bims-traimu Biomed News
on Trained immunity
Issue of 2025–06–22
eleven papers selected by
Yantong Wan, Southern Medical University
  1. Trained immunity: A new player in cancer immunotherapy.
  2. The Role of Pattern Recognition Receptors in Epigenetic and Metabolic Reprogramming: Insights into Trained Immunity.
  3. Trained Innate Immunity in Extracorporeal Photopheresis.
  4. Experimental evolution of a pathogen confronted with innate immune memory increases variation in virulence.
  5. Inactivated Rothia nasimurium promotes a persistent antiviral immune status in porcine alveolar macrophages.
  6. Enhanced resistance to Listeria infection in mice surviving sepsis: the role of lipid metabolism and myeloid cell reprogramming.
  7. Piezo1 senses hyphae and initiates host defense against pathogenic fungi.
  8. Itaconate promotes inflammatory responses in tissue-resident alveolar macrophages and exacerbates acute lung injury.
  9. Epigenetic Preparation of Future Gene Induction Kinetics.
  10. The RNA-binding E3 ligase MKRN2 selectively disrupts Il6 translation to restrain inflammation.
  11. TNF switches homeostatic efferocytosis to lytic caspase-8-dependent pyroptosis and IL-1β maturation.
  1. Elife. 2025 Jun 18. pii: e104920. [Epub ahead of print]14
    Trained immunity: A new player in cancer immunotherapy.
    Shu Li, Yi Zou, Austin McMasters, Fuxiang Chen, Jun Yan.
      In the past, immune memory was considered an exclusive feature of the adaptive immune system. However, accumulating evidence suggests that the innate immune system, the most primitive and fundamental component of immunity, can mount more robust responses to non-specific stimuli following prior exposure to different types of initial stimuli, a phenomenon known as trained immunity. Trained immunity has been extensively studied in diverse disease contexts, including infectious diseases, autoimmune disorders, and chronic inflammatory conditions. Notably, significant advancements have been made in recent years in understanding the roles and therapeutic potential of trained immunity in oncology. This review aims to explore the multifaceted roles of trained immunity across different cancer types, providing a comprehensive summary of the pertinent stimuli and associated molecular mechanisms. Additionally, we evaluate the clinical applications of various trained immunity stimuli in cancer therapy and offer perspectives on future directions for integrating trained immunity into cancer treatment strategies.
    Keywords:  cancer immunotherapy; immunology; inflammation; innate immune cells; trained immunity
    DOI:  https://doi.org/10.7554/eLife.104920
  2. J Inflamm Res. 2025 ;18 7795-7811
    The Role of Pattern Recognition Receptors in Epigenetic and Metabolic Reprogramming: Insights into Trained Immunity.
    Yanjie Li, Mingzhu Chen, Junxiong Li, Jiangtian Hu.
      Pattern recognition receptors (PRRs) function as pivotal components of the innate immune system by orchestrating trained immunity through dynamic epigenetic and metabolic reprogramming. Recent discoveries demonstrate that PRRs not only detect pathogens but also actively regulate immune cell metabolism and transcriptional landscapes, thereby potentiating the speed and magnitude of defensive responses upon secondary challenges. These functional adaptations are coordinated through evolutionarily conserved signaling cascades that establish persistent immunological modifications at cellular and systemic levels. Nevertheless, despite substantial advances in characterizing PRR-driven immune activation, the molecular mechanisms governing their role in innate immune memory formation remain incompletely elucidated. This review systematically explores emerging paradigms of PRR-mediated epigenetic remodeling and metabolic rewiring, with particular emphasis on their mechanistic integration into trained immunity. We critically assess current evidence, identify unresolved questions regarding signal transduction specificity and memory maintenance, and propose novel methodological approaches to decipher the multilayered regulatory networks of innate immune adaptation. By elucidating these processes, our analysis establishes a conceptual framework for developing immunomodulatory therapies and leveraging trained immunity in precision medicine applications.
