bims-traimu 2025-03-30 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–03–30
nine papers selected by
Yantong Wan, Southern Medical University

Metabolic Adaptations Driving Innate Immune Memory: Mechanisms and Therapeutic Implications.
BCG-derived acellular membrane vesicles elicit antimycobacterial immunity and innate immune memory.
KK2DP7 Stimulates CD11b+ Cell Populations in the Spleen to Elicit Trained Immunity for Anti-Tumor Therapy.
Aminobisphosphonates Potentiate Non-Specific Immunological Memory.
Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages.
Roles of TLR4 in macrophage immunity and macrophage-pulmonary vascular/lymphatic endothelial cell interactions in sepsis.
BNT162b2 mRNA vaccination attenuates innate immune function in humans.
Acute LPS exposure enhances susceptibility to peripheral prion infection.
Macrophages harness hepatocyte glutamate to boost liver regeneration.

J Leukoc Biol. 2025 Mar 26. pii: qiaf037. [Epub ahead of print]

Metabolic Adaptations Driving Innate Immune Memory: Mechanisms and Therapeutic Implications.

Dan Hao, Margaret A McBride, Julia K Bohannon, Antonio Hernandez, Benjamin Klein, David L Williams, Edward R Sherwood.

  Immune memory is a hallmark of the adaptive immune system. However, recent research reveals that innate immune cells also retain memory of prior pathogen exposure that prompts enhanced responses to subsequent infections. This phenomenon is termed "innate immune memory" or "trained immunity." Notably, remodeling of cellular metabolism, which closely links to epigenetic reprogramming, is a prominent feature of innate immune memory. Adaptations in glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), glutaminolysis, and lipid synthesis pathways are critical for establishing innate immune memory. This review provides an overview of the current understanding of how metabolic adaptations drive innate immune memory. This understanding is fundamental to understanding innate immune system functions and advancing therapies against infectious diseases.

Keywords:  Innate immune memory; immune therapy; metabolism; trained immunity

DOI:  https://doi.org/10.1093/jleuko/qiaf037
Front Immunol. 2025 ;16 1534615

BCG-derived acellular membrane vesicles elicit antimycobacterial immunity and innate immune memory.

Takehiro Yamaguchi, Noriaki Samukawa, Sohkichi Matsumoto, Masayuki Shiota, Masaki Matsumoto, Ryoma Nakao, Satoru Hirayama, Yutaka Yoshida, Akihito Nishiyama, Yuriko Ozeki, Shuhei Tomita.

  Tuberculosis (TB) is one of the leading causes of death due to infectious disease. The sole established vaccine against TB is the Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine. However, owing to the lack of durable immunity with the BCG vaccine and its risk of infection, safer vaccines that can also be used as boosters are needed. Here, we examined whether membrane vesicles (MVs) from BCG (BCG-MVs) isolated from BCG statically cultured in nutrient-restricted Sauton's medium (s-MVs) and from BCG planktonically cultured in nutrient-rich medium commonly used in the laboratory (p-MVs) could be used as novel TB vaccines. MVs are extracellular vesicles produced by various bacteria, including mycobacteria. Differences in the culture conditions affected the morphology, contents, immunostimulatory activity and immunogenicity of BCG-MVs. s-MVs presented greater immunostimulatory activity than p-MVs via the induction of TLR2 signaling. Mouse immunization experiments revealed that s-MVs, but not p-MVs, induced mycobacterial humoral and mucosal immunity, especially when administered in combination with adjuvants. In a BCG challenge experiment using BCG Tokyo type I carrying pMV361-Km, subcutaneous vaccination with s-MVs reduced the bacterial burden in the mouse lung to a level similar to that after intradermal vaccination with live BCG. Furthermore, the administration of s-MVs induced a significant lipopolysaccharide-induced proinflammatory response in macrophages in vitro. These results indicate that BCG-MVs obtained from static culture in Sauton's medium induce not only humoral immunity against mycobacteria but also trained immunity, which can allow the clearance of infectious agents other than mycobacteria. Together, these findings highlight the immunological properties of BCG-MVs and the availability of acellular TB vaccines that confer broad protection against various infectious diseases.

Keywords:  BCG; acellular vaccines; membrane vesicles (MVs); trained immunity; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2025.1534615
Adv Sci (Weinh). 2025 Mar 27. e2500032

KK2DP7 Stimulates CD11b+ Cell Populations in the Spleen to Elicit Trained Immunity for Anti-Tumor Therapy.

Rui Zhang, Lin Tang, Yusi Wang, Xuejing Zhou, Zhenyu Ding, Li Yang.

