bims-traimu 2025-08-31 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–08–31
seventeen papers selected by
Yantong Wan, Southern Medical University

Trained Immunity and Its Potential Implications in the Etiopathogenesis of Hidradenitis Suppurativa: A New Paradigm in Chronic Inflammation?
From "Traditional" to "Trained" Immunity: Exploring the Novel Frontiers of Immunopathogenesis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).
CpG-oligodeoxynucleotides challenged macrophages ameliorate acetaminophen induced liver injury by activating TLR9/IRG1/itaconate metabolic pathway.
Pre-stimulation of precision-cut bovine udder slices with zymosan before LPS exposure indicates aspects of trained immunity especially in the absence of FCS.
Metabolism-dependent succinylation governs resource allocation for antibiotic resistance.
Is postoperative cognitive dysfunction a disease of microglial inflammatory memory? A state-transition model from metabolic stress to epigenetic lock-in.
scIVNL-seq resolves in vivo single-cell RNA dynamics of immune cells during Salmonella infection.
Activation of aryl hydrocarbon receptor alleviates sepsis by promoting Nuclear Factor Erythroid 2-related Factor 2 expression to inhibit ferroptosis.
Variations in Innate Immune Cell Subtypes Correlate with Epigenetic Clocks, Inflammaging and Health Outcomes.
Biofilm-associated molecular patterns: BAMPs.
Unlocking immunity's memory: Epigenetic keys to HBV control.
Dietary saturated fatty acids promote lung myeloid cell inflammasome activation and IL-1β-mediated inflammation in mice and humans.
Lactate metabolic reprogramming and histone lactylation modification in sepsis.
Prolonged exposure to low-dose traffic-derived PM2.5 causes fatty liver disorder in mice.
A computational workflow for assessing drug effects on temporal signaling dynamics reveals robustness in stimulus-specific NFκB signaling.
Hepatocyte-Specific GSDMD Deficiency Aggravates Sepsis by Disrupting Non-Canonical Secretion of Anti-Inflammatory Factors.
In vitro and in vivo lipopolysaccharide-driven activation of human neutrophils in healthy volunteers as a tool for clinical drug development.

Exp Dermatol. 2025 Aug;34(8): e70160

Trained Immunity and Its Potential Implications in the Etiopathogenesis of Hidradenitis Suppurativa: A New Paradigm in Chronic Inflammation?

Annalisa Marcuzzi, Erika Rimondi, Giada Lodi, Marta Manfredini, Paola Maura Tricarico, Chiara Moltrasio, Angelo Valerio Marzano, Muhammad Suleman, Paola Secchiero, Elisabetta Melloni, Sergio Crovella.

  Hidradenitis suppurativa (HS) is a chronic auto-inflammatory skin disorder characterised by recurrent, painful nodules, abscesses and tunnels, often leading to tissue destruction with a significant impairment in quality of life. Despite advancements in understanding, HS remains a complex disease, whose exact pathogenesis is yet to be revealed. Nevertheless, the role of a dysregulated innate immune response has been established, potentially contributing to the persistent and chronic inflammation. Recent advances in immunology have highlighted the concept of trained immunity, a form of innate immune memory that may provide new insights into HS pathophysiology. Trained immunity is mediated by epigenetic and metabolic reprogramming of innate immune cells, enabling them to mount a heightened and prolonged inflammatory response upon subsequent stimuli, even in the absence of the original trigger. We hypothesize that trained immunity could contribute to the persistent inflammatory state, influencing HS progression and severity. Environmental and microbial factors may act as persistent stimuli, leading to activation of innate immune pathways. From a mechanistic perspective, trained immunity in HS might involve increased cytokine production, altered myeloid cell differentiation and persistent epigenetic modifications favouring a pro-inflammatory phenotype. Identifying specific molecular markers associated with trained immunity in HS could provide new diagnostic and prognostic tools and may open novel therapeutic avenues. By exploring the potential role of trained immunity in HS, we provide a new perspective on chronic inflammation, thus hypothesizing another actor involved in the aetiology/pathogenesis of this complex disease.

