bims-traimu 2025-01-26 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–01–26
nine papers selected by
Yantong Wan, Southern Medical University

Extracellular HSP70 facilitated β-glucan induced trained immunity in macrophages to suppress sepsis via TLR2-NF-κB axis.
Microbiota translocation following intestinal barrier disruption promotes Mincle-mediated training of myeloid progenitors in the bone marrow.
Discovery of Innate Immune Response mRNAs That Are Impacted by Structure-Specific Oral Baker's Yeast Beta Glucan Consumption.
Irreversible Electroporation and β-Glucan Induced Trained Innate Immunity for the Treatment of Pancreatic Ductal Adenocarcinoma: A Phase II Study.
Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion.
Itaconate mechanism of action and dissimilation in Mycobacterium tuberculosis.
4-Octyl Itaconate Alleviates Myocardial Ischemia-Reperfusion Injury Through Promoting Angiogenesis via ERK Signaling Activation.
Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation.
Transcriptomic atlas reveals organ-specific disease tolerance in sickle cell mice.

Cytokine. 2025 Jan 16. pii: S1043-4666(25)00008-0. [Epub ahead of print]187 156861

Extracellular HSP70 facilitated β-glucan induced trained immunity in macrophages to suppress sepsis via TLR2-NF-κB axis.

Ran Qi, Xin Cheng, Shan Chen, Jinjun Fan.

  Sepsis is a common systemic infectious disease followed by extremely high incidence and mortality with no effective treatment and clinical drugs. As a key mediator involved in infection and immunity, it has been reported that sepsis patients are accompanied by increased heat shock protein 70 (HSP70). Trained immunity is a novel innate immunity approach that can be activated by β-glucan to fight against sepsis. The mechanism of HSP70 activating trained macrophages against sepsis needs further elucidation. Trained immunity and sepsis models were established by β-glucan and LPS individually both in vivo and in vitro. We demonstrated that HSP70 was significantly upregulated in septic mice serum, and HSP70 could protect mice from sepsis by activating β-glucan-trained macrophages as an ideal secondary inducer via TLR2-NF-κB pathway. Additionally, the sepsis resistant effects of HSP70 could be blocked by its antibody. In summary, more than a molecular chaperone to maintain homeostasis, HSP70 could be an important trained immunity inducer to help the body fighting against sepsis, which provided new stimuli for trained immunity and novel therapeutic solutions for sepsis.

Keywords:  HSP70; Macrophages; Sepsis; TLR2; Trained immunity

DOI:  https://doi.org/10.1016/j.cyto.2025.156861
Immunity. 2025 Jan 16. pii: S1074-7613(24)00577-6. [Epub ahead of print]

Microbiota translocation following intestinal barrier disruption promotes Mincle-mediated training of myeloid progenitors in the bone marrow.

Iñaki Robles-Vera, Aitor Jarit-Cabanillas, Paola Brandi, María Martínez-López, Sarai Martínez-Cano, Manuel Rodrigo-Tapias, Marcos Femenía-Muiña, Ana Redondo-Urzainqui, Vanesa Nuñez, Cristina González-Correa, Javier Moleón, Juan Duarte, Laura Conejero, Pablo Mata-Martínez, Carmen María Díez-Rivero, Marta Bergón-Gutiérrez, Iván Fernández-López, Manuel J Gómez, Ana Quintas, Ana Dopazo, Fátima Sánchez-Cabo, Esther Pariente, Carlos Del Fresno, José Luis Subiza, Salvador Iborra, David Sancho.

  Impairment of the intestinal barrier allows the systemic translocation of commensal bacteria, inducing a proinflammatory state in the host. Here, we investigated innate immune responses following increased gut permeability upon administration of dextran sulfate sodium (DSS) in mice. We found that Enterococcus faecalis translocated to the bone marrow following DSS treatment and induced trained immunity (TI) hallmarks in bone-marrow-derived mouse macrophages and human monocytes. DSS treatment or heat-killed E. faecalis reprogrammed bone marrow progenitors (BMPs), resulting in enhanced inflammatory responses in vitro and in vivo and protection against subsequent pathogen infections. The C-type lectin receptor Mincle (Clec4e) was essential for E. faecalis-induced TI in BMPs. Clec4e-/- mice showed impaired TI upon E. faecalis administration and reduced pathology following DSS treatment. Thus, Mincle sensing of E. faecalis induces TI that may have long-term effects on pathologies associated with increased gut permeability.

