bims-traimu Biomed News
on Trained immunity
Issue of 2025–05–11
seven papers selected by
Yantong Wan, Southern Medical University
  1. Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory.
  2. Long-term and non-specific immune memory induced by muramyl dipeptide and its protective effect against Vibrio anguillarum in rainbow trout (Oncorhynchus mykiss).
  3. PGI2 restricts trained ILC2 responses in allergic inflammation.
  4. Itaconate potentiates hepatic gluconeogenesis through NRF2 induction.
  5. Protocol for the imputation of stimulus-induced single-cell gene expression trajectories from time-series scRNA-seq data.
  6. Chronic Lipopolysaccharide Exposure Causes AD-Like Pathology in Male Mice With Intact Blood-Brain Barrier.
  7. Bactericidal activity of mammalian histones is caused by large membrane pore formation.
  1. Cell. 2025 Apr 25. pii: S0092-8674(25)00400-3. [Epub ahead of print]
    Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory.
    Athanasios Ziogas, Boris Novakovic, Lorenzo Ventriglia, Noriko Galang, Kim A Tran, Wenchao Li, Vasiliki Matzaraki, Nienke van Unen, Titus Schlüter, Anaísa V Ferreira, Simone J C F M Moorlag, Valerie A C M Koeken, Mthabisi Moyo, Xiaolin Li, Marijke P A Baltissen, Joost H A Martens, Yang Li, Maziar Divangahi, Leo A B Joosten, Musa M Mhlanga, Mihai G Netea.
      Trained immunity, a de facto innate immune memory characterized by enhanced responsiveness to future challenges, is underpinned by epigenetic and metabolic rewiring. In individuals vaccinated with Bacille Calmette-Guérin (BCG), lactate release was associated with enhanced cytokine responsiveness upon restimulation. Trained monocytes/macrophages are characterized by lactylation of histone H3 at lysine residue 18(H3K18la), mainly at distal regulatory regions. Histone lactylation was positively associated with active chromatin and gene transcription, persisted after the elimination of the training stimulus, and was strongly associated with "trained" gene transcription in response to a secondary stimulus. Increased lactate production upon induction of trained immunity led to enhanced production of proinflammatory cytokines, a process associated with histone lactylation. Pharmacological inhibition of lactate production or histone lactylation blocked trained immunity responses, while polymorphisms of LDHA and EP300 genes modulated trained immunity. Long-term histone lactylation persisted in vivo 90 days after vaccination with BCG, highlighting H3K18la as an epigenetic mark of innate immune memory.
    Keywords:  BCG; Bacillus Calmette-Guérin; H3K18la; lactate; lactylation; trained immunity
    DOI:  https://doi.org/10.1016/j.cell.2025.03.048
  2. Dev Comp Immunol. 2025 May 05. pii: S0145-305X(25)00075-8. [Epub ahead of print]167 105386
    Long-term and non-specific immune memory induced by muramyl dipeptide and its protective effect against Vibrio anguillarum in rainbow trout (Oncorhynchus mykiss).
    Kyung Min Lee, Ki Hong Kim.
      Muramyl dipeptide (MDP), a minimal bioactive peptidoglycan motif derived from the bacterial cell wall, is known to trigger a wide range of signaling cascades related to inflammatory and antibacterial responses, thereby enhancing the antimicrobial function of various innate immune cells including monocytes, macrophages, neutrophils, natural killer (NK) cells, and lymphocytes. To date, several studies have demonstrated that MDP has the capacity to stimulate non-specific immunity in fish. However, the long-term effect of MDP on fish remains unclear. In this study, we aimed to investigate the long-term protective effect of MDP against Vibrio anguillarum in rainbow trout (Oncorhynchus mykiss). MDP was administered to the rainbow trout by intraperitoneal (IP) injection, and the bacterial challenge was conducted at 4 weeks post-administration. The MDP-injected fish exhibited significantly higher survival rates than fish injected with PBS. Following bacterial infection, significantly reduced bacterial loads were shown in the head kidney of MDP-injected fish, accompanied by elevated expression levels of TNF-α, IL-1β, IL-6, IL-12, and HIF-1α. Furthermore, a significant increase of acetylation of histone 3 at lysine 27 (H3K27ac) was evident at the promoter regions of TNF-α and IL-1β in the fish of the MDP group at 4 weeks post-administration. These results suggest that MDP-induced histone acetylation in immune-related genes' promoters enhanced immune gene expression upon infection, possibly contributing to the observed long-term antibacterial effect and protection against V. anguillarum.