Keywords:  epigenetics; hidradenitis suppurativa; inflammation; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.1111/exd.70160
Biomedicines. 2025 Aug 18. pii: 2004. [Epub ahead of print]13(8):

From "Traditional" to "Trained" Immunity: Exploring the Novel Frontiers of Immunopathogenesis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Mario Romeo, Alessia Silvestrin, Giusy Senese, Fiammetta Di Nardo, Carmine Napolitano, Paolo Vaia, Annachiara Coppola, Pierluigi Federico, Marcello Dallio, Alessandro Federico.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic hepatopathy and a leading precursor of hepatocellular carcinoma (HCC) worldwide. Initially attributed to insulin resistance (IR)-driven metabolic imbalance, recent insights highlight a multifactorial pathogenesis involving oxidative stress (OS), chronic inflammation, and immune dysregulation. The hepatic accumulation of free fatty acids (FFAs) initiates mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, culminating in lipotoxic intermediates and mitochondrial DNA damage. These damage-associated molecular patterns (DAMPs), together with gut-derived pathogen-associated molecular patterns (PAMPs), activate innate immune cells and amplify cytokine-mediated inflammation. Kupffer cell activation further exacerbates OS, while ROS-induced transcriptional pathways perpetuate inflammatory gene expression. Traditional immunity refers to the well-established dichotomy of innate and adaptive immune responses, where innate immunity provides immediate but non-specific defense, and adaptive immunity offers long-lasting, antigen-specific protection. However, a paradigm shift has occurred with the recognition of trained immunity (TI)-an adaptive-like memory response within innate immune cells that enables enhanced responses upon re-exposure to stimuli. Following non-specific antigenic stimulation, TI induces durable epigenetic and metabolic reprogramming, leading to heightened inflammatory responses and altered functional phenotypes. These rewired cells acquire the capacity to produce lipid mediators, cytokines, and matrix-modifying enzymes, reinforcing hepatic inflammation and fibrogenesis. In this context, the concept of immunometabolism has gained prominence, linking metabolic rewiring with immune dysfunction. This literature review provides an up-to-date synthesis of emerging evidence on immunometabolism and trained immunity as pathogenic drivers in MASLD. We discuss their roles in the transition from hepatic steatosis to steatohepatitis, fibrosis, and cirrhosis, and explore their contribution to the initiation and progression of MASLD-related HCC. Understanding these processes may reveal novel immunometabolic targets for therapeutic intervention.

Keywords:  immunometabolism; inflammation; oxidative stress; trained immunity

DOI:  https://doi.org/10.3390/biomedicines13082004
Mol Med. 2025 Aug 25. 31(1): 282

CpG-oligodeoxynucleotides challenged macrophages ameliorate acetaminophen induced liver injury by activating TLR9/IRG1/itaconate metabolic pathway.

Yibai Qu, Zehui Jiang, Zhixia Chen, Sidan Luo, Bingyao Xie, Xubo Wu, Gang Yuan, Kan Wu, Li Chen, Tian Tian, Shan Li, Haihua Luo, Quan Li, Ding Yuan, Yan Zhang, Yanxia Gao, Jun Zhou, Zhengzheng Yan, Yong Jiang.

   BACKGROUND: Acetaminophen, or N-acetyl-para-aminophenol (APAP), causes severe liver damage and acute liver failure when overdosed. Oligodeoxynucleotides containing CpG motifs (CpG ODN) can regulate the function of macrophages, which play an important role in drug-induced liver injury. It is unclear whether CpG ODN-treated macrophages play an immune regulation role in APAP-induced liver injury. In the present study, we aim to explore the role of CpG ODN-activated macrophages in APAP-induced liver injury and the underlying mechanism in protecting against the cytotoxicity of APAP.
METHODS: In vivo, C57BL/6 mice were treated with APAP (300 mg/Kg) or/and CpG ODN (ODN 1826, 1.65 mg/Kg) by intraperitoneal injection, then survival rate, histopathological evaluation, and inflammatory factors were observed to ascertain the protective effect of CpG ODN. Then, CpG ODN-treated macrophages were reinfused into the animal model to determine the effector cells. In vitro, RNA sequencing and untargeted metabolomics detection were performed to illustrate the underlying mechanism. Last, Acod1 siRNA interference was used to clarify the role of IRG1 in resistance to APAP cytotoxicity by ROS and apoptosis indicator detections.
RESULTS: We found that CpG ODN showed a protective effect against APAP cytotoxicity by stimulating macrophages rather than hepatic parenchymal cells. In particular, reinfusion of CpG ODN-treated macrophages to mice can alleviate APAP-induced liver injury. Transcriptome and metabolome analysis revealed that the expression of aconitate decarboxylase 1 (Acod1; also known as immune responsive gene 1, IRG1) and the metabolite itaconate generated by IRG1 catalysis increased after CpG ODN stimulation. In addition, we found that the mechanism of this protective effect is ascribed to the increased expression of Acod1 and the antioxidative function of itaconate by the activation of the TLR9/NF-κB signaling pathway.
CONCLUSION: CpG ODN alleviated liver injury induced by APAP through the activation of the TLR9/NF-κB signaling pathway in macrophages, upregulating the expression of IRG1 protein, promoting the production of endogenous metabolite itaconate, and inhibiting macrophage apoptosis which was regulated by upregulating the expression of Nrf2 to inhibit ROS production. This study sheds new light on CpG ODN as a therapeutic strategy in resistance to APAP-induced liver injury.