Keywords:  Mincle receptor; bone marrow progenitors; gut bacterial translocation; inflammation; macrophages; trained immunity

DOI:  https://doi.org/10.1016/j.immuni.2024.12.012
BioTech (Basel). 2025 Jan 13. pii: 4. [Epub ahead of print]14(1):

Discovery of Innate Immune Response mRNAs That Are Impacted by Structure-Specific Oral Baker's Yeast Beta Glucan Consumption.

Brian K McFarlin, John H Curtis, Jakob L Vingren, David W Hill, Elizabeth A Bridgeman.

  The study of nutritional compounds with the potential to train the innate immune response has implications for human health. The objective of the current study was to discover by what means 6 weeks of oral baker's yeast beta glucan (BYBG) supplementation altered the mRNA expression of genes that reflect innate immune training in the absence of a physical stressor. Nineteen adults were randomly assigned to either a Wellmune® BYBG or Placebo for 6 weeks. BYBG uniquely altered the expression of 40 mRNAs associated with Dectin-1 and trained innate immunity, the innate immune response, the pathogen-associated (PAMP) and damage-associated molecular pattern (DAMP), and the inflammatory response. The observed changes were classified as immune training rather than immune priming due to the progressive increase in the expression of myeloid immune-associated mRNA. Combined with the findings of previous research, the findings of the present study support the claim that oral BYBG supplementation may be associated with trained innate immunity during resting homeostasis. Further, the key findings associated with BYBG may reflect improved responsiveness to future infection (exogenous) and/or sterile-inflammatory (endogenous) challenge.

Keywords:  NanoString; infection; inflammation; innate immune priming; trained innate immunity

DOI:  https://doi.org/10.3390/biotech14010004
J Am Coll Surg. 2025 Jan 22.

Irreversible Electroporation and β-Glucan Induced Trained Innate Immunity for the Treatment of Pancreatic Ductal Adenocarcinoma: A Phase II Study.

Robert Cg Martin, Yan Li, Emily A Shore, Danial A Malik, Hong Li, Xiaoling Hu, Traci Hayat, Min Tan, Kelly M McMasters, Jun Yan.

INTRODUCTION: Irreversible electroporation(IRE) has augmented the effects of certain immunotherapies in pancreatic cancer(PDA). Yeast-derived particulate beta-glucan induces trained innate immunity and has successfully reduces murine PC tumor burden. This is a Phase II study to test the hypothesis that IRE may augment beta-glucan induced trained immunity in patients with PDA.
METHODS: Phase II clinical trial (NCT03080974), surgical ablative IRE was performed on clinical stage-III PDA followed by oral beta-Glucan administration for 12-months or until disease recurrence. Peripheral blood was taken pre-op, 14-days, and every 3-months and was evaluated by mass cytometry and compared to patients who received IRE alone.
RESULTS: Thirty consecutive patients with pre-operative clinical stage-III PDA were treated with IRE and then initiated on oral beta-glucan post-operatively was compared to 20 patients treated with IRE alone. There were no dose limiting toxicities with oral beta-glucan and compliance with therapy was 96% in all patients. Seven(23%) patients developed grade 3/4 treatment related adverse events(AEs) at 90-days; none required a dose modification of oral beta-glucan. Median disease-free interval of 18 months (range 6-48), with a median overall survival of 32.5 months(range 4-53). At 12-months post IRE, immunophenotyping was demonstrated a significant effect with improvement in the IRE-Beta-Glucan treated group. This also resulted in a significant decrease on naïve CD4 and CD8 T cells with increased CD4 and CD8 terminal effector cells in the IRE-Beta glucan treated group, which correlated with a significant improvement in disease free interval (DFI) and overall survival (OS)(P=0.001).
CONCLUSIONS: Combined beta-glucan with IRE ablated PDA tumor cells elicited a potent trained response and augmented anti-tumor functionality at 12 months post IRE, which translated into an improved DFI and OS.

