bims-traimu Biomed News
on Trained immunity
Issue of 2025–04–20
seventeen papers selected by
Yantong Wan, Southern Medical University
  1. Hematopoietic stem cell state and fate in trained immunity.
  2. Hematopoietic stem and progenitor cells fine-tunning the "sweet" of trained immunity.
  3. Beyond Adaptive Immunity: Trained Innate Immune Responses as a Novel Frontier in Hepatocellular Carcinoma Therapy.
  4. Alzheimer's disease as an auto-innate immune pathology with potential cell trans-differentiation and enhanced trained immunity in 3xTg-AD mouse model.
  5. Coevolutionary interplay: Helminths-trained immunity and its impact on the rise of inflammatory diseases.
  6. Effects of Yeast β-Glucan Supplementation on Calf Intestinal and Respiratory Health.
  7. Innate immune reprogramming in circulating neutrophils of COPD patients.
  8. Systemic inflammation impairs myelopoiesis and interferon type I responses in humans.
  9. The role of heme in sepsis induced Kupffer cell PANoptosis and senescence.
  10. Lipopolysaccharide preconditioning augments the antibacterial activity of renal macrophages and ameliorates acute kidney injury caused by Staphylococcus aureus bacteremia in mice.
  11. The five senses of immunity.
  12. Oral and transdermal administration of lipopolysaccharide safely enhances self-healing ability through the macrophage network.
  13. Itaconate modulates immune responses via inhibition of peroxiredoxin 5.
  14. Macrophages maintain signaling fidelity in response to ligand mixtures.
  15. Mechanical Force Triggers Macrophage Pyroptosis and Sterile Inflammation by Disrupting Cellular Energy Metabolism.
  16. A Snapshot of National Institutes of Health Funding for Sepsis Research: 2019-2023.
  17. Innate immune sensor NLRP3 drives PANoptosome formation and PANoptosis.
  1. Cell Commun Signal. 2025 Apr 14. 23(1): 182
    Hematopoietic stem cell state and fate in trained immunity.
    Weinian Liao, Xiaodong Zai, Jun Zhang, Junjie Xu.
      Trained immunity serves as a de facto memory for innate immune responses, resulting in long-term functional reprogramming of innate immune cells. It enhances resistance to pathogens and augments immunosurveillance under physiological conditions. Given that innate immune cells typically have a short lifespan and do not divide, persistent innate immune memory may be mediated by epigenetic and metabolic changes in long-lived hematopoietic stem cells (HSCs) in the bone marrow. HSCs fine-tune their state and fate in various training conditions, thereby generating functionally adapted progeny cells that orchestrate innate immune plasticity. Notably, both beneficial and maladaptive trained immunity processes can comprehensively influence HSC state and fate, leading to divergent hematopoiesis and immune outcomes. However, the underlying mechanisms are still not fully understood. In this review, we summarize recent advances regarding HSC state and fate in the context of trained immunity. By elucidating the stem cell-intrinsic and extrinsic regulatory network, we aim to refine current models of innate immune memory and provide actionable insights for developing targeted therapies against infectious diseases and chronic inflammation. Furthermore, we propose a conceptual framework for engineering precision-trained immunity through HSC-targeted interventions.
    Keywords:  Cell fate decision; Hematopoietic stem cell; Innate immune cell; Stem cell state; Trained immunity
    DOI:  https://doi.org/10.1186/s12964-025-02192-1
  2. J Leukoc Biol. 2025 Apr 15. pii: qiaf043. [Epub ahead of print]
    Hematopoietic stem and progenitor cells fine-tunning the "sweet" of trained immunity.
    Jiawei Li, Hui Wang, Sheng Xia.
      Recent studies have challenged the traditional view of innate immunity as non-specific and transient by demonstrating that innate immune cells can develop immune memory in response to various activating factors, a phenomenon known as trained immunity. This process involves epigenetic modifications, such as changes in chromatin accessibility, and metabolic reprogramming, which can provide protection against unrelated pathogens but may also trigger immune-mediated damage. This review summarizes the current understanding of innate immune memory, with a particular focus on recent findings regarding the training of innate immune cells at the hematopoietic stem and progenitor cell stage. We present observations of trained immunity in innate immune cells, summarize key activating factors and underlying mechanisms, and propose potential host-directed immunotherapeutic strategies and preventive measures based on trained immunity. Our aim is to highlight the biological significance of trained immunity and its potential applications in enhancing long-term immunity, improving vaccine efficacy, and preventing immune-related diseases.