Keywords:  Acetaminophen; IRG1; Itaconate; Liver injury; Macrophage apoptosis; Mitochondrial dysfunction

DOI:  https://doi.org/10.1186/s10020-025-01324-0
Innate Immun. 2025 Jan-Dec;31:31 17534259251360484

Pre-stimulation of precision-cut bovine udder slices with zymosan before LPS exposure indicates aspects of trained immunity especially in the absence of FCS.

Viviane Filor, Joanna Myslinska, Amitis Saliani, Jesmond Dalli, Peter Olinga, Wolfgang Bäumer, Dirk Werling.

  Mastitis in cattle poses a significant health challenge and results in substantial economic losses for the dairy industry. This study aimed to extend the existing precision-cut bovine udder slices (PCBUS) model as an in vitro model to explore the potential of inducing trained immunity in the udder with the goal to use the resulting knowledge for potential new treatment strategies. Interestingly, incubation of PCBUS with 10% fetal calf serum (FCS), but no 2% or FCS-free, negatively affected the production of some of the chemokines/cytokines analysed. When trained immunity was induced by zymosan, followed by stimulation with E. coli-derived lipopolysaccharide (LPS), production of interleukin (IL)-1β, IL-6, tumor necrosis factor α and interferon (IFNγ) was downregulated while production of IL-17A and pro-resolving lipid mediators (leukotrienes and prostaglandins) was upregulated. While the current experimental setup did not definitively confirm the induction of trained immunity for all parameters analysed in PCBUS, it validated the utility of PCBUS as a robust in vitro model for studying bovine udder inflammation. This model offers a promising platform for developing innovative mastitis treatments, particularly given the growing concern over antimicrobial resistance, as well as offering alternatives to the use of live animals in experimental studies in line with the 3Rs principles. It also provides a valuable tool for advancing our understanding of immune responses in the bovine udder. By adapting the precision-cut tissue slice technique to bovine udders, this model enables extensive research into new therapeutic approaches and supports basic research efforts to characterise complex pathophysiological processes associated with mastitis. Furthermore, our data highlight the potential limitations of FCS in in vitro studies. Our data should not only stimulate the discussion about FCS in homologues or heterologues species, but should also be kept in mind regarding the need for foetal calves to generate FCS in line with the 3Rs guideline.

Keywords:  Precision cut bovine udder slices; bovine mastitis; immune response; lipidomics; specialised pro-resolving mediators; trained immunity

DOI:  https://doi.org/10.1177/17534259251360484
Sci Adv. 2025 Aug 22. 11(34): eadu2856

Metabolism-dependent succinylation governs resource allocation for antibiotic resistance.

Jia-Han Wu, Xuan-Wei Chen, Ying-Li Liu, Jia-Yao Wu, Zhuang-Gui Chen, Bo Peng.

