bims-traimu 2025-06-29 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–06–29
eleven papers selected by
Yantong Wan, Southern Medical University

BCG-Derived Outer Membrane Vesicles Induce TLR2-Dependent Trained Immunity to Protect Against Polymicrobial Sepsis.
Trained Immunity Induced by Oxidized Low-Density Lipoprotein Is Dependent on Glutaminolysis.
A fungal-derived adjuvant amplifies the antitumoral potency of Bacillus Calmette-Guérin via reprogramming granulopoiesis.
Alternative splicing of KLF4 in myeloid cells: implications for cellular plasticity and trained immunity in cancer and inflammatory disease.
Heat-inactivated Mycobacterium marinum as a vaccine adjuvant and a trained immunity inducer in rainbow trout (Oncorhynchus mykiss).
Enhanced Trained Immunity in Peripheral Monocytes in Unstable Angina With Elevated High-Sensitivity C-Reactive Protein.
Gut bacteriophages induce specific-reprogramming of macrophages to generate a protective innate immunity response to lipopolysaccharide exposure.
Immunometabolic Regulation of Innate Immunity in Systemic Lupus Erythematosus.
SPI1 upregulated LILRB2 to enhance the immunosuppressive phenotype of LPS-tolerant macrophages by inhibiting TLR8-mediated MyD88/NF-κB signaling.
Methylglyoxal is an antibacterial effector produced by macrophages during infection.
Hypothermia protects against ventilator-induced lung injury by limiting IL-1β release and NETs formation.

Adv Sci (Weinh). 2025 Jun 24. e04101

BCG-Derived Outer Membrane Vesicles Induce TLR2-Dependent Trained Immunity to Protect Against Polymicrobial Sepsis.

Yuan Gong, Wenyan Hao, Lingqi Xu, Yingyi Yang, Zhenzhen Dong, Peng Pan, Zhenjiang Bai, Jie Huang, Kaidi Yang, Zhu Jin, Rui Kang, Qiang Shan, Jiang Huai Wang, Zijian Zhou, Daolin Tang, Jian Wang, Huiting Zhou.

  Trained immunity, an innate immune memory, has emerged as a promising strategy to enhance host defense against sepsis, a leading cause of mortality in critical care. While Bacillus Calmette-Guérin (BCG) is the most widely used vaccine for tuberculosis prevention, its broader use as an inducer of trained immunity is limited by adverse reactions. Here, it is reported that BCG-derived outer membrane vesicles (B-OMVs) effectively trigger trained immunity to protect against experimental polymicrobial sepsis. Comprehensive characterization and safety assessments confirmed that B-OMVs exhibited no significant toxicity or pathological effects, positioning them as a promising alternative to conventional BCG vaccines and E. coli-derived outer membrane vesicles (E-OMVs) in terms of both efficacy and safety. Mechanistically, B-OMVs enhanced trained immunity by promoting hematopoietic stem cell expansion and myelopoiesis via toll like receptor 2 (TLR2)-dependent activation of aerobic glycolysis and epigenetic reprogramming. This led to an amplified immune response and enhanced phagocytic activity in bone marrow-derived macrophages. Together, these findings establish B-OMVs as a novel immunomodulatory agent against sepsis-induced immune dysfunction, with translational potential.

Keywords:  BCG; OMVs; sepsis; trained immunity

DOI:  https://doi.org/10.1002/advs.202504101
FASEB J. 2025 Jul 15. 39(13): e70774

Trained Immunity Induced by Oxidized Low-Density Lipoprotein Is Dependent on Glutaminolysis.

Alice Scarpa, Yerin Jung, Arslan Hamid, Vasiliki Matzaraki, Tushar More, Alexander Heinz, Laszlo Groh, Siroon Bekkering, Karsten Hiller, Leo A B Joosten, Mihai G Netea, Katarzyna Placek, Niels P Riksen.

