bims-traimu 2025-08-24 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–08–24
ten papers selected by
Yantong Wan, Southern Medical University

A systems approach for elucidating the role of the microbiome in epigenetic cellular memory.
Research trends and topics on sepsis immunosuppression: a bibliometric and visual analysis of global research from 2004 to 2024.
Gut commensal microbiota drive tailored macrophage responses.
Stimulation of microglia in adolescence produces a long-lasting prophylactic effect on single prolonged stress-induced PTSD-like behavior in adult mice.
Long-term hyperglycaemia exerts contrasting effects on M1- and M2-like macrophages.
The epigenetic circle: feedback loops in the maintenance of cellular memory.
Constitutive Androstane Receptor in Macrophages Regulates Toll-Like Receptor 4-Mediated Innate Immune Responses Against Endotoxemic Liver Injury.
Mitochondrial Transplantation Augments the Reparative Capacity of Macrophages Following Myocardial Injury.
Molecular and subcellular mechanisms of vital macrophage extracellular trap formation.
Macrophages and macrophage extracellular vesicles confer cancer ferroptosis resistance via PRDX6-mediated mitophagy inhibition.

mSystems. 2025 Aug 18. e0018525

A systems approach for elucidating the role of the microbiome in epigenetic cellular memory.

Jacob W Pederson, Aleksandra Nita-Lazar.

  The microbiome plays an essential role in the development of the immune system. Both the immune system and microbiome dynamically respond to internal and external cues, and dysregulation of either of these systems can lead to disease pathology. Separate from the adaptive immune system, the innate immune system retains a memory of inflammatory events that determine the quality of future immune responses. The phenomenon is characterized by epigenetic modifications that lead to immunosuppressive or hyperinflammatory cell phenotypes, collectively designated as epigenetic cellular memory. It remains unclear whether and how the microbiome influences epigenetic cellular memory phenotypes to promote immunopathology and chronic disease. Inflammatory signals from the microbiota regulate hematopoiesis and systemic immunity through the production of immunomodulatory ligands and activation of circulating immune cells; however, few studies have directly implicated these mechanisms in the development of epigenetic cellular memory. We posit that a multi-omic systems approach is well-suited to elucidating the complex factors mediating the microbiome's contribution to this phenomenon. By measuring responses to exogenous influences through multi-omic technologies, it will be possible to identify the regulatory axis that next-generation therapies should target to reverse immunopathology. As chronic inflammatory disorders are on the rise, it is imperative that future therapies leverage both dietary and pharmacological interventions to promote self-reinforcing homeostatic immunity by targeting the mechanisms of epigenetic cellular memory.

Keywords:  immune memory; innate immunity; microbiome; systems biology

DOI:  https://doi.org/10.1128/msystems.00185-25
Front Med (Lausanne). 2025 ;12 1615753

Research trends and topics on sepsis immunosuppression: a bibliometric and visual analysis of global research from 2004 to 2024.

Ji Yin, Yantong Wan, Guangqin Chen, Nanhong Li, Fei Liu, Haihua Luo, Yijing Li, Shan Li, Yong Jiang.

   Background: Sepsis, a condition characterized by critical organ impairment resulting from dysregulated response to infection, remains a leading cause of mortality globally. Immunosuppression significantly dictates the clinical trajectory and ultimate prognosis in sepsis. Research on sepsis-related immunosuppression has gained substantial attention in recent years. However, a comprehensive and objective analysis of the current state of research remains scarce. This study employs bibliometric techniques and knowledge mapping to provide a visual analysis of trends and developments in sepsis immunosuppression, offering a systematic overview for researchers in the field.
Objectives: This study aims to: (1) Quantitatively characterize global publication trends, key contributors (countries/institutions/journals/authors), and collaborative networks in sepsis immunosuppression research (2004-2024); (2) Identify current hotspots and future directions in this field.
Materials and methods: Articles and reviews related to sepsis immunosuppression were sourced from the Web of Science Core Collection via subject-specific searches. Bibliometric analyses were executed using Excel 365, CiteSpace, VOSviewer, and Bibliometrix (R-Studio's R-Tool).
Results: From January 1, 2004, to March 22, 2024, 3,082 articles on sepsis immunosuppression authored by 16,545 individuals across 116 institutions from 30 countries were identified. Collaborative network analysis highlights the United States as the leading contributor, with key institutions including the University of Florida and Washington University. Strong international collaboration is evident, particularly between the United States and China, as well as the United States and Germany. Frontiers in Immunology emerged as the most prolific journal, while Journal of Immunology garnered the highest co-citation frequency. Guillaume Monneret has published the greatest number of relevant articles, while Richard S. Hotchkiss is the most frequently co-cited author. The research predominantly focuses on immunology, molecular biology, and clinical treatments. Keyword analysis suggests that immune cells, cell death, and personalized clinical treatments are emerging research hotspots in the field.
Conclusion: This bibliometric analysis maps evolving trends and forecasts emerging hotspots in sepsis immunosuppression research, providing direction for future studies.