The mechanisms that organisms allocate resources to sustain biological phenotypes remain largely unknown. Here, we use mobilized colistin resistance (mcr-1), which modifies lipopolysaccharide (LPS) to confer colistin resistance, as a model to explore how bacteria reallocate resources to support mcr-1-mediated resistance. We show that bacteria redirect resources from glycolysis, the pyruvate cycle, and LPS biosynthesis toward glycerophospholipid metabolism to produce phosphatidylethanolamine, the substrate for mcr-1 to modify LPS, while reducing LPS content to limit colistin binding. This reallocation down-regulates succinyl-coenzyme A (CoA) to diminish succinylation of proteins including triosephosphate isomerase (TPI), CpxR, and PdhR, thereby sustaining resistance. Exogenous succinate or α-ketoglutarate restores succinylation in a succinyl-CoA-dependent manner. Succinylation of TPI redirects metabolic flux to glycolysis and the pyruvate cycle, while succinylation of CpxR and PdhR up-regulates LPS biosynthesis, ultimately attenuating colistin resistance. Thus, we reveal a previously unrecognized mechanism by which bacteria regulate resource allocation through metabolism-driven posttranslational protein modification, offering strategies to combat antibiotic resistance.

DOI: https://doi.org/10.1126/sciadv.adu2856
Front Mol Neurosci. 2025 ;18 1648161

Is postoperative cognitive dysfunction a disease of microglial inflammatory memory? A state-transition model from metabolic stress to epigenetic lock-in.

Xiangyu Wu, Tingye He, Fei He, Li Liu.

  Postoperative cognitive dysfunction (POCD) remains a significant challenge in perioperative medicine, especially among older adults. Despite its prevalence, existing models centered on transient neuroinflammation fail to explain why cognitive deficits often persist long after systemic immune responses resolve. This review proposes a new framework: POCD is driven not by ongoing inflammation, but by a stable shift in microglial identity. We describe a closed-loop "inflammatory memory circuit" in which mitochondrial dysfunction, chromatin remodeling, and persistent polarization co-evolve to lock microglia into a hypersensitive, neurotoxic state. Recent studies suggest that surgical trauma triggers mitochondrial damage and mtDNA release, initiating innate immune activation via the cGAS-STING and NLRP3 pathways. These events engage epigenetic machinery-including HDAC3, DNMT3a, and long non-coding RNAs like MEG3-which reinforce transcriptional programs that lower activation thresholds and amplify cytokine output. Sustained M1-like polarization further propagates this loop, driving neuronal injury even in the absence of continued systemic cues. We outline experimental strategies to validate this model, including time-resolved single-cell transcriptomics and chromatin accessibility profiling. Therapeutically, we highlight HDAC inhibitors, SIRT1 agonists, and lncRNA-targeted interventions as potential strategies to disrupt the circuit before state-locking occurs. By reframing POCD as a glial fate transition rather than a transient immune reaction, this model offers mechanistic clarity and opens a path toward time-sensitive, precision interventions.

Keywords:  epigenetic reprogramming; microglial inflammatory memory; mitochondrial dysfunction; neuroimmune plasticity; postoperative cognitive dysfunction

DOI:  https://doi.org/10.3389/fnmol.2025.1648161
Nat Commun. 2025 Aug 26. 16(1): 7937

scIVNL-seq resolves in vivo single-cell RNA dynamics of immune cells during Salmonella infection.

Zhen Xiong, Runyuan Wu, Yuanxin Wang, Yuwei Xu, Cunzhen Li, Deyuan Kong, Ziqi Xiao, Peikang Zhang, Zhonglong Wang, Peng Zhang, Ying Du, Hui Guo, Pingping Zhu, Shunmin He, Zusen Fan.

The immune response against pathogens involves multiple cell state transitions and complex gene expression changes. Here, we establish a single-cell in vivo new RNA labeling sequencing method (scIVNL-seq) and apply it to survey time-resolved RNA dynamics during immune response to acute enteric infection with Salmonella. We show that the detection of new RNA synthesis reflects more realistic information on cell activation and gene transcription than total RNA level. Interplay of RNA synthesis and degradation modulates the dynamics of total RNA. The bone marrow macrophages are first primed at a very early stage upon Salmonella infection. In contrast, the innate immune response of macrophages in intestine is limited. Notably, intestinal CD8+ T cells and plasma cells are rapidly and specifically activated at the early stage post infection. Intestinal late enterocytes quickly express MHC-I molecules and present Salmonella antigen to CD8+ T cells for their activation, serving as antigen presenting cells for the initiation of adaptive immunity. Our findings reveal the RNA control strategies and the dynamic activation rules of immune cells in response to Salmonella infection, challenging the doctrine boundary between innate immunity and adaptive immunity against bacterial infection.