DOI: https://doi.org/10.1097/XCS.0000000000001291
Sci Adv. 2025 Jan 24. 11(4): eadq7307

Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion.

Alessia Zotta, Juliana Toller-Kawahisa, Eva M Palsson-McDermott, Shane M O'Carroll, Órlaith C Henry, Emily A Day, Anne F McGettrick, Ross W Ward, Dylan G Ryan, Mark A Watson, Martin D Brand, Marah C Runtsch, Kathrin Maitz, Anna Lueger, Julia Kargl, Jan L Miljkovic, Ed C Lavelle, Luke A J O'Neill.

The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.

DOI: https://doi.org/10.1126/sciadv.adq7307
Proc Natl Acad Sci U S A. 2025 Jan 28. 122(4): e2423114122

Itaconate mechanism of action and dissimilation in Mycobacterium tuberculosis.

Manisha Priya, Sonu Kumar Gupta, Anil Koundal, Srajan Kapoor, Snigdha Tiwari, Saqib Kidwai, Luiz Pedro Sorio de Carvalho, Krishan Gopal Thakur, Dinesh Mahajan, Deepak Sharma, Yashwant Kumar, Ramandeep Singh.

  Itaconate, an abundant metabolite produced by macrophages upon interferon-γ stimulation, possesses both antibacterial and immunomodulatory properties. Despite its crucial role in immunity and antimicrobial control, its mechanism of action and dissimilation are poorly understood. Here, we demonstrate that infection of mice with Mycobacterium tuberculosis increases itaconate levels in lung tissues. We also show that exposure to itaconate inhibits M. tuberculosis growth in vitro, in macrophages, and mice. We report that exposure to sodium itaconate (ITA) interferes with the central carbon metabolism of M. tuberculosis. In addition to the inhibition of isocitrate lyase (ICL), we demonstrate that itaconate inhibits aldolase and inosine monophosphate (IMP) dehydrogenase in a concentration-dependent manner. Previous studies have shown that Rv2498c from M. tuberculosis is the bona fide (S)-citramalyl-CoA lyase, but the remaining components of the pathway remain elusive. Here, we report that Rv2503c and Rv3272 possess itaconate:succinyl-CoA transferase activity, and Rv2499c and Rv3389c possess itaconyl-CoA hydratase activity. Relative to the parental and complemented strains, the ΔRv3389c strain of M. tuberculosis was attenuated for growth in itaconate-containing medium, in macrophages, mice, and guinea pigs. The attenuated phenotype of ΔRv3389c strain of M. tuberculosis is associated with a defect in the itaconate dissimilation and propionyl-CoA detoxification pathway. This study thus reveals that multiple metabolic enzymes are targeted by itaconate in M. tuberculosis. Furthermore, we have assigned the two remaining enzymes responsible for the degradation of itaconic acid into pyruvate and acetyl-CoA. Finally, we also demonstrate the importance of enzymes involved in the itaconate dissimilation pathway for M. tuberculosis pathogenesis.

Keywords:  Mycobacterium tuberculosis; dissimilation; itaconate; pathogenesis

DOI:  https://doi.org/10.1073/pnas.2423114122
Adv Sci (Weinh). 2025 Jan 21. e2411554

4-Octyl Itaconate Alleviates Myocardial Ischemia-Reperfusion Injury Through Promoting Angiogenesis via ERK Signaling Activation.

Jiqin Yang, Chenqi Duan, Peng Wang, Sijia Zhang, Yuanqing Gao, Shan Lu, Yong Ji.