    Keywords:  H3K27ac modification; Muramyl dipeptide (MDP); Pro-inflammatory cytokines; Rainbow trout; Vibrio anguillarum
    DOI:  https://doi.org/10.1016/j.dci.2025.105386
  3. J Immunol. 2025 May 07. pii: vkaf088. [Epub ahead of print]
    PGI2 restricts trained ILC2 responses in allergic inflammation.
    Weisong Zhou, Jian Zhang, Allison E Norlander, Daniel P Cook, Shinji Toki, Masako Abney, Mark Rusznak, Christopher Thomas, Christian Warren, Bradley W Richmond, Katherine Gibson-Corley, Ginger L Milne, Dawn C Newcomb, R Stokes Peebles.
      Pulmonary type 2 innate lymphoid cells (ILC2s) exhibit immune memory, termed "trained immunity," which enhances their activation following exposure to an independent protease-containing allergen. The role of prostaglandin I2 (PGI2), a cyclooxygenase (COX) pathway metabolite, in modulating these trained ILC2 responses remains unclear. PGI2 acts through its G protein-coupled receptor IP. We hypothesized that IP signaling inhibits ILC2 training. To test this hypothesis, we used a mouse ILC2 training model in which we challenged wild-type (WT) and IP knockout (KO) mice with Alternaria alternata extract (Alt) to induce ILC2 activation and training. After a 33-d resting period, ILC2 responses subsided to a homeostatic level. Mice were then intranasally challenged with papain to evaluate responses to an unrelated allergen. IP KO mice displayed significantly heightened ILC2 interleukin (IL)-13 expression and with concomitant increased eosinophilia in the lungs post-papain challenge compared with WT control mice. Notably, neither WT nor IP KO mice challenged with papain only, devoid of ILC2 training, exhibited lung type 2 responses. The augmented type 2 inflammation observed in IP KO mice following both Alt and papain challenges correlated with increased numbers and percentages of IL-13-producing ILC2s and greater mean fluorescence intensity of IL-13 compared with WT mice. Furthermore, RNA sequencing of sorted ILC2s from WT and IP KO mice following Alt-papain challenges revealed heightened activation of immune response pathways and mitochondrial respiratory pathways in IP-deficient ILC2s. These findings reveal an inhibitory role of PGI2 signaling in trained ILC2 responses, emphasizing its pivotal contribution to innate immune responses and allergic inflammation.
    Keywords:  ILC2; inflammation; lung; mouse
    DOI:  https://doi.org/10.1093/jimmun/vkaf088
  4. PLoS One. 2025 ;20(5): e0322946
    Itaconate potentiates hepatic gluconeogenesis through NRF2 induction.
    Marwa O El-Derany, Sadeesh K Ramakrishnan, Yingjie Li, Kathryn Buscher, Christina A Jarad, Megan L Schaller, Marc Cantwell, Thomas M Vigil, Ryan A Frieler, Peter Sajjakulnukit, Costas A Lyssiotis, Richard M Mortensen, Yatrik M Shah.
      The interplay between systemic metabolism and immune responses is increasingly recognized as a significant factor in the dysregulation of glucose homeostasis associated with diabetes and obesity. Immune metabolites play crucial roles in mediating this crosstalk, with itaconate emerging as an important immune metabolite involved in the inflammatory response of macrophages. Recent studies have highlighted the role of itaconate as a regulator of glucose metabolism, particularly in the context of obesity, although the underlying mechanisms remain poorly understood. In this study, we identified itaconate as one of the metabolites that significantly increase in the liver during fasting compared to fed conditions. Mechanistically, we found that itaconate enhances glucagon-induced liver gluconeogenesis independently of insulin signaling. Notably, itaconate upregulates the expression of gluconeogenic genes both under basal conditions and in the presence of palmitic acid. Furthermore, our data indicate that the effects of itaconate occur independently of CREB activation. Instead, we demonstrate that these potentiating effects are mediated through the induction of nuclear factor erythroid 2-related factor 2 (NRF2). Our findings demonstrate that itaconate has a glucagon-potentiating effects in the liver, suggesting that itaconate may play a significant role in the pathogenesis of metabolic-associated liver diseases.
    DOI:  https://doi.org/10.1371/journal.pone.0322946
  5. STAR Protoc. 2025 May 07. pii: S2666-1667(25)00217-5. [Epub ahead of print]6(2): 103811
    Protocol for the imputation of stimulus-induced single-cell gene expression trajectories from time-series scRNA-seq data.
    Katherine M Sheu, Alexander Hoffmann.