DOI: https://doi.org/10.1038/s41467-025-63155-1
Am J Med Sci. 2025 Aug 19. pii: S0002-9629(25)01149-8. [Epub ahead of print]

Activation of aryl hydrocarbon receptor alleviates sepsis by promoting Nuclear Factor Erythroid 2-related Factor 2 expression to inhibit ferroptosis.

Hongxuan Liu, Meixia Yang, Zhiyong Zhao, Hongqing Zhang, Chunyan Gao, Liqiong Guo.

   BACKGROUND: Sepsis-induced acute kidney injury (AKI) is a major global public health challenge. Key pathogenic mechanisms include inflammatory responses and renal tubular epithelial cell damage. The aryl hydrocarbon receptor (AhR), a widely expressed protein receptor, has been reported to alleviate AKI upon activation; however, its precise mechanisms remain unclear.
METHODS: Lipopolysaccharide (LPS) was used to establish sepsis-induced AKI models in vivo and in vitro. Protein expression was analyzed by western blotting, and histological staining was performed to assess tissue injury.
RESULTS: AhR activation significantly attenuated LPS-induced AKI and reduced cell death following treatment with the AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ). Mechanistically, FICZ decreased renal accumulation of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and Fe²⁺, while upregulating glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression. Furthermore, FICZ promoted AhR nuclear translocation, which subsequently enhanced nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation and expression, ultimately mitigating LPS-induced cellular ferroptosis.
CONCLUSIONS: This study demonstrates that AhR activation enhances NRF2 nuclear translocation and expression, thereby upregulating GPX4 and SLC7A11. This mechanism reduces intracellular lipid peroxide accumulation and suppresses ferroptosis, providing potential therapeutic targets for AKI treatment and translational research.

Keywords:  AhR; NRF2; Sepsis-induced acute kidney injury; ferroptosis

DOI:  https://doi.org/10.1016/j.amjms.2025.08.013
Adv Sci (Weinh). 2025 Aug 27. e05922

Variations in Innate Immune Cell Subtypes Correlate with Epigenetic Clocks, Inflammaging and Health Outcomes.

Xiaolong Guo, Josephine A Robertson, Andrea Aparicio, Kirsten Seale, Qingwen Chen, Anne Richmond, Zhaozhen Du, Mahnoor Sulaiman, Shijie C Zheng, Esteban Ballestar, Charlotte Am Cecil, Bastiaan T Heijmans, Steve Horvath, Varun B Dwaraka, Jessica Lasky-Su, Ryan Smith, Riccardo E Marioni, Andrew E Teschendorff.

  Epigenetic clocks in blood have shown promise as tools to quantify biological age, displaying robust associations with morbidity and all-cause mortality. Whilst the effect of cell-type heterogeneity on epigenetic clock estimates has been explored, such studies have been limited to studying heterogeneity within the adaptive immune system. Much less is known about whether heterogeneity within the innate immune system can impact epigenetic clock estimates and their associations with health outcomes. Here, we apply a high-resolution DNAm reference panel of 19 immune cell-types, including young and adult monocyte, natural killer, and neutrophil subsets, demonstrating how shifts within these innate subtypes display associations with epigenetic clock acceleration, inflammaging, and all-cause mortality. The associations of monocyte heterogeneity with inflammation are further validated using transcriptomic and metabolomic data. Additionally, a non-negligible fraction of nucleated red blood cell-like cells in circulation is found to associate with inflammaging, markers of dysfunctional erythropoiesis, and is a major risk factor for all-cause mortality. These results extend findings obtained within the adaptive immune system to innate immune and erythrocyte-like cells, demonstrating how heterogeneity within these other blood cell compartments is also associated with inflammaging, epigenetic clocks, and health outcomes.

Keywords:  DNA methylation; aging Biomarkers; epigenetic clocks; health outcomes; inflammaging; innate immune system

DOI:  https://doi.org/10.1002/advs.202505922
Infect Immun. 2025 Aug 21. e0030425

Biofilm-associated molecular patterns: BAMPs.

Peter Østrup Jensen, Morten Rybtke, Tim Tolker-Nielsen.