    Keywords:  epigenetic changes; hematopoietic stem and progenitor cells; metabolic reprogramming; trained immunity
    DOI:  https://doi.org/10.1093/jleuko/qiaf043
  3. Cancers (Basel). 2025 Apr 07. pii: 1250. [Epub ahead of print]17(7):
    Beyond Adaptive Immunity: Trained Innate Immune Responses as a Novel Frontier in Hepatocellular Carcinoma Therapy.
    Ching-Hua Hsieh, Pei-Chin Chuang, Yueh-Wei Liu.
      Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, with the majority of cases detected at advanced stages when curative options are limited. Current systemic therapies, including immune checkpoint inhibitors, demonstrate limited efficacy with durable responses in only 15-20% of patients. This poor response is largely attributed to HCC's immunosuppressive microenvironment, which blunts effective T-cell responses. By illustrating that innate immune cells can acquire memory-like characteristics through a process known as trained immunity, recent evidence has challenged the conventional belief that innate immunity is devoid of memory. This review investigates the potential of trained immunity, which is defined by the long-term functional reprogramming of innate immune cells through epigenetic, transcriptomic, and metabolic changes, to provide new therapeutic opportunities for HCC. We discuss mechanisms by which trained immunity can transform the HCC microenvironment, including enhanced inflammatory cytokine production, repolarization of tumor-associated macrophages toward anti-tumor phenotypes, increased immune cell infiltration, and improved bridging to adaptive immunity. We further evaluate emerging therapeutic strategies leveraging trained immunity principles, including BCG vaccination, β-glucan administration, cytokine-trained NK cell therapy, and innovative combination approaches. Finally, we address potential resistance mechanisms and future directions for clinical application. By integrating trained immunity into conventional immunotherapeutic regimens, we may significantly improve outcomes for HCC patients, potentially transforming advanced disease into a more manageable condition.
    Keywords:  hepatocellular carcinoma (HCC); immune checkpoint inhibitors (ICIs); innate immune reprogramming; trained immunity; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/cancers17071250
  4. J Alzheimers Dis. 2025 Apr 15. 13872877251329583
    Alzheimer's disease as an auto-innate immune pathology with potential cell trans-differentiation and enhanced trained immunity in 3xTg-AD mouse model.
    Fatma Saaoud, Lu Liu, Keman Xu, Yifan Lu, Ying Shao, Mohammed Ben Issa, Xiaohua Jiang, Xianwei Wang, Xiaolei Liu, Michael Autieri, Sheng Wu, Juncheng Wei, Jun Yu, Rihab Bouchareb, Avrum Gillespie, Jin Jun Luo, Laisel Martinez, Roberto Vazquez-Padron, Jianxin Sun, Huaqing Zhao, Hong Wang, Domenico Pratico, Xiaofeng Yang.
      BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment. Neuroinflammatory processes, mediated by glial and immune cells, contribute to neuronal damage. Emerging evidence implicates innate immune mechanisms, including trained immunity and cell trans-differentiation, in AD pathogenesis, though their roles remain unclear.ObjectiveTo investigate transcriptomic changes in the 3xTg-AD mouse model, focusing on trained immunity and cell trans-differentiation in disease mechanisms.MethodsRNA-sequencing was performed on brain tissue (cortex plus hippocampus) from 11-month-old female 3xTg-AD and wild-type mice (n = 3/group). Differentially expressed genes (fold change > 1.5, p < 0.05) were identified and followed by bioinformatics and knowledge-based transcriptomic profiling. Public AD datasets were also analyzed.Results3xTg-AD mice exhibited 316 upregulated and 412 downregulated genes. Downregulated genes included those for blood-brain barrier protein, while upregulated genes related to cerebrospinal fluid. Increased expression of proinflammatory markers, as well as genes related to cell differentiation, proliferation, activation, and adhesion. Upregulation of genes associated with cell migration and trans-differentiation suggests a potential role for inflammation and cellular plasticity. Additionally, genes involved in inflammasome pathways, immunometabolism, and trained immunity were upregulated. Mechanistically, these genes were modulated by knockdown of trained immunity promoter SET-7, overexpression of trained immunity inhibitor IL-37, and knockout of inflammasome genes IL-1 receptor, caspase-1, and pattern recognition receptor CD36.ConclusionsThe finding underscore the potential role of trained immunity and cell trans-differentiation in AD, revealing a mechanistic framework in which danger-associated molecular patterns drive innate immune responses, inflammasome activation, and cell plasticity contribute to AD, offering therapeutic targets for neuroinflammation and cellular reprograming.