      Single-cell RNA sequencing (scRNA-seq) measures cell-to-cell heterogeneous mRNA abundance but destroys the cell and precludes tracking of heterogeneous gene expression trajectories. Here, we present an approach to impute single-cell gene expression trajectories (scGETs) from time-series scRNA-seq measurements. We describe four main computational steps: dimensionality reduction, calculation of transition probability matrices, spline interpolation, and deconvolution to scGETs. Imputing scGETs can aid in studying heterogeneous stimulus responses over time, such as cancer cell responses to drugs or immune cell responses to pathogens. For complete details on the use and execution of this protocol, please refer to Sheu et al.1.
    Keywords:  RNA-seq; bioinformatics; gene expression; molecular biology
    DOI:  https://doi.org/10.1016/j.xpro.2025.103811
  6. FASEB J. 2025 May 15. 39(9): e70601
    Chronic Lipopolysaccharide Exposure Causes AD-Like Pathology in Male Mice With Intact Blood-Brain Barrier.
    Fady Eid, Mohammad Boushehri, Chloé Boucher, Nischwethaa Rajkanth, Ana Flor Sa, Thamir Alhoutan, Konstantina Vavetsi, Serge Dibart, Yun Ma.
      Chronic inflammatory conditions like periodontitis and inflammatory bowel disease (IBD) are reported to contribute to the pathogenesis of late-onset Alzheimer's disease (AD). Gram-negative bacteria are the main bacterial species causing oral and gut mucosal infections. Lipopolysaccharide (LPS) is a major inflammation-inducing molecule in Gram-negative bacteria. LPS derived from the oral bacterium Porphyromonas gingivalis exhibits heterogeneous tetra-acylated and penta-acylated lipid A, while LPS from Escherichia coli exhibits the classical hexa-acylated lipid A. Whether P. gingivalis-LPS and E. coli-LPS play a similar role in the progression of late-onset AD is unknown. Using adult, wild-type C57BL/6J mice to mimic the adult population without genetically determined predisposition to AD, we showed that chronic inflammation induced by a 28-day, subcutaneous infusion of P. gingivalis-LPS or E. coli-LPS can lead to neuroinflammation and AD-like cognitive decline and pathology in male mice. At this relatively early stage (4 weeks) of chronic inflammation when the blood-brain barrier is intact, both P. gingivalis-LPS and E. coli-LPS cause neuroinflammation through Toll-like receptor 4 (TLR4) and Toll-like receptor 2 (TLR2) expressed at microglia in the brain. Notably, only E. coli-LPS induces significant inflammatory responses systemically. In short, our results suggest that chronic P. gingivalis-LPS release (occurring in chronic periodontitis) or E. coli-LPS release (occurring in IBD) could harm the brain before the blood-brain barrier is disrupted; continuous local P. gingivalis-LPS release might do harm to the brain before exhibiting adverse effects systemically.
    Keywords:   Escherichia coli ; Porphyromonas gingivalis ; Alzheimer's disease; inflammation; lipopolysaccharide
    DOI:  https://doi.org/10.1096/fj.202403117RR
  7. Cell Rep. 2025 May 06. pii: S2211-1247(25)00429-2. [Epub ahead of print]44(5): 115658
    Bactericidal activity of mammalian histones is caused by large membrane pore formation.
    Leora Duong, Yonghan Wu, Summer J Kasallis, Serena Abbondante, Paul J Hurst, Michaela E Marshall, Katherine McCarthy, Babu J N Reddy, Jean-Louis Bru, Kumar Perinbam, Eric Pearlman, Joseph P Patterson, Steven P Gross, Albert Siryaporn.
      Histones have an important role in eukaryotic innate immunity, wherein histones co-localize with antimicrobial peptides (AMPs). The mechanism of histone cooperation with AMPs and the extent to which histones form pores both remain a mystery. Here, we show that histones form large pores in bacterial membranes that lack lipopolysaccharide (LPS) and that their antimicrobial effect is significantly stronger than that of the clinical AMP polymyxin B. We find that histones and AMPs together produce potent antimicrobial synergy through the formation of 26 nm pores, whereby the pore-forming activity of AMPs on LPS-containing membranes enables histones to enter the periplasmic space and subsequently attack unprotected membranes to create pores. We provide a mechanistic explanation for the long-standing observations of histone antimicrobial activity and demonstrate how antimicrobial synergy arises. The ubiquity of histones and AMPs in innate immunity has significant implications for organismal defense and can be leveraged for novel antibiotic strategies.
    Keywords:  CP: Microbiology; antibiotics; antimicrobial peptides; antimicrobial synergy; bacterial membrane pores; colistin; histones; innate immunity; lipopolysaccharide; polymyxin; pore formation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115658
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