Keywords:  bibliometric analysis; clinical treatment; immunoparalysis; immunosuppression; sepsis

DOI:  https://doi.org/10.3389/fmed.2025.1615753
Cell Rep. 2025 Aug 18. pii: S2211-1247(25)00928-3. [Epub ahead of print]44(8): 116157

Gut commensal microbiota drive tailored macrophage responses.

Josh Jones, Karla Y García-Martínez, Yi-Yuan Lee, Matt Rhee, Rahul R Nath, Sola Takahashi, Benjamin Grodner, Iwijn De Vlaminck, Cynthia A Leifer, Ilana L Brito.

  Macrophages serve as sentinels at the intestinal surface, responding to organismal cues to drive proinflammatory or tolerogenic responses. To date, studies of combinations of these cues do not fully capture the heterogeneity of macrophage responses. To address this gap, we performed multiplexed single-cell RNA sequencing on 74,476 human monocyte-derived macrophages following exposure to 15 bacteria, mostly commensals. We observe clusters that appeared only after macrophage exposure to bacteria, and transcriptional responses within each cluster varied by species and Gram status. The proportion of each cluster also varied among exposure conditions. Macrophages exposed to defined combinations of organisms revealed that Fusobacterium nucleatum drives inflammatory responses, whereas Mediterraneibacter gnavus tempers them. Overall, our results show that macrophages distinguish between commensal organisms, relevant to intestinal diseases characterized by altered microbiome compositions. This sequencing dataset will be a useful resource to probe human macrophage response to a broad range of bacteria.

Keywords:  CP: Immunology; CP: Microbiology; TLR; bacteria; commensals; cytokine; inflammation; macrophages; microbiome; mucosal; scRNA-seq; transcriptomes

DOI:  https://doi.org/10.1016/j.celrep.2025.116157
Brain Behav Immun. 2025 Aug 15. pii: S0889-1591(25)00314-9. [Epub ahead of print]130 106079

Stimulation of microglia in adolescence produces a long-lasting prophylactic effect on single prolonged stress-induced PTSD-like behavior in adult mice.

Rongrong Song, Minxiu Ye, Zhiwei Gao, Xu Lu, Lijun Liu, Fei Cao, Rongrong Yang, Zhuo Chen, Micona Sun, Fu Li, Wenfeng Hu, Jie Ren, Haojie Zhu, Qijie Feng, Chao Huang.

  Our previous studies have reported that pre-stimulation of microglia in adult mice by a single injection of low-dose lipopolysaccharide (LPS) one day before stress stimulation prevents the occurrence of PTSD-like behavior induced by single prolonged stress (SPS), which disappears when the time interval between LPS injection and stress stimulation is extended to 10 days. This disappearance can be rescued by repeated LPS injection, suggesting that enhancing the response of microglia may increase stress tolerance. Since microglia exhibit strong functional plasticity during adolescence, we hypothesize that mice administered LPS during this period acquire a strong ability to resist SPS stimulation. As expected, the results showed that a single injection of LPS (100 μg/kg) on post-natal day 28 (PND28) could prevent SPS-induced development of anxiety- and fear-like behaviors and neuroinflammatory responses in the hippocampus and medial prefrontal cortex of adult mice of different ages, including PND70, PND154 and PND266. Both pre-inhibition of microglia by minocycline pretreatment and pre-depletion of microglia by PLX3397 pre-administration were able to abolish the preventive effect of low-dose LPS injection in adolescence on SPS-induced development of neuroinflammatory responses and anxiety- and fear-like behaviors in adult mice of different ages, including PND70, PND154, and PND266. These results suggest that pre-stimulation of microglia during adolescence may enable adult mice to resist harmful stress-induced PTSD-like behaviors in the long term, which could be useful for developing an approach to prevent the occurrence of PTSD from the root by a vaccine-like method.

Keywords:  Adolescence; Long-term prevention; Microglia; Neuroinflammation; PTSD

DOI:  https://doi.org/10.1016/j.bbi.2025.106079
Front Immunol. 2025 ;16 1639650

Long-term hyperglycaemia exerts contrasting effects on M1- and M2-like macrophages.

Sona Margaryan, David Poghosyan, Susanna Ghonyan, Lina Hakobyan, Anush Martirosyan, Gayane Manukyan.