  Atherosclerosis is a chronic inflammatory disease of the arterial wall that causes cardiovascular disease. Monocyte-derived macrophages are an important contributor to atherogenesis. Monocytes can become primed for higher responsiveness to secondary, unrelated stimuli-a phenomenon known as trained immunity-a process driven by intracellular metabolic and epigenetic reprogramming. Oxidized low-density lipoprotein (oxLDL) induces trained immunity by enhancing glycolysis and oxidative phosphorylation (OXPHOS). Glutamine is known to enter the Krebs cycle through glutaminolysis where it can be used for ATP synthesis via OXPHOS. We therefore explored the role of the glutaminolysis pathway in oxLDL-induced trained immunity. Primary human monocytes from healthy donors were exposed to oxLDL for 24 h, followed by differentiation into macrophages over 6 days in culture medium. Thereafter, cytokine production capacity was assessed by stimulating them with Toll-like receptor agonist. Co-administration of the glutaminase inhibitor CB-839 during oxLDL exposure reduces glutamine anaplerosis. This prevented oxLDL-induced trained immunity, with diminished cytokine production capacity, associated with a reduced oxygen consumption rate (OCR), and glycolysis rate (ECAR). The role of glutaminolysis for induction of trained immunity was validated genetically, by showing significant associations between several single-nucleotide polymorphisms in genes related to glutaminolysis and ex vivo cytokine production in oxLDL-trained monocytes from 243 healthy volunteers. Finally, we identified a positive correlation between glutamate and Krebs cycle metabolites with inflammatory circulating biomarkers and monocyte counts in an independent cohort of 302 obese individuals. Altogether, these data suggest a crucial role of glutaminolysis in the establishment of oxLDL-induced trained immunity.

Keywords:  Krebs cycle; atherosclerosis; glutamine; glutaminolysis; oxLDL; trained immunity

DOI:  https://doi.org/10.1096/fj.202500802R
Immunity. 2025 Jun 19. pii: S1074-7613(25)00247-X. [Epub ahead of print]

A fungal-derived adjuvant amplifies the antitumoral potency of Bacillus Calmette-Guérin via reprogramming granulopoiesis.

Leonardo F Jurado, Andrew W Daman, Ziyi Li, Vanessa M S Ross, Kristina Nikolaou, Kim A Tran, Oleg Loutochin, Victor A McPherson, Renaud Prével, Raquel Tarancón, Katalina Couto, Erwan Pernet, Nargis Khan, Jin-Gyu Cheong, Reshma Ramaiah, Mythili Ketavarapu, Eva Kaufmann, Michael S Glickman, Ajitha Thanabalasuriar, Steven Z Josefowicz, Maziar Divangahi.

  In patients with non-muscle invasive bladder cancer, the standard immunotherapy involves intravesical Bacillus Calmette-Guérin (BCG). However, its success requires repeated doses, and ∼50% of patients do not benefit. Using a preclinical orthotopic bladder cancer model, we found that a single intravesical dose of combined BCG and β-glucan immunotherapy eradicated aggressive tumors, resulting in 100% survival. Through single-cell transcriptomic/epigenomic analysis, flow cytometry, and intravital imaging, we show that BCG and β-glucan reprogrammed hematopoietic stem and progenitor cells with imprinting in innate immune cells, particularly neutrophils. Reprogrammed neutrophils exhibited increased reactive oxygen species (ROS) production and infiltration into the tumor core, reducing tumor vascularization and growth. The tumor microenvironment can convert neutrophils into protumor cells; BCG and β-glucan prevented this conversion, promoting sustained antitumoral activity. These findings support β-glucan as a safe, effective adjuvant to enhance BCG immunotherapy in bladder cancer and other solid tumors.

Keywords:  BCG; bladder cancer; granulopoiesis; immunotherapy; innate immune memory; melanoma; neutrophils; trained immunity; β-glucan

DOI:  https://doi.org/10.1016/j.immuni.2025.05.026
Front Immunol. 2025 ;16 1585528

Alternative splicing of KLF4 in myeloid cells: implications for cellular plasticity and trained immunity in cancer and inflammatory disease.

Amanda Rosewell Shaw, Attoria Bennett, Daping Fan, Walden Ai.