    Keywords:  Alzheimer's disease; amyloid-β; blood-brain barrier; cell trans-differentiation; trained immunity
    DOI:  https://doi.org/10.1177/13872877251329583
  5. Elife. 2025 Apr 15. pii: e105393. [Epub ahead of print]14
    Coevolutionary interplay: Helminths-trained immunity and its impact on the rise of inflammatory diseases.
    Eugenio Antonio Carrera Silva, Juliana Puyssegur, Andrea Emilse Errasti.
      The gut biome, a complex ecosystem of micro- and macro-organisms, plays a crucial role in human health. A disruption in this evolutive balance, particularly during early life, can lead to immune dysregulation and inflammatory disorders. 'Biome repletion' has emerged as a potential therapeutic approach, introducing live microbes or helminth-derived products to restore immune balance. While helminth therapy has shown some promise, significant challenges remain in optimizing clinical trials. Factors such as patient genetics, disease status, helminth species, and the optimal timing and dosage of their products or metabolites must be carefully considered to train the immune system effectively. We aim to discuss how helminths and their products induce trained immunity as prospective to treat inflammatory and autoimmune diseases. The molecular repertoire of helminth excretory/secretory products (ESPs), which includes proteins, peptides, lipids, and RNA-carrying extracellular vesicles (EVs), underscores their potential to modulate innate immune cells and hematopoietic stem cell precursors. Mimicking natural delivery mechanisms like synthetic exosomes could revolutionize EV-based therapies and optimizing production and delivery of ESP will be crucial for their translation into clinical applications. By deciphering and harnessing helminth-derived products' diverse modes of action, we can unleash their full therapeutic potential and pave the way for innovative treatments.
    Keywords:  ESPs; EVs; excretory/secretory products; extracelular vesicles; gut biome; helminths; immunology; inflammation; inflammatory disorders; trained immunity
    DOI:  https://doi.org/10.7554/eLife.105393
  6. Animals (Basel). 2025 Mar 30. pii: 997. [Epub ahead of print]15(7):
    Effects of Yeast β-Glucan Supplementation on Calf Intestinal and Respiratory Health.
    Jiamin Wang, Fang Yan, Meng Xiong, Jieru Dong, Wenqian Yang, Xiurong Xu.
      The physiological functions of newborn calves are undeveloped, especially the immune system, making them susceptible to infections. In recent years, the theory of trained immunity has attracted attention and provided new strategies to prevent unknown infections in animals. This study investigated the effects of feeding yeast β-glucan on the intestinal and respiratory health of calves during the suckling period. Newborn Holstein calves (average birth weight: 36.18 ± 0.61 kg, mean ± SE) were randomly assigned to two groups: the PO (Per Os) group (n = 22) and the CON (Control) group (n = 22). Calves in the PO group were fed a yeast β-glucan solution (0.1 g/mL, 65 mg/kg body weight) at 3 and 6 days of age, respectively, while calves in the CON group received equal volumes of sterile saline orally at the same time. Blood and fecal samples were collected at 7 and 30 days of age, respectively. The results showed that (1) Compared to the CON group, being fed yeast β-glucan resulted in an inflammatory response after 24 h of the second administration, including increased gene expression of interleukin-6 (IL-6, p < 0.01), interleukin-1 beta (IL-1β, p < 0.01), and malonaldehyde (MDA, p < 0.001) content. Also, stimulation with β-glucan increased the concentrations of secreted immunoglobulin A (sIgA, p < 0.01) and defensins (p < 0.05) in the rectal feces. (2) Pre-stimulation with yeast β-glucan effectively reduced the incidence of diarrhea (p < 0.05) and bovine respiratory disease (BRD, p < 0.05) from day 31 to day 60. (3) At 30 days of age, the pre-stimulated calves had significantly lower serum DAO (p < 0.001) and MDA levels (p < 0.05), while they had higher levels of serum IL-6 (p < 0.01) and fecal slgA (p < 0.05) than calves in the CON group. (4) Pre-stimulation with yeast β-glucan altered the intestinal bacterial community; the Beta diversity results showed that the CON group and the PO group were clustered separately in the principal coordinate analysis (PCoA) graph. Obviously, the PO group sample points were more clustered. In conclusion, this study highlights the potential of yeast β-glucan-induced trained immunity to improve calf health during the suckling period. The findings offer new insights into the prevention of intestinal and respiratory infections in calves.
