bims-traimu 2025-04-06 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–04–06
seven papers selected by
Yantong Wan, Southern Medical University

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.
Pathogen-derived peptidoglycan skeleton enhances innate immune defense against Staphylococcus aureus via mTOR-HIF-1α-HK2-mediated trained immunity.
M28 family peptidase derived from Peribacillus frigoritolerans initiates trained immunity to prevent MRSA via the complosome-phosphatidylcholine axis.
Eosinophil innate immune memory after bacterial skin infection promotes allergic lung inflammation.
BCG-trained macrophages couple LDLR upregulation to type I IFN responses and antiviral immunity.
Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.
A Self-Assembled Metabolic Regulator Reprograms Macrophages to Combat Cytokine Storm and Boost Sepsis Immunotherapy.

bioRxiv. 2025 Mar 19. pii: 2025.03.18.644013. [Epub ahead of print]

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

Anant Jaiswal, Laszlo Halasz, David L Williams, Timothy Osborne.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

DOI: https://doi.org/10.1101/2025.03.18.644013
Microbiol Res. 2025 Mar 29. pii: S0944-5013(25)00116-8. [Epub ahead of print]296 128160

Pathogen-derived peptidoglycan skeleton enhances innate immune defense against Staphylococcus aureus via mTOR-HIF-1α-HK2-mediated trained immunity.

Zheng Jia, Lingdi Niu, Junjie Guo, Jiaqing Wang, Hai Li, Runhang Liu, Ning Liu, Shuhe Zhang, Fang Wang, Junwei Ge.

  Regulation of the innate immune response may be an effective strategy to enhance Staphylococcus aureus vaccines. Based on our previous findings that the Listeria peptidoglycan skeleton (pBLP) enhances the immune response through an unknown mechanism, we hypothesized that pBLP provides protection by modulating the innate immune response via trained immunity. In vitro, pBLP increased phagocytosis and inflammatory cytokine levels and elevated the anti-inflammatory cytokine TGF-β following secondary stimulation. In an in vivo model, our findings indicate that pBLP, when administered with a vaccine, protects mice from methicillin-resistant S. aureus challenge and also provides protection against S. aureus CMCC26003 in the absence of antigens. Using an ex vivo model, we demonstrated that pBLP increases markers of trained immunity in peritoneal macrophages. Transcriptome analysis of differentially expressed genes and inhibitor experiments revealed that the trained immunity process induced by pBLP depends on mTOR-HIF-1α and hexokinase 2. This study is the first to demonstrate that pBLP can induce trained immunity. Furthermore, we show that the peptidoglycan skeleton induces a distinct trained immunity phenotype compared to β-glucan, enhancing vaccine protection. Our study provides valuable insights for the design of novel vaccines that integrate both specific and innate immune responses.

Keywords:  Innate immunity; Metabolic reprogramming; Methicillin-resistance; Peptidoglycan skeleton; Staphylococcus aureus; Trained immunity

DOI:  https://doi.org/10.1016/j.micres.2025.128160
Gut Microbes. 2025 Dec;17(1): 2484386

M28 family peptidase derived from Peribacillus frigoritolerans initiates trained immunity to prevent MRSA via the complosome-phosphatidylcholine axis.

Cheng-Kai Zhou, Zhen-Zhen Liu, Zi-Ran Peng, Xue-Yue Luo, Xiao-Mei Zhang, Jian-Gang Zhang, Liang Zhang, Wei Chen, Yong-Jun Yang.

  Methicillin-resistant Staphylococcus aureus (MRSA) represents a major global health threat due to its resistance to conventional antibiotics. The commensal microbiota maintains a symbiotic relationship with the host, playing essential roles in metabolism, energy regulation, immune modulation, and pathogen control. Mammals harbor a wide range of commensal bacteria capable of producing unique metabolites with potential therapeutic properties. This study demonstrated that M28 family peptidase (M28), derived from commensal bacteria Peribacillus frigoritolerans (P. f), provided protective effects against MRSA-induced pneumonia. M28 enhanced the phagocytosis and bactericidal activity of macrophages by inducing trained immunity. RNA sequencing and metabolomic analyses identified the CFB-C3a-C3aR-HIF-1α axis-mediated phosphatidylcholine accumulation as the key mechanism for M28-induced trained immunity. Phosphatidylcholine, like M28, also induced trained immunity. To enhance M28-mediated therapeutic potential, it was encapsulated in liposomes (M28-LNPs), which exhibited superior immune-stimulating properties compared to M28 alone. In vivo experiments revealed that M28-LNPs significantly reduced bacterial loads and lung damage following MRSA infection, which also provided enhanced protection against Klebsiella pneumoniae and Candida albicans. We first confirmed a link between complement activation and trained immunity, offering valuable insights into the treatment and prevention of complement-related autoimmune diseases.

Keywords:  M28 family peptidase; MRSA; Peribacillus frigoritolerans; complosome; phosphatidylcholine; trained immunity

DOI:  https://doi.org/10.1080/19490976.2025.2484386
Sci Immunol. 2025 Apr 04. 10(106): eadp6231

Eosinophil innate immune memory after bacterial skin infection promotes allergic lung inflammation.

Mariem Radhouani, Asma Farhat, Anna Hakobyan, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anastasiya Hladik, Karin Lakovits, Jessica Brösamlen, Vojtech Dvorak, Natalia Nunes, Andreas Zech, Marco Idzko, Thomas Krausgruber, Jörg Köhl, Ozge Uluckan, Jiri Kovarik, Kai Hoehlig, Axel Vater, Margret Eckhard, Andy Sombke, Nikolaus Fortelny, Jörg Menche, Sylvia Knapp, Philipp Starkl.