  The role of transcription factor Krüppel-like factor 4 (KLF4) in the modulation of myeloid cells is well known. KLF4 is involved in the differentiation and polarization of monocytes and macrophages as part of the immune response after infection, in wound healing, and in cancer. In addition, KLF4 is essential in stem cell reprogramming and the phenomenon of trained immunity - a form of innate immune memory marked by epigenetic and metabolic reprogramming. A novel and underexplored dimension of KLF4 biology lies in its alternative splicing (AS), which generates distinct isoforms that may drive the transcription factor's functions, depending on specific cellular environments, disease states, or signaling programs. This review presents current knowledge of KLF4 splicing in myeloid cells and explores novel connections for how KLF4 isoform diversity may contribute to cellular plasticity and differential immune responses of myeloid cells across physiological and pathological conditions.

Keywords:  AS; Krüppel-like factor 4 (KLF4); cancer stem cells; cellular plasticity; epigenetics; innate immunity; myeloid-derived suppressor cells (MDSCs); trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1585528
Fish Shellfish Immunol. 2025 Jun 25. pii: S1050-4648(25)00410-3. [Epub ahead of print] 110521

Heat-inactivated Mycobacterium marinum as a vaccine adjuvant and a trained immunity inducer in rainbow trout (Oncorhynchus mykiss).

Kyung Min Lee, Ki Hong Kim.

  The increasing need for effective disease prevention strategies in aquaculture highlights the importance of developing novel vaccine adjuvants and immunostimulants. This study aimed to investigate the immunomodulatory potential of heat-killed Mycobacterium marinum in rainbow trout (Oncorhynchus mykiss), with a focus on its dual role as a vaccine adjuvant and an inducer of trained immunity. To this end, we evaluated the effects of co-immunizing fish with heat-killed M. marinum and a live attenuated Vibrio anguillarum vaccine. This combination significantly enhanced protective efficacy, as demonstrated by increased survival rates, elevated serum antibody titers, and early upregulation of pro-inflammatory cytokines and immune-related genes. In addition, heat-killed M. marinum alone conferred non-specific protection against V. anguillarum infection, characterized by earlier bacterial clearance, heightened inflammatory gene expression, and epigenetic modifications, including increased H3K4me3 and H3K27ac at cytokine gene promoters. These findings support the use of heat-killed M. marinum as both an effective vaccine adjuvant and a promising inducer of trained immunity in aquaculture species.

Keywords:  Epigenetic modification; Heat-killed Mycobacterium marinum; Vaccine adjuvant efficacy; Vibrio anguillarum

DOI:  https://doi.org/10.1016/j.fsi.2025.110521
JACC Basic Transl Sci. 2025 Jun 24. pii: S2452-302X(25)00220-7. [Epub ahead of print]10(7): 101300

Enhanced Trained Immunity in Peripheral Monocytes in Unstable Angina With Elevated High-Sensitivity C-Reactive Protein.

Jiyu Zhang, Fen Yang, Yuhan Liao, Xinyi Xia, Miao Yu, Desheng Hu, Weimin Wang, Li Zhang, Chaolong Wang, Huirong Liu, Chen Chen, Qing K Wang, Zhilei Shan, Peter Libby, Xiang Cheng.

  Despite effective secondary prevention for coronary heart diseases, recurrent events remain high. Elevated high-sensitivity C-reactive protein (hsCRP) indicates increased inflammation risk. This study aimed to investigate the trained immunity of circulating monocytes in unstable angina (UA) patients with elevated hsCRP. We analyzed CD14+ monocytes from UA patients, comparing high-risk (hsCRP ≥3 mg/L) and low-risk (hsCRP <1 mg/L) groups. We assessed cytokine production and conducted metabolic, transcriptional, and epigenetic profiling. Patients with elevated hsCRP exhibited enhanced proinflammatory responses, glycolytic activity, and altered immune profiles, indicating sustained monocyte trained immunity, which contributes to residual inflammation risk in cardiovascular disease.

Keywords:  hsCRP; inflammatory risk; monocyte; trained immunity; unstable angina

DOI:  https://doi.org/10.1016/j.jacbts.2025.04.014
Gut Microbes. 2025 Dec;17(1): 2524540

Gut bacteriophages induce specific-reprogramming of macrophages to generate a protective innate immunity response to lipopolysaccharide exposure.