   Introduction: Chronic hyperglycemia can contribute to metabolic disorders, disrupting cellular homeostasis and potentially leading to immunological disturbances. As highly adaptable innate immune cells, macrophages can effectively utilize glucose for energy and adjust their activities in response to environmental changes. We hypothesized that hyperglycemia induces distinct effects on M1 and M2 macrophages, thereby promoting their divergent roles in the inflammatory response.
Methods: For this, we applied an in vitro hyperglycemia model to investigate its impact on M1- and M2-like macrophages differentiated from primary monocytes.
Results: M1-like macrophages exhibited diminished capacity to produce reactive oxygen species (ROS), IL-6, TNF-α, as well as reduced antigen presentation and co-stimulatory abilities under long exposure to high glucose. In contrast, M2-like macrophages showed a shift toward M1 polarization, characterized by increased production of ROS and IL-6, upregulation of CD86 and HLA-DR expression, and reduced reparative abilities. We also observed disturbance of endotoxin tolerance evidenced by increased production of TNF-α and diminished phagocytic ability.
Discussion: The results suggest that hyperglycemia disrupts the typical functional dichotomy of M1 and M2 macrophages, which may explain mixed polarization of tissue macrophages in individuals with metabolic syndromes associated with chronic hyperglycemia.

Keywords:  GM-CSF and M-CSF-derived cells; LPS; M1 and M2 macrophages; endotoxin tolerance; hyperglycemia; phagocytosis

DOI:  https://doi.org/10.3389/fimmu.2025.1639650
Epigenetics Chromatin. 2025 Aug 20. 18(1): 56

The epigenetic circle: feedback loops in the maintenance of cellular memory.

Marko Tomljanović, Cita Hanif Muflihah, Dejan Rajkovski, Pawel Mikulski.

The memory of gene expression states, active or repressive, is a fundamental biological concept as it controls cell fate in development, immunity and abiotic stress responses. Such memory is maintained through cell division as a cornerstone of epigenetics. Cell division poses a threat to the stability of epigenetic memory as memory-encoding factors become diluted between daughter cells. Thus, long-term epigenetic memory must depend on the feedback loops to sustain it over cell generations.Despite a widespread presence and fundamental importance, maintenance mechanisms of epigenetic memory are far from being clear. Here, we summarize present knowledge about feedback loops that allow maintenance of epigenetic information. We describe conceptually distinct, cis- and trans-, feedback loops, which rely on local, read-write propagation mechanisms or regulatory loops of diffusible factors, respectively. Furthermore, we provide cases of their frequent coupling in epigenetic systems in cells and synthesize current challenges in understanding feedback mechanisms. Overall, we believe this review to benefit the scientific community in bringing a holistic perspective on such fundamental biological phenomenon.

DOI: https://doi.org/10.1186/s13072-025-00621-6
Adv Sci (Weinh). 2025 Aug 18. e06725

Constitutive Androstane Receptor in Macrophages Regulates Toll-Like Receptor 4-Mediated Innate Immune Responses Against Endotoxemic Liver Injury.

Renjie Cao, Tingting Zhao, Ying Wang, Shaofei Song, Yuan Li, Mengling Hou, Yanxin Zhang, Sengpeng Wong, Siqi Wang, Yuran Wang, Hong Peng, Min Huang, Yiming Jiang.

  Macrophage proinflammatory hyperactivation drives the pathogenesis of acute liver injury, a common complication of sepsis. The role of the nuclear receptor constitutive androstane receptor (CAR) in endotoxin-induced liver injury remains unclear. Here, this study reports that CAR is highly expressed in human and murine macrophages. CAR activation markedly attenuated endotoxin-induced liver damage, alleviating hepatocyte death and hepatic inflammation. Macrophage-hepatocyte coculture confirmed that CAR inhibited inflammation through macrophage crosstalk. CAR-mediated hepatoprotection and anti-inflammatory effects are absent in AAV8-F4/80-shCar-treated mice, confirming the essential role of CAR in macrophages. Mechanistically, CAR is found to interact with Tlr4, and the suppressive effects of CAR on TLR4 are proven in Tlr4-/- mice. Furthermore, CAR activation reduced LPS-induced inflammation in hMDMs, BMDMs, RAW264.7, and THP-1 cells, and Car or Tlr4 knockdown abolished CAR-mediated immunosuppression. Overall, these findings showed that macrophage CAR activation attenuated endotoxin-induced liver injury and hepatic inflammation through the TLR4 signaling pathway, providing insights for treating inflammatory liver diseases.

Keywords:  constitutive androstane receptor; endotoxemia; liver injury; toll‐like receptor 4

DOI:  https://doi.org/10.1002/advs.202506725
Adv Sci (Weinh). 2025 Aug 19. e06337

Mitochondrial Transplantation Augments the Reparative Capacity of Macrophages Following Myocardial Injury.

Yuning Zhang, Xiaolei Sun, Yawei Jin, Kanghui Chen, Lu Zhang, Xiong Gao, Mohan Li, Ze Yuan, Jianguo Jia, Aijun Sun, Junbo Ge.