    Keywords:  bovine respiratory disease; diarrhea; holstein cows; trained immunity; yeast β-glucan
    DOI:  https://doi.org/10.3390/ani15070997
  7. J Allergy Clin Immunol. 2025 Apr 14. pii: S0091-6749(25)00418-X. [Epub ahead of print]
    Innate immune reprogramming in circulating neutrophils of COPD patients.
    Barbara Mariotti, Chiara Bracaglia, Sara Gasperini, Giulia Sartori, Ernesto Crisafulli, Flavia Bazzoni.
       BACKGROUND: Chronic obstructive pulmonary disease (COPD) involves both local and systemic neutrophilic inflammation, with dysregulation in blood neutrophil numbers, frequencies, and functions.
    OBJECTIVE: To characterize the transcriptional and epigenetic profiles of circulating neutrophils in COPD patients and explore correlations with neutrophil dysfunction and clinical disease parameters.
    METHODS: Circulating neutrophils of COPD patients and control donors were subjected to RNA-sequencing (RNA-seq) and genome-wide analysis of histone 3 lysine 4 trimethylation (H3K4me3) by Chromatin Immunoprecipitation coupled with sequencing (ChIP-seq). Neutrophils' activation was assessed by cytofluorimetric analysis, O2- release and C. albicans phagocytosis assays.
    RESULTS: RNA-seq and ChIP-seq analysis of H3K4me3 revealed a poised state in genes involved in innate immune activation, resembling the phenotype observed in neutrophils from BCG-vaccinated individuals, referred to as "trained", that is marked by weak or no expression under resting conditions but ready to be expressed at higher levels upon stimulation. The epigenetic signature identified in neutrophils from BCG-vaccinated subjects was enriched in COPD neutrophils. In particular, and consistent with what has been described in "trained" neutrophils, COPD neutrophils exhibited transcriptional reprogramming of metabolically relevant genes. Functionally, COPD neutrophils produced higher CXCL8 and IL-1β levels, released more O2-, and displayed greater phagocytic activity upon in vitro stimulation.
    CONCLUSION: These findings suggest that COPD neutrophils undergo epigenetic, transcriptomic, and metabolic reprogramming, which enhances their responsiveness and aligns with the phenotype of neutrophils previously identified as "trained", offering mechanistic insight into the functional dysregulation observed in COPD.
    Keywords:  COPD; epigenetic; neutrophils; trained-immunity
    DOI:  https://doi.org/10.1016/j.jaci.2025.04.011
  8. Nat Immunol. 2025 Apr 18.
    Systemic inflammation impairs myelopoiesis and interferon type I responses in humans.
    Farid Keramati, Guus P Leijte, Niklas Bruse, Inge Grondman, Ehsan Habibi, Cristian Ruiz-Moreno, Wout Megchelenbrink, Annemieke M Peters van Ton, Hidde Heesakkers, Manita E Bremmers, Erinke van Grinsven, Kiki Tesselaar, Selma van Staveren, Walter J van der Velden, Frank W Preijers, Brigit Te Pas, Raoul van de Loop, Jelle Gerretsen, Mihai G Netea, Hendrik G Stunnenberg, Peter Pickkers, Matthijs Kox.
      Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory CD163+SLC39A8+CALR+ monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.
    DOI:  https://doi.org/10.1038/s41590-025-02136-4
  9. Cell Death Dis. 2025 Apr 13. 16(1): 284
    The role of heme in sepsis induced Kupffer cell PANoptosis and senescence.
    Tingting Li, Joseph Adams, Peilin Zhu, Tao Zhang, Fei Tu, Amy Gravitte, Xiaojin Zhang, Li Liu, Jared Casteel, Valentin Yakubenko, David L Williams, Chuanfu Li, Xiaohui Wang.
      Elevated heme levels, a consequence of hemolysis, are strongly associated with increased susceptibility to bacterial infections and adverse sepsis outcomes, particularly in older populations. However, the underlying mechanisms remain poorly understood. Using a cecal ligation and puncture (CLP) model of sepsis, we demonstrate that elevated heme levels correlate with Kupffer cell loss, increased bacterial burden, and heightened mortality. Mechanistically, we identify mitochondrial damage as a key driver of heme- and bacterial-induced Kupffer cell PANoptosis, a form of cell death integrating pyroptosis, apoptosis, and necroptosis, as well as cellular senescence. Specifically, heme activates phospholipase C gamma (PLC-γ), facilitating the translocation of cleaved gasdermin D (c-GSDMD) to mitochondria, resulting in GSDMD pore formation, mitochondrial dysfunction, and the release of mitochondrial DNA (mtDNA) during bacterial infection. This mitochondrial damage amplifies PANoptosis and triggers the cGAS-STING signaling pathway, further driving immune senescence. Notably, PLC-γ inhibition significantly reduces mitochondrial damage, cell death, and senescence caused by heme and bacterial infection. Furthermore, we show that hemopexin, a heme scavenger, effectively mitigates sepsis-induced Kupffer cell death and senescence, enhances bacterial clearance, and improves survival outcomes in both young and aged mice. These findings establish mitochondrial damage as a central mediator of heme induced Kupffer cell loss and highlight PLC-γ inhibition and hemopexin administration as promising therapeutic strategies for combating sepsis associated immune dysfunction.
    DOI:  https://doi.org/10.1038/s41419-025-07637-6
  10. Innate Immun. 2025 Jan-Dec;31:31 17534259251335770
    Lipopolysaccharide preconditioning augments the antibacterial activity of renal macrophages and ameliorates acute kidney injury caused by Staphylococcus aureus bacteremia in mice.
    Keiko Tanoue, Manabu Kinoshita, Bradley M Kearney, Seigo Ito, Hiroyasu Goto, Aoi Yamashiro, Tsugumi Fukunaga, Hiroki Sato, Kazuma Mori, Koji Kuwata, Hidehito Matsubara, Azusa Kato, Masahiro Nakashima, Hiroyuki Nakashima, Toshihiko Imakiire, Naoki Oshima.
      IntroductionRepeated injections of low-dose lipopolysaccharide (LPS preconditioning) augment the antibacterial activity of liver macrophages. In this study, a mouse model of acute kidney injury (AKI) induced by Staphylococcus aureus (S. aureus) bacteremia was used to investigate the effects of LPS preconditioning on renal macrophages.MethodsEight-week-old C57BL/6J mice were preconditioned with either low-dose LPS (5 μg/kg) or the vehicle for three consecutive days. Kidney immune cells were isolated, and the antibacterial activity of renal macrophages was assessed by pHrodoTM-labeled S. aureus in vitro. Twenty-four hours after the last LPS injection, the mice were intravenously challenged with S. aureus (2 × 107 CFU) and their renal function was evaluated to identify the changes.ResultsMouse renal macrophages exhibited a weak antibacterial activity against S. aureus compared with the liver and spleen macrophages. LPS preconditioning elevated the count of F4/80low CD11bhigh bone marrow-derived macrophages (BMDM) and augmented their antibacterial activities in the mouse kidney. It also enhanced the antibacterial activity of F4/80high CD11blow tissue-resident macrophages (TRM) without altering their abundance. LPS preconditioning lowered the bacterial propagation in the kidney in the challenged mice and ameliorated sepsis-associated AKI compared with the control. LPS preconditioning upregulated the CD80/CD206 expression (M1/M2) ratio in BMDMs in the kidney before bacterial challenge and reduced their M1/M2 ratio following S. aureus challenge compared with the control.ConclusionLPS preconditioning enhanced the antibacterial activity of the renal macrophages against S. aureus and suppressed the excessive activation of M1 macrophages following S. aureus challenge, resulting in the amelioration of AKI caused by S. aureus bacteremia.