  Chronic infections involving bacterial biofilms are a major clinical challenge due to the ability of biofilm to resist antimicrobial treatments and host immune responses. The resulting persistent infections are often accompanied by collateral damage mainly executed by activated components of the innate immune system in response to the infectious biofilm. The innate immune system responds to the recognition of pathogen-associated molecular patterns (PAMPs), which are broadly expressed by both planktonic and biofilm-forming bacteria. However, the expression of special PAMPs in association with biofilms remains poorly defined. Here, we review prior studies that provide experimental evidence of the existence of immune-activating molecular patterns that are expressed at immunostimulatory levels in biofilms but not in planktonic bacteria. Accordingly, we introduce the concept of biofilm-associated molecular patterns (BAMPs) as a subset of PAMPs that are expressed in biofilms. Identifying BAMPs and elucidating their role in innate immune activation may inform the development of targeted therapies to reduce collateral tissue damage in biofilm-associated infections.

Keywords:  BAMPs; biofilm; infection; innate immune response

DOI:  https://doi.org/10.1128/iai.00304-25
Hepatology. 2025 Sep 01. 82(3): 547-548

Unlocking immunity's memory: Epigenetic keys to HBV control.

Brett M McGettigan.

DOI: https://doi.org/10.1097/HEP.0000000000001455
Sci Transl Med. 2025 Aug 27. 17(813): eadp5653

Dietary saturated fatty acids promote lung myeloid cell inflammasome activation and IL-1β-mediated inflammation in mice and humans.

Sam J McCright, Olivia Harding, Julia Chini, Nicole DeMarco, Li-Yin Hung, Christopher F Pastore, Wenyun Lu, Joshua Rabinowitz, Jorge Henao-Mejia, De'Broski R Herbert, Lisa R Young, David A Hill.

Resident tissue macrophages and monocytes (RTMs) integrate local and systemic signals to coordinate immune cell function at homeostasis and in response to inflammatory stimuli. Obesity-associated metabolic dysfunction drives the development of RTM populations that contribute to disease states in multiple tissues. However, the contribution of specific dietary components to innate immune cell activation and function, as opposed to the direct effects of obesity, is largely unknown. Here, we studied the mechanisms by which high-fat (HF) diets shape lung RTM phenotype and function at steady state and influence responses to inflammatory insults. We found that, during HF diet feeding, lung RTMs accumulate saturated long-chain fatty acids, specifically stearic acid (SA), and demonstrate features of NLRP3 inflammasome priming and activation. In vivo, increased dietary SA was sufficient to cause neutrophil-predominant lung inflammation in the steady state and exacerbate a model of innate airway inflammation, whereas increased dietary oleic acid, the monounsaturated counterpart of SA, was sufficient to reduce inflammasome activation in the steady state and attenuate airway inflammation. Depletion of interleukin-1β (IL-1β) or pharmacologic inhibition of the endonuclease inositol requiring enzyme 1α (IRE1α) protected against SA-induced exacerbated lung inflammation. Last, we identified a population of lung monocytes with hallmarks of HF diet-induced RTM activation that were present in samples from obese humans with asthma. Together, these results identify a class of dietary lipids that regulate lung RTM phenotype and function in the steady state and modulate the severity of inflammation in the lung.

DOI: https://doi.org/10.1126/scitranslmed.adp5653
Int J Biol Sci. 2025 ;21(11): 5034-5055

Lactate metabolic reprogramming and histone lactylation modification in sepsis.

Ji Zhang, Dan Wu, Fu Zeng, Haiyun Gu, Chengbao Li, Juan P Cata, Kefang Guo, Changhong Miao, Hao Zhang.

  Sepsis, a serious condition characterized by life-threatening organ dysfunction owing to infection, lacks specific therapeutic interventions. Lactate serves as a crucial biomarker in sepsis, reflecting both the patient's metabolic state and the severity of the condition. Lactylation, the process whereby lactate is conjugated to lysine residues in proteins, profoundly alters protein structure and function. This review delves into the crucial roles of lactate and lactylation within the septic environment, illuminating the intricate feedback loop between metabolic reprogramming and lactylation in sepsis. Herein, fluctuations in lactate levels influence patterns of lactylation, which subsequently regulate energy metabolism. Lactylation is essential for modulating immune responses, adjusting gene expression profiles in immune cells, and shifting the balance between pro-inflammatory and anti-inflammatory pathways. The discovery of these pathways has significant implications for development of targeted therapies against sepsis. Furthermore, this review addresses the advancements and current limitations associated with lactylation research methodologies, and proposes new directions for future research. Overall, this narrative underscores the transformative potential of lactylation in understanding and managing sepsis, advocating for a multidisciplinary approach to unravel the complex interplay between metabolic processes and epigenetic regulation in critical illnesses.