    Keywords:  epigenetic; immunocyte; metabolic reprogramming; pattern recognition receptors; trained immunity
    DOI:  https://doi.org/10.2147/JIR.S513325
  3. Ther Apher Dial. 2025 Jun 17.
    Trained Innate Immunity in Extracorporeal Photopheresis.
    Yandy Marx Castillo-Aleman.
      
    DOI:  https://doi.org/10.1111/1744-9987.70057
  4. PLoS Pathog. 2025 Jun;21(6): e1012839
    Experimental evolution of a pathogen confronted with innate immune memory increases variation in virulence.
    Ana Korša, Moritz Baur, Nora K E Schulz, Jaime M Anaya-Rojas, Alexander Mellmann, Joachim Kurtz.
      Understanding the drivers and mechanisms of virulence evolution is still a major goal of evolutionary biologists and epidemiologists. Theory predicts that the way virulence evolves depends on the balance between the benefits and costs it provides to pathogen fitness. Additionally, host responses to infections, such as resistance or tolerance, play a critical role in shaping virulence evolution. But, while the evolution of pathogens has been traditionally studied under the selection pressure of host adaptive immunity, less is known about their evolution when confronted to simpler and less effective forms of immunity such as immune priming. In this study, we used a well-established insect model for immune priming - red flour beetles and their bacterial pathogen Bacillus thuringiensis tenebrionis - to test how this form of innate immune memory drives the pathogen evolution. Through controlled experimental evolution of the pathogen in primed versus non-primed hosts, we found no change in average virulence after eight selection cycles in primed host. Nonetheless, we observed a notable rise in the variability of virulence, defined as the ability to kill hosts, among independent pathogen lines that evolved in primed hosts, and the bacteria were unable to develop resistance to host priming. Whole genome sequencing revealed increased activity in the bacterial mobilome (prophages and plasmids). Expression of the Cry toxin - a well-known virulence factor - was linked to evolved differences in copy number variation of the cry-carrying plasmid, though this did not correlate directly with virulence. These findings highlight that innate immune memory can drive variability in pathogen traits, which may favor adaptation to variable environments. This underscores the need to consider pathogen evolution in response to innate immune memory when applying these mechanisms in medicine, aquaculture, pest control, and insect mass production.
    DOI:  https://doi.org/10.1371/journal.ppat.1012839
  5. Front Immunol. 2025 ;16 1584092
    Inactivated Rothia nasimurium promotes a persistent antiviral immune status in porcine alveolar macrophages.
    Aida Tort-Miró, Uxía Alonso, Beatriz Martín-Mur, Jordana Muñoz-Basagoiti, Yan Zeng, David Marín-Moraleda, Enrique Ezcurra, Sergio Montaner-Tarbes, María J Navas, Marta Muñoz, Paula Monleón, Judith González-Oliver, Esmeralda Cano, Carles Vilalta, Marc Caballé, Lourdes Criado, Karl Kochanowski, Francesc Accensi, Virginia Aragón, Florencia Correa-Fiz, Anna Esteve-Codina, Fernando Rodríguez, Jordi Argilaguet.