  The induction of trained immunity for anti-tumor therapy represents an emerging frontier in immunotherapy research, though its mechanistic underpinnings remain poorly understood. Adjuvant-induced trained innate immune responses constitute a critical yet underexplored component of adjuvant mechanisms of action. Here, KK2DP7, a dendrimer-structured peptide derived from the immunomodulatory antimicrobial peptide DP7 (VQWRIRVAVIRK) is employed, as a model adjuvant to establish standardized protocols for investigating adjuvant efficacy and mechanisms in enhancing anti-tumor immunity via trained immunity. Initial studies revealed that KK2DP7 administration significantly delayed tumor growth post-inoculation in murine models. The comprehensive analysis demonstrated that splenic cells exhibited cardinal features of trained immunity, whereas splenectomized mice exhibited complete loss of this protective effect. Strikingly, the adoptive transfer of CD11b+ cells isolated from the non-lymphoid splenic compartment of KK2DP7-trained mice to naïve recipients conferred robust tumor suppression. Mechanistic investigations linked this phenomenon to TLR2-IRF7 axis activation and epigenetic reprogramming of CD11b+ cells, as evidenced by chromatin accessibility assays and histone modification profiling. These findings not only unveil a novel therapeutically actionable dimension of trained immunity, centered on spleen-resident CD11b+ cell reprogramming but also establish a standardized protocol framework for systematically investigating adjuvant mechanisms in the context of trained innate immunity.

Keywords:  CD11b+ cells; anti‐tumor therapy; congenital immunity; training immunity; tumor immunotherapy

DOI:  https://doi.org/10.1002/advs.202500032
Bull Exp Biol Med. 2025 Mar 25.

Aminobisphosphonates Potentiate Non-Specific Immunological Memory.

Y Sh Schwartz, O V Semenova, A V Salmin.

  Innate immune cells have the ability to acquire non-specific immunological memory (NIM), which provides resistance to a variety of bacterial and viral infections. Experiments in vitro and in vivo have verified the hypothesis that the farnesyl pyrophosphate synthase inhibitor (aminobisphosphonates) can potentiate BCG-induced NIM. The aminobisphosphonate zoledronate induced the NIM phenotype in human monocyte cultures and provided nonspecific protection against staphylococcal infection in mice. Additionally, zoledronate significantly enhanced BCG-induced NIM, resulting in a synergistic protective effect. The phenomenon of potentiation of NIM/anti-infectious resistance discovered by us can form the basis for designing powerful universal vaccines of a new type.

Keywords:  BCG; Staphylococcus aureus; non-specific immunological memory; trained innate immunity; zoledronate

DOI:  https://doi.org/10.1007/s10517-025-06350-w
Mol Syst Biol. 2025 Mar 25.

Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages.

Alexander Simonis, Sebastian J Theobald, Anna E Koch, Ram Mummadavarapu, Julie M Mudler, Andromachi Pouikli, Ulrike Göbel, Richard Acton, Sandra Winter, Alexandra Albus, Dmitriy Holzmann, Marie-Christine Albert, Michael Hallek, Henning Walczak, Thomas Ulas, Manuel Koch, Peter Tessarz, Robert Hänsel-Hertsch, Jan Rybniker.

  Immune memory plays a critical role in the development of durable antimicrobial immune responses. How precisely mRNA vaccines train innate immune cells to shape protective host defense mechanisms remains unknown. Here we show that SARS-CoV-2 mRNA vaccination significantly establishes histone H3 lysine 27 acetylation (H3K27ac) at promoters of human monocyte-derived macrophages, suggesting epigenetic memory. However, we found that two consecutive vaccinations were required for the persistence of H3K27ac, which matched with pro-inflammatory innate immune-associated transcriptional changes and antigen-mediated cytokine secretion. H3K27ac at promoter regions were preserved for six months and a single mRNA booster vaccine potently restored their levels and release of macrophage-derived cytokines. Interestingly, we found that H3K27ac at promoters is enriched for G-quadruplex DNA secondary structure-forming sequences in macrophage-derived nucleosome-depleted regions, linking epigenetic memory to nucleic acid structure. Collectively, these findings reveal that mRNA vaccines induce a highly dynamic and persistent training of innate immune cells enabling a sustained pro-inflammatory immune response.

Keywords:  Epigenetic Memory; G-quadruplex; H3K27ac; SARS-Cov-2 mRNA Vaccination; Trained Innate Immunity

DOI:  https://doi.org/10.1038/s44320-025-00093-6
Commun Biol. 2025 Mar 21. 8(1): 469

Roles of TLR4 in macrophage immunity and macrophage-pulmonary vascular/lymphatic endothelial cell interactions in sepsis.

Yu Fu, Ting Gong, Patricia A Loughran, Yuehua Li, Timothy R Billiar, Youtan Liu, Zongmei Wen, Jie Fan.

In sepsis, acute lung injury (ALI) is a severe complication and a leading cause of death, involving complex mechanisms that include cellular and molecular interactions between immune and lung parenchymal cells. In recent decades, the role of Toll-like receptor 4 (TLR4) in mediating infection-induced inflammation has been extensively studied. However, how TLR4 facilitates interactions between innate immune cells and lung parenchymal cells in sepsis remains to be fully understood. This study aims to explore the role of TLR4 in regulating macrophage immunity and metabolism in greater depth. It also seeks to reveal how changes in these processes affect the interaction between macrophages and both pulmonary endothelial cells (ECs) and lymphatic endothelial cells (LECs). Using TLR4 knockout mice and the combined approaches of single-cell RNA sequencing and experimental validation, we demonstrate that in sepsis, TLR4-deficient macrophages upregulate Abca1, enhance cholesterol efflux, and reduce glycolysis, promoting M2 polarization and attenuating inflammation. These metabolic and phenotypic shifts significantly affect their interactions with pulmonary ECs and LECs. Mechanistically, we uncovered that TLR4 operates through multiple pathways in endothelial dysfunction: macrophage TLR4 mediates inflammatory damage to ECs/LECs, while endothelial TLR4 both directly sensitizes cells to lipopolysaccharide-induced injury and determines their susceptibility to macrophage-derived inflammatory signals. These findings reveal the complex role of TLR4 in orchestrating both immune-mediated and direct endothelial responses during sepsis-induced ALI, supporting that targeting TLR4 on multiple cell populations may present an effective therapeutic strategy.