Keywords:  inflammation; lactylation; sepsis; therapeutic targets

DOI:  https://doi.org/10.7150/ijbs.116088
J Environ Sci (China). 2025 Dec;pii: S1001-0742(25)00032-4. [Epub ahead of print]158 621-632

Prolonged exposure to low-dose traffic-derived PM2.5 causes fatty liver disorder in mice.

Min Feng, Matthew P Padula, Sara Al Asaad, Xu Bai, Charles Cranfield, Stephanie El Town, Sonia Saad, Brian G Oliver, Jacob George, Hui Chen.

  There is no safe level of exposure to air pollution, including particulate matter smaller than 2.5 µm (PM2.5), to human health. Whilst it is well known that exposure to heavily polluted air is associated with several liver disorders, it is unclear how long-term exposure to low-level traffic-derived PM2.5 affects liver health. BALB/c mice (5 weeks, male) were exposed to traffic-derived PM2.5 (10 µg/mouse/day, intranasally) daily for 4, 8 and 12 weeks. Markers of inflammation and fibrosis were measured at each time point. Changes in liver proteome and lipid profiles were measured using proteomics and lipidomics at 12 weeks. Low-dose PM2.5 exposure increased macrophage infiltration, pro-inflammatory cytokine production, and increased collagen deposition at 12 weeks. Despite liver lipid metabolism being increased, the abundance of triglycerides, precursor diacylglycerols, and ceramide was also significantly increased by PM2.5 exposure, whereas glycogen content was reduced. Proteomics analysis revealed 64 proteins to be significantly changed in PM2.5-exposed mice, and KEGG pathway enrichment analysis indicated their involvement in lipid metabolism, alcohol-related liver disease, neutrophil extracellular trap formation, and transcriptional dysregulation related to cancer. In conclusion, prolonged exposure to low-dose traffic-derived PM2.5 promotes pathological changes in the liver, suggestive of an increased risk of metabolic dysfunction-associated fatty liver disease. Future studies can enable the identification of the signalling pathways underlying low-dose PM2.5-induced lipid accumulation in the liver.

Keywords:  Fibrosis; Inflammation; Lipidomics; Metabolic dysfunction-associated fatty liver disease; Proteomics

DOI:  https://doi.org/10.1016/j.jes.2025.01.025
PLoS Comput Biol. 2025 Aug;21(8): e1013344

A computational workflow for assessing drug effects on temporal signaling dynamics reveals robustness in stimulus-specific NFκB signaling.

Emily R Bozich, Xiaolu Guo, Jennifer L Wilson, Alexander Hoffmann.

Single-cell studies of signal transduction have revealed complex temporal dynamics that determine downstream biological function. For example, the stimulus-specific dynamics of the transcription factor NFκB specify stimulus-specific gene expression programs, and loss of specificity leads to disease. Thus, it is intriguing to consider drugs that may restore signaling specificity in disease contexts, or reduce activity but maintain signaling specificity to avoid unwanted side effects. However, while steady-state dose-response relationships have been the focus of pharmacological studies, there are no established methods for quantifying drug impact on stimulus-response signaling dynamics. Here we evaluated how drug treatments affect the stimulus-specificity of NFκB activation dynamics and its ability to accurately code ligand identity and dose. Specifically, we simulated the dynamic NFκB trajectories in response to 15 stimuli representing various immune threats under treatment of 10 representative drugs across 20 dosage levels. To quantify the effects on coding capacity, we introduced a Stimulus Response Specificity (SRS) score and a stimulus confusion score. We constructed stimulus confusion maps by employing epsilon network clustering in the trajectory space and in various dimensionally reduced spaces: canonical polyadic decomposition (CPD), functional principal component analysis (fPCA), and NFκB signaling codons (i.e., established, informative dynamic features). Our results indicated that the SRS score and the stimulus confusion map based on signaling codons are best-suited to quantify stimulus-specific NFκB dynamics confusion under pharmacological perturbations. Using these tools we found that temporal coding capacity of the NFκB signaling network is generally robust to a variety of pharmacological perturbations, thereby enabling the targeting of stimulus-specific dynamics without causing broad side-effects.