      Globalization has increased the incidence of infectious diseases in livestock, further aggravated by the reduction of antibiotic usage. To minimize the resulting economic consequences to the meat production industry, as well as the risk of zoonotic events, the use of immunostimulants has emerged as a potential strategy to enhance animal resilience to diseases. In particular, the capability of bacterial-based immunostimulants to modulate innate immune cells functionality makes them cost-effective candidates as vaccine adjuvants, antimicrobials, or preventive immunostimulators inducing long-term innate immune memory in livestock. However, further research is required to identify novel bacterial strains with immunostimulatory properties. Here we characterized in vitro the immunostimulatory properties of Rothia nasimurium isolated from warthog fecal microbiota. Stimulation with heat-inactivated Rothia induced cytokine production by porcine immune cells, and a robust innate immune transcriptomic signature in porcine alveolar macrophages. Interestingly, the bacteria induced inflammasome activation and IL-1β production, thus confirming its pro-inflammatory properties, and suggesting its potential as vaccine adjuvant. Importantly, this immunostimulatory status functionally resulted in an antimicrobial state, enhancing the phagocytic capability of alveolar macrophages, and hampering the replication levels of two major porcine viral pathogens: the porcine reproductive and respiratory syndrome virus (PRRSV) and the African swine fever virus (ASFV). Moreover, macrophages showed an enhanced cytokine response upon ASFV infection several days after heat-inactivated Rothia stimulation, suggesting the induction of an innate immune memory phenotype. This nonspecific response resulted in a significant reduction of ASFV replication kinetics, demonstrating the capacity of the bacteria to induce a more resistant state in macrophages against a virus infection. Altogether, these results demonstrate the immunostimulatory capability of heat-inactivated R. nasimurium in porcine macrophages, showing potential to enhance animal resilience to diseases through the modulation of innate immune cells responsiveness to infections.
    Keywords:  Rothia nasimurium; adjuvants; antivirals; immunostimulant; innate immune memory; porcine alveolar macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1584092
  6. Front Pharmacol. 2025 ;16 1588987
    Enhanced resistance to Listeria infection in mice surviving sepsis: the role of lipid metabolism and myeloid cell reprogramming.
    Haruki Watanabe, Tengfei Song, Jaewoo Choi, Moses Lee, Kwangmin Choi, Junhwan Kim, Barbara Sherry, Betty Diamond, Yong-Rui Zou, Myoungsun Son.
       Introduction: Immune resilience is the capacity of the immune system to recover from sepsis-induced organ injury and reestablish host defense. While sepsis survivors are often viewed as immunocompromised, recent studies suggest that some may acquire adaptive immune traits that enhance resistance to secondary infections.
    Methods: We employed a murine cecal ligation and puncture (CLP) model to study polymicrobial sepsis and subsequent immune responses. Listeria monocytogenes was used as a model intracellular pathogen to assess immune protection. We analyzed myeloid cell phenotypes using single-cell RNA sequencing and evaluated lipid metabolic changes through quantitative RT-PCR, immunohistochemistry, serum cytokine assays, and plasma lipidomics.
    Results: Sepsis-surviving mice showed enhanced resistance to Listeria infection. Single-cell RNA sequencing revealed transcriptional reprogramming in splenic CD11b+Ly6Chigh myeloid cells, including downregulation of lipoprotein lipase and lipid efflux genes. CD11b+ myeloid cells exhibited increased lipid droplet accumulation, accompanied by elevated serum interferon-gamma (IFN-γ) levels. Plasma lipidomics identified systemic lipid remodeling, with increased phosphatidylserine and decreased phosphatidylinositol and phosphatidylglycerol levels.
    Discussion: Our findings suggest that sepsis survival induces lipid metabolic reprogramming in myeloid cells, contributing to enhanced immunity against intracellular pathogens. These insights reveal potential therapeutic targets within lipid metabolic pathways to improve host defense in sepsis survivors.
    Keywords:  Listeria monocytogenes; lipid droplets; lipid metabolism; lipidomics; myeloid cells; sepsis; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fphar.2025.1588987
  7. Cell Rep. 2025 Jun 16. pii: S2211-1247(25)00610-2. [Epub ahead of print]44(6): 115839
    Piezo1 senses hyphae and initiates host defense against pathogenic fungi.
    Yiran Shi, Bingying Yang, Yueyue Linghu, Yue Liu, Haoran Li, Yunzhi Xing, Binbin Wu, Yuting Gao, Liuqi Liao, Yi Zheng, Lei Pan, Xiufeng Sun, Qinghua Chen, Yongqiang Hou, Dongxue Su, Hongling Huang, Jiahuai Han, Shih-Chin Cheng, Dawang Zhou, Lanfen Chen.