Xiang Hou, Huiyan Ding, Heye Wang, Jing Wang, Hui Liu, Hao Hu, Craig Billington, Ran Wang, Lili Zhang.

  Macrophages play essential roles in generating a tolerogenic resident environment, but the interactions between bacteriophages and their action in macrophage tolerance memory remain unknown. Here, we find that gut bacteriophage exposure in vivo induces tolerance immunity via reprogrammed macrophages which significantly enhances protection against bacterial lipopolysaccharide (LPS). Bacteriophage-memory macrophages orchestrate LPS-challenge responses into tolerization or hyperresponsive gene expression clusters in a function-specific manner. The tolerized gene cluster encodes pro-inflammatory cytokines, while the induction cluster is a defense-specific response including anti-inflammatory cytokines, antiviral and antimicrobial effectors, and negative regulators of inflammation. Mechanistically, this augmented defense response is dependent on increased expression of IL-10, but not suppression of pro-inflammatory cytokines. Furthermore, bacteriophages suppressed LPS-induced pro-inflammatory genes by repressing histone acetylation target enhancers that coordinate chromatin accessibility to limit inflammation. Thus, our study identifies the function and mechanism of reprogramming actions for bacteriophage in moderating LPS immune responses.

Keywords:  Bacteriophage; IL-10; epigenetic mechanisms; innate immune memory; macrophage

DOI:  https://doi.org/10.1080/19490976.2025.2524540
Acta Med Okayama. 2025 Jun;79(3): 147-155

Immunometabolic Regulation of Innate Immunity in Systemic Lupus Erythematosus.

Haruki Watanabe, Yoshinori Matsumoto, Jun Wada.

  Pathogens or their components can induce long-lasting changes in the behavior of innate immune cells, a process analogous to "training" for future threats or environmental adaptation. However, such training can sometimes have unintended consequences, such as the development of autoimmunity. Systemic lupus erythematosus (SLE) is a chronic and heterogeneous autoimmune disease characterized by the production of autoantibodies and progressive organ damage. Innate immunity plays a central role in its pathogenesis, contributing through impaired clearance of apoptotic cells, excessive type I interferon production, and dysregulated formation of neutrophil extracellular traps. Recent studies have revealed that metabolites and nucleic acids derived from mitochondria, a crucial energy production site, directly regulate type I interferon and anti-inflammatory cytokine production. These insights have fueled interest in targeting metabolic pathways as a novel therapeutic approach for SLE, offering promise for improving long-term patient outcomes.

Keywords:  innate immune memory; interferon; systemic lupus erythematosus; trained immunity; tricarboxylic acid cycle

DOI:  https://doi.org/10.18926/AMO/68722
Biol Direct. 2025 Jun 23. 20(1): 73

SPI1 upregulated LILRB2 to enhance the immunosuppressive phenotype of LPS-tolerant macrophages by inhibiting TLR8-mediated MyD88/NF-κB signaling.

Ruojing Bai, Jun Guo.

  In sepsis, immunosuppression is commonly observed as lipopolysaccharide (LPS) tolerance in macrophages. Leukocyte immunoglobulin-like receptor B2 (LILRB2) is an inhibitory receptor on immune cells that may play a crucial role in the immunosuppressive phenotype of LPS-tolerant macrophages, although its exact function in sepsis remains unclear. In this study, macrophages were exposed to single or sequential LPS doses to induce LPS stimulation or tolerance. Cell viability was assessed using CCK-8 assay, apoptosis, and macrophage polarization were detected by flow cytometry, and pro-inflammatory cytokine levels were measured by RT-qPCR and ELISA. Molecular interactions were explored using Co-IP, ChIP, and dual-luciferase assays, while mRNA and protein expression were assessed by RT-qPCR and Western blotting. The results showed that LILRB2 was upregulated in macrophages following LPS stimulation, with a more significant increase in the LPS-tolerant group. Knocking down LILRB2 reversed the immunosuppressive phenotype of LPS-tolerant macrophages and restored the inhibition of MyD88/NF-κB signaling and p65 nuclear translocation caused by LPS tolerance. Mechanistically, LILRB2 interacted with Toll-like receptor 8 (TLR8) to inhibit the MyD88/NF-κB signaling pathway in LPS-tolerant macrophages. Furthermore, the upregulation of the Spi-1 proto-oncogene (SPI1) enhanced the immunosuppressive phenotype by transcriptionally activating LILRB2. In conclusion, SPI1 upregulation promoted the immunosuppressive phenotype of LPS-tolerant macrophages by activating LILRB2 transcription, which inhibited TLR8-mediated MyD88/NF-κB signaling. This study clarifies the role of LILRB2 and its underlying mechanisms in LPS-tolerant macrophages.