DOI: https://doi.org/10.1038/s42003-025-07921-3
Clin Immunol. 2025 Mar 25. pii: S1521-6616(25)00063-4. [Epub ahead of print] 110488

BNT162b2 mRNA vaccination attenuates innate immune function in humans.

Sarah A Connolly, Aaron Walsh, Anna Ledwith, Karen Mc Carthy, Sinead A O'Rourke, Dearbhla M Murphy, Anna Blasinska, Aisling Dunne, Jean M Fletcher, Kingston H G Mills, Ross McManus, Frederick J Sheedy, Sharee A Basdeo.

DOI: https://doi.org/10.1016/j.clim.2025.110488
Sci Rep. 2025 Mar 21. 15(1): 9754

Acute LPS exposure enhances susceptibility to peripheral prion infection.

Reiss Pal, Charlotte M Thomas, Khalid Salamat, Stephen J Jenkins, Barry M Bradford, Neil A Mabbott.

  After peripheral infections, the initial accumulation of prions within secondary lymphoid tissues is essential for the transmission of disease to the brain. Macrophages are considered to sequester or destroy prions, but little was known of their impact on disease susceptibility after a peripheral infection. Inflammation in the peritoneal cavity can trigger the macrophage disappearance reaction, whereby the macrophages are temporarily contained within cellular aggregates on the mesothelium. We studied the impact of the bacterial lipopolysaccharide (LPS)-mediated macrophage disappearance reaction on susceptibility to an intraperitoneal prion infection. Intraperitoneal LPS injection significantly enhanced prion disease susceptibility approximately 100X when given 24-3 h before infection. The effects on disease susceptibility coincided with the reduced abundance of macrophages within the peritoneal cavity at the time of infection and the enhanced early accumulation of prions in the spleen. This suggests that the reduced recoverable abundance of macrophages in the peritoneal cavity following acute LPS-treatment, increased disease susceptibility by enhancing the initial propagation of the prions from site of exposure (peritoneal cavity) to the spleen from where they subsequently spread to the brain. Further studies may help identify novel macrophage-targeted treatments that can reduce susceptibility to peripherally acquired prion infections.

Keywords:  Disease susceptibility; LPS; Macrophage; Peritoneal cavity; Prion diseases; Spleen; Transmissible spongiform encephalopathies

DOI:  https://doi.org/10.1038/s41598-025-94003-3
Nature. 2025 Mar 26.

Macrophages harness hepatocyte glutamate to boost liver regeneration.

María Del Mar Rigual, Mariana Angulo-Aguado, Sladjana Zagorac, Ruth Álvarez-Díaz, Marta Benítez-Mondéjar, Fengming Yi, Carlos Martínez-Garay, Karla Santos-de-Frutos, Eunjeong Kim, Ramón Campos-Olivas, Nabil Djouder.

Liver regeneration after hepatectomy follows accurate coordination with the body's specific requirements1-3. However, the molecular mechanisms, factors and particular hepatocyte population influencing its efficiency remain unclear. Here we report on a unique regeneration mechanism involving unconventional RPB5 prefoldin interactor 1 (URI1), which exclusively colocalizes with, binds to and activates glutamine synthase (GS) in pericentral hepatocytes. Genetic GS or URI1 depletion in mouse pericentral hepatocytes increases circulating glutamate levels, accelerating liver regeneration after two-third hepatectomy. Conversely, mouse hepatocytic URI1 overexpression hinders liver restoration, which can be reversed by elevating glutamate through supplementation or genetic GS depletion. Glutamate metabolically reprograms bone-marrow-derived macrophages, stabilizing HIF1α, which transcriptionally activates WNT3 to promote YAP1-dependent hepatocyte proliferation, boosting liver regeneration. GS regulation by URI1 is a mechanism that maintains optimal glutamate levels, probably to spatiotemporally fine-tune liver growth in accordance with the body's homeostasis and nutrient supply. Accordingly, in acute and chronic injury models, including in cirrhotic mice with low glutamate levels and in early mortality after liver resection, as well as in mice undergoing 90% hepatectomy, glutamate addition enhances hepatocyte proliferation and survival. Furthermore, URI1 and GS expression co-localize in human hepatocytes and correlate with WNT3 in immune cells across liver disease stages. Glutamate supplementation may therefore support liver regeneration, benefiting patients awaiting transplants or recovering from hepatectomy.

DOI: https://doi.org/10.1038/s41586-025-08778-6