      Candida albicans metamorphoses from benign yeast to a rigid hyphal, becoming an opportunistic pathogen in immunocompromised patients. The process by which immune cells discern fungal transformations remains elusive. Here, we report that the mechanosensitive ion channel Piezo1 is indispensable for recognizing fungal hyphae and triggering antifungal innate immune responses. Hyphae-triggered Piezo1 activation increased C-type lectin receptor (CLR) expression in innate immune cells by inducing the expression of CCAAT/enhancer-binding protein beta (C/EBPβ) via the Piezo1/Ca2+/calmodulin-dependent kinase (CaMK)/cAMP response element-binding protein (CREB) axis. In addition, Piezo1/CaMK signaling activated kinases nuclear Dbf2-related protein 1/2 (NDR1/2), which augmented NLRP3 inflammasome assembly and promoted hyphae-induced inflammation. Abolishing the yeast-to-hyphae transition dampens CLR expression and NLRP3 activation. Piezo1-deficient mice exhibit compromised clearance of C. albicans infection, whereas Piezo1 agonist amplifies C. albicans clearance. In addition, CaMK, CREB, or NDR1/2 inhibition exacerbates hyphae infections, such as Piezo1 deficiency. Therefore, we ascertain Piezo1-mediated mechanotransduction as vital for immune surveillance and control of hyphal C. albicans, heralding Piezo1 agonist as a potential remedy for fungal infections.
    Keywords:  C-type lectin receptors; C. albicans; CP: Immunology; CP: Microbiology; NLRP3 inflammasome; Piezo1; fungal infection; mechanical force
    DOI:  https://doi.org/10.1016/j.celrep.2025.115839
  8. Cell Metab. 2025 Jun 14. pii: S1550-4131(25)00268-2. [Epub ahead of print]
    Itaconate promotes inflammatory responses in tissue-resident alveolar macrophages and exacerbates acute lung injury.
    Mengtian Shan, Song Zhang, Zhibing Luo, Shengjie Deng, Linyu Ran, Quan Zhou, Huimin Wan, Jihui Ye, Chenchen Qian, Ximin Fan, Yun Feng, David W Morse, Joerg Herrmann, Qiang Li, Zhongliang Guo, Feilong Wang.
      Itaconate is an anti-inflammatory metabolite with therapeutic potential in multiple inflammatory diseases. However, its immunomodulatory function has been mainly based on ex vivo-generated macrophages or cell lines, whereas its role in tissue-resident macrophages is still poorly understood. Here, we report that, in contrast to its effects on bone-marrow-derived macrophages (BMDMs), itaconate promotes the production of proinflammatory cytokines and augments the activation of the NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome in resident alveolar macrophages (AMs). Unlike native itaconate, the itaconate derivatives dimethyl itaconate (DI) and 4-octyl itaconate (4OI) suppress the inflammatory response in AMs. Notably, the intratracheal transfer of BMDMs reversed their responsiveness to itaconate, indicating an essential role of the alveolar microenvironment in shaping macrophage immunometabolism. We also demonstrate that itaconate promotes AM-mediated inflammatory responses in vivo and aggravates lung injury. Taken together, our study unexpectedly demonstrates a proinflammatory role of itaconate in tissue-resident AMs, suggesting that further investigations are needed before its clinical application.
    Keywords:  inflammatory responses; itaconate; macrophages; succinate dehydrogenase; the NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.012
  9. Annu Rev Genet. 2025 Jun 16.
    Epigenetic Preparation of Future Gene Induction Kinetics.
    Jun Xiong, Bing Zhu.