Keywords:  Immunosuppressive phenotype; LILRB2; LPS-tolerant macrophages; MyD88/NF-κB signaling; SPI1; Sepsis

DOI:  https://doi.org/10.1186/s13062-025-00669-0
Cell Host Microbe. 2025 Jun 13. pii: S1931-3128(25)00209-4. [Epub ahead of print]

Methylglyoxal is an antibacterial effector produced by macrophages during infection.

Andrea Anaya-Sanchez, Samuel B Berry, Scott Espich, Alex Zilinskas, Phuong M Tran, Carolina Agudelo, Helia Samani, K Heran Darwin, Daniel A Portnoy, Sarah A Stanley.

  Infected macrophages transition into aerobic glycolysis, a metabolic program crucial for controlling bacterial infection. However, antimicrobial mechanisms supported by aerobic glycolysis are unclear. Methylglyoxal is a highly toxic aldehyde that modifies proteins and DNA and is produced as a side product of glycolysis. We show that despite this toxicity, infected macrophages generate high levels of methylglyoxal during aerobic glycolysis while downregulating the detoxification system, including glyoxalase 1 (GLO1). Dampening methylglyoxal generation in mice resulted in enhanced survival of Listeria monocytogenes and Mycobacterium tuberculosis, whereas mice lacking Glo1 have increased methylglyoxal levels and improved infection control. Furthermore, bacteria unable to detoxify methylglyoxal (ΔgloA) exhibit attenuated virulence but are partially rescued in mice that cannot enter glycolysis and generate methylglyoxal. This loss of bacterial GloA results in up to a 1,000-fold greater genomic mutation frequency during infection. Collectively, these results suggest that methylglyoxal is an antimicrobial innate effector that defends against bacterial pathogens.

Keywords:  bacterial pathogens; glycolysis; innate immunity; methylglyoxal

DOI:  https://doi.org/10.1016/j.chom.2025.05.026
Elife. 2025 Jun 24. pii: RP101990. [Epub ahead of print]14

Hypothermia protects against ventilator-induced lung injury by limiting IL-1β release and NETs formation.

Nobuyuki Nosaka, Vanessa Borges, Daisy Martinon, Timothy R Crother, Moshe Arditi, Kenichi Shimada.

  Although mechanical ventilation is a critical intervention for acute respiratory distress syndrome (ARDS), it can trigger an IL-1β-associated complication known as ventilator-induced lung injury. In mice, we found that lipopolysaccharide (LPS) and high-volume ventilation, LPS-HVV, lead to hypoxemia with neutrophil extracellular traps (NETs) formation in the alveoli. Furthermore, Il1r1-/- LPS-HVV mice did not develop hypoxemia and had reduced NETs, indicating that IL-1R1 signaling is important for NETs formation and hypoxemia. Therapeutic hypothermia (TH) is known to reduce the release of inflammatory mediators. In LPS-HVV mice, TH (32°C body temperature) prevented hypoxemia development, reducing albumin leakage, IL-1β, gasdermin D (GSDMD), and NETs formation. We also observed that LPS-primed macrophages, when stimulated at 32°C with ATP or nigericin, release less IL-1β associated with reduced GSDMD cleavage. Thus, hypothermia is an important modulating factor in the NLRP3 inflammasome activation, IL-1β release, and NETs formation, preventing LPS-HVV-induced acute respiratory failure.

Keywords:  ARDS; acute; immunology; inflammation; lung; macrophages; mouse; neutrophils; ventilator

DOI:  https://doi.org/10.7554/eLife.101990