  Myocardial ischemia-reperfusion (IR) injury is a critical complication following revascularization therapy for ischemic heart disease. Itaconate, a macrophage-derived metabolite, has been implicated in inflammation and metabolic regulation. This study investigates the protective role of itaconate derivatives against IR injury. Using a mice model of IR injury, the impact of 7-day 4-Octyl itaconate (4-OI) administration on cardiac function is assessed. Exogenous administration of 4-OI significantly reduces myocardial damage, enhances angiogenesis, and alleviates myocardial hypoxia injury during reperfusion. RNA sequencing and molecular docking techniques are used to find the target of itaconate, and changes in cardiac function are observed in Immune-Responsive Gene1 (IRG1) global knockout mice. In cell culture studies, 4-OI promotes endothelial cell proliferation and migration, mediated by Mitogen-Activated Protein Kinases (MAPK) signaling pathway activation, particularly through Extracellular Signal-Regulated Kinase (ERK) signaling. Inhibition of ERK blocks these beneficial effects on endothelial cells. Furthermore, itaconate synthesis inhibition worsens myocardial damage, which is mitigated by 4-OI supplementation. The results indicate that 4-OI promotes angiogenesis by activating MAPK signaling via FMS-like tyrosine kinase 1 (Flt1), highlighting its potential as a therapeutic strategy for myocardial IR injury.

Keywords:  4‐OI; IRG1; angiogenesis; myocardial ischemia‐reperfusion injury

DOI:  https://doi.org/10.1002/advs.202411554
Cell Discov. 2025 Jan 21. 11(1): 4

Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation.

Jie Ruan, Xuxia Wei, Suizhi Li, Zijian Ye, Linyi Hu, Ru Zhuang, Yange Cao, Shaozhou Wang, Shengpeng Wu, Dezhi Peng, Shangwu Chen, Shaochun Yuan, Anlong Xu.

Apoptotic protease activating factor 1 (Apaf-1) was traditionally defined as a scaffold protein in mammalian cells for assembling a caspase activation platform known as the 'apoptosome' after its binding to cytochrome c. Although Apaf-1 structurally resembles animal NOD-like receptor (NLR) and plant resistance (R) proteins, whether it is directly involved in innate immunity is still largely unknown. Here, we found that Apaf-1-like molecules from lancelets, fruit flies, mice, and humans have conserved DNA sensing functionality. Mechanistically, mammalian Apaf-1 recruits receptor-interacting protein 2 (RIP2, also known as RIPK2) via its WD40 repeat domain and promotes RIP2 oligomerization to initiate NF-κB-driven inflammation upon cytoplasmic DNA recognition. Furthermore, DNA binding of Apaf-1 determines cell fate by switching the cellular processes between intrinsic stimuli-activated apoptosis and inflammation. These findings suggest that Apaf-1 is an evolutionarily conserved DNA sensor and may serve as a cell fate checkpoint, which determines whether cells initiate inflammation or undergo apoptosis by distinct ligand binding.

DOI: https://doi.org/10.1038/s41421-024-00750-4
Blood Adv. 2025 Jan 22. pii: bloodadvances.2024013435. [Epub ahead of print]

Transcriptomic atlas reveals organ-specific disease tolerance in sickle cell mice.

Anne Grunenwald, Julie Peliconi, Julien Lavergne, Margot Revel, Elodie Voilin, Tania Robe-Rybkine, Gilles Crambert, Jordan D Dimitrov, Olivier Blanc-Brude, Lubka T Roumenina.

Sickle cell disease (SCD) is the most common genetic disease in the world and a societal challenge. SCD is characterized by multi-organ injury related to intravascular hemolysis. To understand tissue-specific responses to intravascular hemolysis and exposure to heme, we present a transcriptomic atlas in the primary target organs of HbSS vs HbAA transgenic SCD mice. We explored the transcriptomes of liver, kidney, heart, lung and bone marrow from HbAA and HbSS Townes littermates at resting state and their changes after injection of heme, assessed by RNA sequencing. Inflammation and myeloid cell signatures were omnipresent in resting HbSS organs, liver being the most affected. The injection of heme triggered a robust inflammatory response in HbAA mice. Signatures of exposure to heme in HbAA mice were downstream of TLR4 (sensor of LPS but also of heme), IL1b, IL6 and IFNg, similarly to HbSS mice at rest. Nevertheless, HbSS mice were strikingly unresponsive to heme administration, irrespective of the organ. This tolerance was driven by upregulation of the heme-detoxifying enzyme HO-1 and was abrogated by its specific inhibition. Therefore, HbSS mice develop robust protective mechanisms, which may explain how they and SCD patients survive bouts of severe hemolysis.

DOI: https://doi.org/10.1182/bloodadvances.2024013435