    Keywords:  LPS preconditioning; S. aureus bacteremia-induced AKI; phagocytosis; renal macrophages; sepsis-associated AKI
    DOI:  https://doi.org/10.1177/17534259251335770
  11. Trends Immunol. 2025 Apr 18. pii: S1471-4906(25)00079-1. [Epub ahead of print]
    The five senses of immunity.
    Douglas F Nixon, Nathaniel D Bachtel, Nathaniel Hupert, Ioannis Eleftherianos.
      A genealogy of immunity reveals increasingly complex systems for pathogen response, organism homeostasis, and multispecies interaction. New studies show how the five senses can all contribute to behavioral, shared and population level immunity redefining our understanding of the ways organisms communicate among and defend themselves.
    DOI:  https://doi.org/10.1016/j.it.2025.03.005
  12. Front Immunol. 2025 ;16 1563484
    Oral and transdermal administration of lipopolysaccharide safely enhances self-healing ability through the macrophage network.
    Gen-Ichiro Soma, Masataka Oda, Vindy Tjendana Tjhin, Chie Kohchi, Hiroyuki Inagawa.
      Lipopolysaccharide (LPS), also known as an endotoxin, is derived from Gram-negative bacteria. The intravenous administration of LPS induces an inflammatory response and causes systemic inflammation, such as cytokine storm. Gram-negative bacteria that produce LPS are found in the environment and digestive tract. The mucous membrane, the primary barrier between the interior of the body and the external environment, is constantly exposed to LPS. Moreover, no toxicity is observed when administering LPS through the mucous membranes of the mouth or skin. The presence of LPS in the mucous membranes is necessary not only for maintaining health but also for inducing preventive and therapeutic effects against multiple diseases when administered orally or topically. LPS is an environmental substance that is useful when administered to mucous membranes. The general information emphasizes the role of LPS as an inflammatory substance that occurs when administered intravenously. Therefore, the valuable role of LPS is unknown. Thus, mucosal administration of LPS has received little attention, and the mechanism underlying the expression of its beneficial effects has not been fully elucidated. We proposed a comprehensive concept, the "macrophage network," which proposes a regulatory system in which the mucosa receives environmental information, membrane-bound cytokines are expressed in phagocytes (macrophages), and these macrophages migrate distally to exert effects, such as anti-inflammatory and tissue repair effects, on distal tissues through cell-to-cell communication (juxtacrine signaling) with tissue macrophages. This macrophage network is effective not only for preventing and treating diseases but also for increasing the efficacy of pharmaceuticals. This review aims to investigate the preventive and therapeutic effects of oral and transdermal administration of LPS on various diseases and present an introduction to the concept of the macrophage network and the latest findings.
    Keywords:  innate immunity; lipopolysaccharide; macrophage; macrophage network; self-healing ability
    DOI:  https://doi.org/10.3389/fimmu.2025.1563484
  13. Nat Metab. 2025 Apr 18.
    Itaconate modulates immune responses via inhibition of peroxiredoxin 5.
    Tomas Paulenda, Barbora Echalar, Lucie Potuckova, Veronika Vachova, Denis A Kleverov, Johannes Mehringer, Ekaterina Potekhina, Alex Jacoby, Devashish Sen, Chris Nelson, Rick Stegeman, Vladimir Sukhov, Danielle Kemper, Cheryl F Lichti, Nicholas J Day, Tong Zhang, Kamila Husarcikova, Monika Bambouskova, Daved H Fremont, Wei-Jun Qian, Sergej Djuranovic, Slavica Pavlovic-Djuranovic, Vsevolod V Belousov, Andrzej M Krezel, Maxim N Artyomov.
