulation after LPS injection. Pathologically, CETP inhibition attenuated LPS-induced diffuse alveolar damage and hepatocyte necrosis, which may contribute to the improved mortality in mice treated with the CETP inhibitor anacetrapib. Taken together, our findings uncover a cellular mechanism by which HDL attenuates LPS-induced pro-inflammatory response via SR-B1-mediated LPS degradation.
    Keywords:  CETP; HDL; IL-1β; LPS; SR-B1
    DOI:  https://doi.org/10.1016/j.jlr.2025.100858
  9. Microbes Infect. 2025 Jul 03. pii: S1286-4579(25)00077-2. [Epub ahead of print] 105545
      Neutrophils play a pivotal role in the innate immune response to bacterial infection, being one of the first immune cells to reach infectious sites. Bacterial infection may induce neutrophil degranulation, production of neutrophil extracellular traps (NETs), or pathogen phagocytosis. While LC3 is typically linked to autophagy, here we observed a non-canonical role of LC3 when peripheral neutrophils interact with bacteria both in vivo and in vitro, using Shigella spp. as a model. Upon incubation with neutrophils, extracellular bacteria became labelled by LC3 (LC3+) along with granules-localised antimicrobial components, such as lactotransferrin, defensin, elastase, and myeloperoxidase, as demonstrated by mass spectrometry. Co-localisation of LC3 and plasma membrane-specific dyes indicated that neutrophil plasma membrane-derived elongated structures covering bacteria were responsible for the labelling. This phenomenon was associated with bacterial growth restriction and bacterial cell-death induction. Testing with specific inhibitors demonstrated that this labelling was dependent on functional V-type ATP synthase. Covering bacteria with membrane-derived elongated structures enhanced the subsequent phagocytosis of bacteria by neutrophils. Finally, the LC3 labelling rate increased with higher bacterial burden. In conclusion, we propose that this defense mechanism is beneficial when the burden of bacterial infection overwhelms neutrophils' capacity for phagocytosis.
    Keywords:  LC3; Neutrophils; Shigella; autophagy; bacterial infection
    DOI:  https://doi.org/10.1016/j.micinf.2025.105545
  10. ILIVER. 2025 Mar;4(1): 100144
       Background and aims: Methane has shown protective effects against ischemia and reperfusion injury (IRI) in the liver, but the mechanism underlying these beneficial effects is unclear. To investigate the hypothesis that itaconate facilitates in methane-induced Nrf2 pathway activation to mitigate liver IRI.
    Methods: An oxygen and glucose derivation (OGD) model using RAW 264.7 cells and a liver IRI model in mice were established. Methane's beneficial effects were assessed through hematoxylin and eosin (HE) staining, Suzuki's score, serum alanine transferase level, superoxide dismutase (SOD) level, malondialdehyde (MDA) level, and cell viability. The relative expression levels of Nrf2, its downstream molecules and some inflammatory factors were detected via western blotting. Itaconate levels were analyzed using liquid chromatography. RAW 264.7 cells were transfected with short hairpin RNA targeting mouse aconitate decarboxylase 1 (Acod1) mRNA for itaconate downregulation.
    Results: Methane significantly alleviated liver IRI, as shown by the significant reduction in Suzuki's scores and alanine transferase (ALT) levels in vivo. Methane treatment significantly increased MTT and SOD levels and decreased MDA levels in the OGD injury model in vitro. Methane also increased the total and nuclear Nrf2 expression levels, activated downstream molecules including heme oxygenase-1 (HO-1), NQO1 and affected the production of inflammatory cytokines such as IL-10, IL-1β, and IL-12. Itaconate levels were significantly elevated after methane treatment compared with the OGD injury group. The protective effects of methane were abolished after itaconate downregulation through Acod1 knockdown.
    Conclusions: Methane alleviates liver IRI through itaconate/Nrf2 pathway activation, with itaconate being critical for methane's beneficial effects.
    Keywords:  Acod1; Ischemia; Itaconate; Liver; Methane; Nrf2; Reperfusion
    DOI:  https://doi.org/10.1016/j.iliver.2025.100144