  The pathologically remodeled myocardial ischemic microenvironment, characterized by sustained hypoxia, metabolic insufficiency, and accumulation of inflammatory mediators, severely disrupts mitochondrial homeostasis. This dysfunction establishes a self-perpetuating cycle that impairs the coordinated healing cascade and compromises cardiac tissue repair following myocardial infarction (MI). To counteract these effects, a novel strategy of mitochondrial augmentation is proposed, whereby healthy exogenous mitochondria are introduced into macrophages to generate mitochondria-transplanted macrophages (Mito-T-Macros or MTMs), which can resist post-MI stress. Mitochondrial transplantation (MT) effectively induces macrophage polarization toward a reparative M2-like phenotype, thereby enhancing pro-healing functions, including migration, invasion, and phagocytosis. In vivo, MTM therapy enhances cardiac function after MI and attenuates left ventricular remodeling by reducing fibrosis, limiting apoptosis, and promoting angiogenesis. Mechanistically, MT accelerates the phenotypic transition of macrophages to a reparative state and prolongs their activity during the healing phase. Notably, a portion of the transplanted mitochondria are released from MTMs and subsequently internalized by cardiomyocytes, suggesting an additional mechanism of myocardial support. Overall, MT enhances the reparative capabilities of macrophages and contributes to the therapeutic efficacy of MTMs in ameliorating post-MI cardiac remodeling. These findings support MTM therapy as a promising and innovative approach for repairing myocardial injury following MI.

Keywords:  macrophage reparative capacity; mitochondrial transplantation; myocardial infarction

DOI:  https://doi.org/10.1002/advs.202506337
Front Immunol. 2025 ;16 1608428

Molecular and subcellular mechanisms of vital macrophage extracellular trap formation.

Yongchan Lee, Max Brenner, Monowar Aziz, Ping Wang.

  Macrophage extracellular traps (METs) are a poorly understood process beneficial for infection control but detrimental in inflammation, autoimmunity and cancer. Our research shows that viable macrophages release METs even when plasma membrane lysis is blocked. We demonstrate, for the first time, that nuclear DNA is extruded directly into the cytoplasm through Gasdermin D pores on the nuclear envelope. Gasdermin D pore formation was triggered by extracellular cold-inducible RNA-binding protein, which activates the TLR4 signal transduction pathway. This DNA is processed in the cytoplasm, enters the vesicular transport system aided by autophagic flux and the Endosomal Sorting Complex. The DNA then enters the lysosomal compartment, where it undergoes histone 3 citrullination, forms nascent traps containing myeloperoxidase, and is released to the extracellular space. Our study provides valuable insights into vital MET formation and its mechanism that will enable future studies on the role of METs in health and disease.

Keywords:  ESCRT; Gasdermin D; LC3; METs; autophagy; macrophage extracellular trap; secretory lysosome; vital

DOI:  https://doi.org/10.3389/fimmu.2025.1608428
Redox Biol. 2025 Aug 16. pii: S2213-2317(25)00339-8. [Epub ahead of print]86 103826

Macrophages and macrophage extracellular vesicles confer cancer ferroptosis resistance via PRDX6-mediated mitophagy inhibition.

Naisheng Zheng, Fuli Li, Qing Huang, Xian Huang, Tomasz Maj.

  Ferroptosis has emerged as a promising therapeutic target in cancer therapy, with the tumor microenvironment (TME) playing a pivotal role in regulating ferroptosis. Although macrophages contribute to ferroptosis regulation within TME, the underlying mechanisms remain unclear. In this study, we demonstrate that macrophages consistently attenuate GPX4 inhibitor-induced lipid peroxidation and cell death in various tumor cell lines, whereas their resistance to cysteine transport inhibitor-triggered ferroptosis varies across cell types. This tumor protection from ferroptosis is mediated through macrophage-tumor cell contact and the delivery of macrophage-derived extracellular vesicles (Mφ-EV). Transcriptomic and proteomic analyses revealed that macrophages and Mφ-EV enhance glutathione metabolism in tumor cells. Notably, Mφ-EV are uniquely enriched with the glutathione metabolism-related protein PRDX6. Mechanistically, the glutathione peroxidase activity of PRDX6 elevates intracellular reduced glutathione, suppresses lipid peroxidation, and thereby mitigates ferroptosis. Furthermore, macrophage-derived PRDX6 reduces mitochondrial superoxide accumulation, alleviates ferroptosis-induced mitophagy, and enhances tumor cell viability, ultimately promoting tumor growth. Together, our findings provide a novel mechanism of ferroptosis resistance in TME, wherein macrophages confer tumor cell resilience by bypassing GPX4 inhibition.

Keywords:  Extracellular vesicles; Ferroptosis; Macrophages; Mitophagy; Peroxiredoxin 6

DOI:  https://doi.org/10.1016/j.redox.2025.103826