      The immunoregulatory metabolite itaconate accumulates in innate immune cells upon Toll-like receptor stimulation. In response to macrophage activation by lipopolysaccharide, itaconate inhibits inflammasome activation and boosts type I interferon signalling; however, the molecular mechanism of this immunoregulation remains unclear. Here, we show that the enhancement of type I interferon secretion by itaconate depends on the inhibition of peroxiredoxin 5 and on mitochondrial reactive oxygen species. We find that itaconate non-covalently inhibits peroxiredoxin 5, leading to the modulation of mitochondrial peroxide in activating macrophages. Through genetic manipulation, we confirm that peroxiredoxin 5 modulates type I interferon secretion in macrophages. The non-electrophilic itaconate mimetic 2-methylsuccinate inhibits peroxiredoxin 5 and phenocopies immunoregulatory action of itaconate on type I interferon and inflammasome activation, providing further support for a non-covalent inhibition of peroxiredoxin 5 by itaconate. Our work provides insight into the molecular mechanism of actions and biological rationale for the predominantly immune specification of itaconate.
    DOI:  https://doi.org/10.1038/s42255-025-01275-0
  14. bioRxiv. 2025 Apr 01. pii: 2025.03.27.645368. [Epub ahead of print]
    Macrophages maintain signaling fidelity in response to ligand mixtures.
    Xiaolu Guo, Supriya Sen, Julian Gonzalez, Alexander Hoffmann.
      As immune sentinel cells, macrophages are required to respond specifically to diverse immune threats and initiate appropriate immune responses. This stimulus-response specificity (SRS) is in part encoded in the signaling dynamics of the NFκB transcription factor. While experimental stimulus-response studies have typically focused on single defined ligands, in physiological contexts cells are exposed to multi-ligand mixtures. It remains unclear how macrophages combine multi-ligand information and whether they are able to maintain SRS in such complex exposure conditions. Here, we leveraged an established mathematical model that captures the heterogeneous single-cell NFκB responses of macrophage populations to extend experimental studies with systematic simulations of complex mixtures containing up to five ligands. Live-cell microscopy experiments for some conditions validated model predictions but revealed a discrepancy when TLR3 and TLR9 are stimulated. Refining the model suggested that the observed but unexpected ligand antagonism arises from a limited capacity for endosomal transport which is required for responses to CpG and pIC. With the updated model, we systematically analyzed SRS across all combinatorial-ligand conditions and employed three ways of quantifying SRS involving trajectory decomposition into informative trajectory features or machine learning. Our findings show that macrophages most effectively distinguish single-ligand stimuli, and distinguishability declines as more ligands are combined. However, even in complex combinatorial conditions, macrophages still maintain statistically significant distinguishability. These results indicate a robustness of innate immune response specificity: even in the context of complex exposure conditions, the NFκB temporal signaling code of macrophages can still classify immune threats to direct an appropriate response.
    Significance ≤120: Macrophages sense diverse pathogens within complex environments and respond appropriately. Experimental studies have found that the NFκB pathway responds with stimulus-specific dynamics when macrophages are exposed to single ligand stimuli. However, it remains unclear complex contexts might erode this stimulus-specificity. Here we systematically studies NFκB responses using a mathematical model that provides simulations of the heterogeneous population of single cell responses. We show that although the model is parameterized to single ligand data it can predict the responses to multi-ligand mixtures. Indeed, model validation uncovered signaling antagonism between two ligands and the underlying mechanism. Importantly, we found that NFκB signaling dynamics distinguish ligands within multi-ligand mixtures indicating a robustness of the NFκB temporal code that was not previously appreciated.
    DOI:  https://doi.org/10.1101/2025.03.27.645368
  15. Int J Mol Sci. 2025 Apr 02. pii: 3321. [Epub ahead of print]26(7):
    Mechanical Force Triggers Macrophage Pyroptosis and Sterile Inflammation by Disrupting Cellular Energy Metabolism.
    Hao Tan, Guoyin Yang, Ye Zhu, Xinyi He, Lan Yang, Yun Hu, Leilei Zheng.