      Epigenetic mechanisms are essential for gene expression regulation. Recent advances have revealed how cells not only stabilize transcriptional states but also actively prepare for future gene expression. This review explores four processes in epigenetic preparation for future gene induction: priming, reining, transcriptional memory, and transcriptional tolerance. Priming establishes chromatin configurations that facilitate future gene activation without immediate transcription. Conversely, reining balances responsiveness with transcriptional stability to prevent premature gene activation or overexpression. Transcriptional memory facilitates faster and stronger responses to recurrent stimuli by reflecting past activation events, whereas transcriptional tolerance imposes restraint on subsequent activation. We examine how these mechanisms, involving DNA methylation, histone modification, and chromatin remodeling, integrate with signaling pathways and transcription factors to orchestrate future gene induction. Leveraging recent insights from mammalian systems, this review highlights the emerging role of epigenetic preparation in adaptive cellular responses, with implications for development, disease, and cellular memory in mammals.
    DOI:  https://doi.org/10.1146/annurev-genet-012825-093148
  10. Nat Immunol. 2025 Jun 16.
    The RNA-binding E3 ligase MKRN2 selectively disrupts Il6 translation to restrain inflammation.
    Zhou Yu, Xuelian Li, Jiaying Huang, Jueyu Pan, Jiale Cheng, Ping Liu, Mingjin Yang, Taoyong Chen, Qian Zhang, Yumei Zhou, Jiacheng Wu, Taotao Han, Jingnan Li, Yue Xu, Mingyue Wen, Xuan Zhang, Chunmei Wang, Xuetao Cao.
      E3 ligases and RNA-binding protein-mediated dysregulation of proinflammatory cytokines leads to autoimmune and inflammatory diseases. However, whether RNA-binding E3 ligases can regulate specific proinflammatory cytokine expression remains unclear. Here we found that the RNA-binding E3 ligase MKRN2 selectively inhibits the expression of interleukin-6 (IL-6) in lipopolysaccharide-activated macrophages. LysM-Cre+Mkrn2fl/fl mice showed increased amounts of IL-6 in the serum after lipopolysaccharide treatment and exhibited increased severity of experimental colitis, which was associated with increased IL-6. Expression of MKRN2 negatively correlated with expression of IL-6 in clinical samples from individuals with ulcerative colitis and rheumatoid arthritis. Mechanistically, after binding to Il6 messenger RNA, MKRN2 linked K29 polyubiquitin chains to the Lys 179 residue of PAIP1, a translation initiation coactivator, which blocked PAIP1-eIF4A interaction and thus inhibited the translational efficiency of Il6 mRNA. Our findings provide mechanistic insight and potential therapeutic strategies for inflammatory autoimmune diseases by disrupting translation of specific proinflammatory cytokines.
    DOI:  https://doi.org/10.1038/s41590-025-02183-x
  11. Sci Immunol. 2025 Jun 20. 10(108): eadq0043
    TNF switches homeostatic efferocytosis to lytic caspase-8-dependent pyroptosis and IL-1β maturation.
    Hayley I Muendlein, Wilson M Connolly, Jamie Leiriao, Mei-An Nolan, Jennifer Judge, Irina Smirnova, Rebecca Batorsky, Alexander Poltorak.
      Efferocytosis, wherein phagocytes engulf dead or dying cells, is a critical function of macrophages that supports cellular turnover, tissue repair, and resolution of inflammation. Despite its well-established anti-inflammatory mechanism in homeostasis, whether efferocytosis remains immunologically silent in the context of dysregulated immune responses such as sepsis or systemic inflammatory response syndrome (SIRS) has not been investigated. Here, we used mouse models of tumor necrosis factor (TNF)-induced SIRS and Escherichia coli-induced septic peritonitis to uncover a potential negative consequence of efferocytosis. We found that when activated with TNF, phagocytes efferocytosing neutrophils initiated a caspase-8-dependent, but NLRP3 inflammasome-independent, form of pyroptosis, which we termed "efferoptosis." The maturation of IL-1β, a hallmark of pyroptotic cell death, also occurred independently of canonical inflammasome activation, supporting direct cleavage by caspase-8. Inhibition of efferocytosis protected mice against TNF-induced SIRS, suggesting that efferoptosis contributes to the pathology of sepsis and other TNF-mediated inflammatory conditions.
    DOI:  https://doi.org/10.1126/sciimmunol.adq0043
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