DOI: https://doi.org/10.1371/journal.pcbi.1013344
Adv Sci (Weinh). 2025 Aug 26. e10412

Hepatocyte-Specific GSDMD Deficiency Aggravates Sepsis by Disrupting Non-Canonical Secretion of Anti-Inflammatory Factors.

Yihan Qian, Bingrui Wang, Chang Yu, Yuge Zhou, Weifan Huang, Xing Rong, Yali Sang, Jiangang Song, Hailong Wu, Xiaoni Kong.

  Gasdermin D (GSDMD)-mediated pyroptosis in macrophages plays a clear role in promoting inflammation and mortality in sepsis. The liver is a commonly damaged organ during sepsis and also an important organ for releasing acute response proteins. However, whether pyroptosis occurs and the function of GSDMD in hepatocytes remains unclear. It is surprising to find that hepatocyte-specific GSDMD knockout (GSDMDhep-/-) mice have significantly reduced survival rates, markedly elevated systemic inflammation, and increased inflammation in the peritoneal cavity and lungs, suggesting that the absence of GSDMD in hepatocytes promotes systemic inflammatory responses. Serum proteomic analysis shows that anti-inflammatory factors such as VEGF-B and Gremlin-1 are significantly reduced in GSDMDhep-/- mice. Through in vitro and in vivo experiments combined with a constructed full-length GSDMD and a mutant GSDMD plasmid (GSDMD-c.D276A) that cannot be cleaved, VEGF-B and Gremlin-1 are verified to be released from hepatocytes through the pore-forming activity of GSDMD, thus inhibiting the production of inflammatory factors by macrophages. More importantly, hepatocyte-specific replenishment of full-length GSDMD can reverse the exacerbated inflammatory response in GSDMDhep-/- mice. These findings together establish that hepatic GSDMD plays a key protective role in sepsis by promoting the release of anti-inflammatory factors through pore formation in hepatocytes.

Keywords:  anti‐inflammatory factors; gasdermin D; hepatocyte; macrophage; sepsis

DOI:  https://doi.org/10.1002/advs.202510412
J Immunol Methods. 2025 Aug 25. pii: S0022-1759(25)00168-1. [Epub ahead of print] 113968

In vitro and in vivo lipopolysaccharide-driven activation of human neutrophils in healthy volunteers as a tool for clinical drug development.

Hendrika W Grievink, Coen Breedveld, John Öhd, Mark Schoonderwoerd, Hjalmar P Permentier, Amanda C Foks, Ilze Bot, Elsa Neubert, Matthijs Moerland.

  Neutrophils are an emerging target for therapeutical intervention in both autoimmune diseases as well as cancer. Since healthy humans lack constitutive neutrophil activation, induction of neutrophil activation is necessary to evaluate investigational compounds and can be achieved via intravenous administration of lipopolysaccharides (LPS). Furthermore, LPS stimulation can be performed ex vivo during clinical trials, and in vitro for pre-clinical analysis. Therefore, we aimed to provide a time course of neutrophil responses after in vivo LPS administration using samples from human endotoxemia trials and compared this to in vitro LPS stimulated whole blood cultures. We performed shotgun proteomics on in vivo stimulated neutrophils, and measured neutrophil activation by flow cytometry using CD11b and CD62L as activation markers and elastase, MPO, LL37 and nucleosome levels as degranulation and NETosis markers. Neutrophil numbers rapidly increased after LPS administration. In line, we found significant increases in neutrophil activation and degranulation markers both in vitro as well as in vivo, which all returned to baseline within 24 h. Degranulation proteins and NETosis related nucleosomes rapidly increased after LPS administration (1 h after exposure) in vivo, while higher concentrations of LPS were necessary in vitro. Lastly, shotgun proteomics revealed little but significant differences in the neutrophil proteome after in vivo LPS administration, pointing to degranulation after LPS stimulation. Both, the in vitro whole blood LPS stimulation assay and the human endotoxemia model, could be valuable tools for evaluation of the effects of future drugs modulating neutrophil responses during preclinical and clinical development.

Keywords:  Flow cytometry NETosis; Lipopolysaccharides; Neutrophils

DOI:  https://doi.org/10.1016/j.jim.2025.113968