      Mechanical force regulates tissue remodeling during orthodontic tooth movement (OTM) by inducing macrophage-mediated sterile inflammatory responses. Pyroptosis, as an inflammatory form of programmed cell death, triggers a robust inflammatory cascade by activating the inflammasome. Although recent reports have demonstrated that pyroptosis can be activated by mechanical force, it remains unclear whether and how orthodontic force induces macrophage pyroptosis and sterile inflammation. In this study, by establishing a rat OTM model and a force-loaded macrophage model, we found that force induces Caspase1-dependent pyroptosis in macrophages and activates sterile inflammation both in vivo and in vitro. Mechanistically, we uncovered that mechanical force disrupts macrophage energy metabolism, characterized by an imbalance between lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase (PDH), as well as mitochondrial dysfunction. Notably, inhibiting pyruvate dehydrogenase kinase 1 (PDK1) effectively restored this metabolic balance, thereby alleviating pyroptosis and sterile inflammation in force-stimulated macrophages. Overall, this study elucidates that force induces macrophage pyroptosis and sterile inflammation, and further identifies imbalances in the LDHA/PDH ratio and mitochondrial dysfunction as pivotal mechanistic features. These insights offer novel perspectives and potential therapeutic targets for the precise and effective modulation of OTM.
    Keywords:  energy metabolism; macrophage; mechanical force; orthodontic tooth movement; pyroptosis; sterile inflammation
    DOI:  https://doi.org/10.3390/ijms26073321
  16. Ann Emerg Med. 2025 Apr 15. pii: S0196-0644(25)00139-8. [Epub ahead of print]
    A Snapshot of National Institutes of Health Funding for Sepsis Research: 2019-2023.
    Joseph Morrison, Joshua Pei Le, Atul Malhotra, Shamim Nemati, Gabriel Wardi, James S Ford.
      
    Keywords:  NIH funding; Sepsis; Septic shock; Septicemia
    DOI:  https://doi.org/10.1016/j.annemergmed.2025.03.011
  17. J Immunol. 2025 Apr 18. pii: vkaf042. [Epub ahead of print]
    Innate immune sensor NLRP3 drives PANoptosome formation and PANoptosis.
    Bhesh Raj Sharma, Sk Mohiuddin Choudhury, Hadia M Abdelaal, Yaqiu Wang, Thirumala-Devi Kanneganti.
      Inflammasomes are multiprotein innate immune complexes formed in response to infections, tissue damage, or cellular stress that promote the maturation and release of IL-1β/IL-18 and are implicated in lytic cell death. The NLRP3 inflammasome is canonically activated by an initial priming event followed by an activation stimulus, leading to rapid cell death that occurs through caspase-1 (CASP1) and gasdermin D (GSDMD) activation, called pyroptosis. CASP1- and GSDMD-deficient cells are protected from the rapid LPS plus ATP-induced pyroptosis. However, innate immune responses physiologically occur over time, extending beyond minutes to hours and days. Therefore, in this study, we assessed lytic cell death beyond the early timepoints. While cells lacking the innate immune sensor NLRP3 were protected from cell death induced by the canonical NLRP3 trigger, LPS priming and ATP stimulation (LPS plus ATP), for extended time, CASP1- and GSDMD-deficient cells started to lyse in a time-dependent manner after 2 h. Nevertheless, robust IL-1β and IL-18 release was still dependent on CASP1 activation. These data suggested that NLRP3 engages an additional innate immune, lytic cell death pathway. Indeed, LPS plus ATP induced the activation of caspases and RIPKs associated with PANoptosis in WT cells, and cells deficient in PANoptosis machinery were protected from cell death for extended times. A PANoptosome complex containing NLRP3, ASC, CASP8, and RIPK3 was observed by microscopy in WT, as well as CASP1- or GSDMD-deficient, cells by 30 min post-stimulation. Overall, these findings highlight the central role of NLRP3 as a PANoptosome sensor. Given the physiological role of innate immune cell death, PANoptosis, in health and disease, our study emphasizes the importance of a comprehensive understanding of PANoptosomes, and their components, as therapeutic targets.
    Keywords:  PANoptosome; RIPK; caspase; inflammasome; inflammation
    DOI:  https://doi.org/10.1093/jimmun/vkaf042
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