Microbial exposure at barrier interfaces drives development and balance of the immune system, but the consequences of local infections for systemic immunity and secondary inflammation are unclear. Here, we show that skin exposure to the bacterium Staphylococcus aureus persistently shapes the immune system of mice with specific impact on progenitor and mature bone marrow neutrophil and eosinophil populations. The infection-imposed changes in eosinophils were long-lasting and associated with functional as well as imprinted epigenetic and metabolic changes. Bacterial exposure enhanced cutaneous allergic sensitization and resulted in exacerbated allergen-induced lung inflammation. Functional bone marrow eosinophil reprogramming and pulmonary allergen responses were driven by the alarmin interleukin-33 and the complement cleavage fragment C5a. Our study highlights the systemic impact of skin inflammation and reveals mechanisms of eosinophil innate immune memory and organ cross-talk that modulate systemic responses to allergens.

DOI: https://doi.org/10.1126/sciimmunol.adp6231
Cell Rep. 2025 Apr 01. pii: S2211-1247(25)00264-5. [Epub ahead of print]44(4): 115493

BCG-trained macrophages couple LDLR upregulation to type I IFN responses and antiviral immunity.

Yangdian Lai, Xiaoxu Yang, Dong Wei, Xin Wang, Ruiming Sun, Yunfei Li, Ping Ji, Yujie Bao, Tiancheng Chu, Chenxing Zhang, Qiming Liang, Jie Xu, Xinxin Zhang, Yingying Chen, Ying Wang.

  Trained immunity refers to memory-like responses of innate immune cells when they re-encounter pathogenic stimuli. Bacillus Calmette-Guérin (BCG) vaccination implies enhanced antiviral immunity, whereas the underlying mechanisms remain unclear. Herein, we have uncovered elevated expression of low-density lipoprotein receptor (LDLR) on BCG-trained macrophages with robust type I interferon (IFNI) production and antiviral effects both in vivo and in vitro. Consequently, cholesterol is accumulated in BCG-trained macrophages, leading to the augmentation of NFE2L1 expression and the formation of NFE2L1/IRAK1/TRIM25 complex where TRIM25 mediates IRAK1 K63 polyubiquitination to exaggerate IFNI responses in an RIG-I-dependent manner. We have also observed LDLR+ macrophages displaying heightened IFNI responses in BCG-treated human macrophages. To antagonize LDLR degradation by PCSK9 inhibitors increases IFNI responses in the macrophages and accelerated viral clearance. Our study thus couples LDLR upregulation to antiviral activity in BCG-trained macrophages, making commercial PCSK9 inhibitors potential antiviral indications in clinic.

Keywords:  BCG; CP: Immunology; IRAK1; LDLR; NFE2L1; PCSK9 inhibitor; RIG-I; antiviral infection; cholesterol; trained immunity; type I interferon pathway

DOI:  https://doi.org/10.1016/j.celrep.2025.115493
Cell Metab. 2025 Mar 24. pii: S1550-4131(25)00107-X. [Epub ahead of print]

Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.

Eva M Pålsson-McDermott, Luke A J O'Neill.

  The reprogramming of metabolic pathways and processes in immune cells has emerged as an important aspect of the immune response. Metabolic intermediates accumulate as a result of metabolic adaptations and mediate functions outside of metabolism in the regulation of immunity and inflammation. In macrophages, there has been a major focus on 3 metabolites linked to the Krebs cycle, itaconate, succinate, and fumarate, which have been shown to regulate multiple processes. Here, we discuss recent progress on these 3 metabolites with regard to their effect on macrophages in host defense and inflammatory diseases. We also consider the therapeutic opportunities presented from the mimicry of these metabolites or by targeting the enzymes that make or metabolize them in order to leverage the body's own anti-inflammatory response.

Keywords:  ETC; Krebs cycle; immunometabolism; immunometabolites; inflammation; therapeutic targets

DOI:  https://doi.org/10.1016/j.cmet.2025.03.004
Research (Wash D C). 2025 ;8 0663

A Self-Assembled Metabolic Regulator Reprograms Macrophages to Combat Cytokine Storm and Boost Sepsis Immunotherapy.

Junyan Zhuang, Yongrui Hai, Xintong Lu, Borui Sun, Renming Fan, Bingjie Zhang, Wenhui Wang, Bingxue Han, Li Luo, Le Yang, Chun Zhang, Minggao Zhao, Gaofei Wei.

Sepsis, a life-threatening inflammatory disorder characterized by multiorgan failure, arises from a dysregulated immune response to infection. Modulating macrophage polarization has emerged as a promising strategy to control sepsis-associated inflammation. The endogenous metabolite itaconate has shown anti-inflammatory potential by suppressing the stimulator of interferon genes (STING) pathway, but its efficacy is inhibited by hyperactive glycolysis, which sustains macrophage overactivation. Here, we revealed a critical crosstalk between the itaconate-STING axis and glycolysis in macrophage-mediated inflammation. Building on this interplay, we developed a novel nanoparticle LDO (lonidamine disulfide 4-octyl-itaconate), a self-assembled metabolic regulator integrating an itaconate derivative with the glycolysis inhibitor Lonidamine. By concurrently targeting glycolysis and STING pathways, LDO reprograms macrophages to restore balanced polarization. In sepsis models, LDO effectively attenuates CCL2-driven cytokine storms, alleviates acute lung injury, and significantly enhances survival via metabolic reprogramming. This study offers a cytokine-regulatory strategy rooted in immunometabolism, providing a foundation for the translational development of immune metabolite-based sepsis therapies.

DOI: https://doi.org/10.34133/research.0663