bims-traimu 2026-07-19 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–07–19
sixteen papers selected by
Yantong Wan, Southern Medical University

Innate Immune Memory Responses in Organ Transplantation.
A core transcriptional signature of human trained immunity.
Trained immunity: An unexplored component of IBD pathogenesis.
Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.
Microglial Epigenetic Memory is Associated with Accelerated Resolution of Inflammatory Pain Induced by Prophylactic Macrophage-Derived Small Extracellular Vesicles.
BCG in the fight against cancer: exploring its applications in diverse tumour types and future directions.
Diabetic cardiomyopathy: Target immune cell from mechanism to treatment.
Emerging insights into inflammation-driven atherosclerosis: immune cell mechanisms.
RXRα suppression drives hepatic metabolic and immune dysfunction in sepsis.
Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
Transcriptomic profiling reveals transcriptomic remodeling linked to inflammatory activation and cell cycle-related gene expression in the early hours of macrophage activation.
Alterations of the host-lung microbiome metasystem in systemic inflammatory response syndrome is associated with secondary pneumonia.
CXCL10/SLC11A1 Axis Exacerbates Septic Liver Injury by Regulating Neutrophil Extracellular Traps Formation to Drive Macrophage Pro‑Inflammatory Polarization.
Propofol Inhibits Neutrophil Extracellular Traps Formation and Alleviates Sepsis-Induced Acute Lung Injury.
Optimized strategies for necroptosis induction and evaluation.
Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.

Arterioscler Thromb Vasc Biol. 2026 Jul 16.

Innate Immune Memory Responses in Organ Transplantation.

Lisanne C de Jong, Nils Rother, Raphaël Duivenvoorden.

  Innate immunity is a critical contributor to graft rejection and cardiovascular complications after organ transplantation, with increasing evidence indicating that innate immune memory significantly influences graft outcomes. The most extensively studied form, trained immunity, involves epigenetic and metabolic reprogramming of innate immune cells, altering their inflammatory responsiveness. Numerous transplantation-related factors, including metabolic disturbances such as hypercholesterolemia and hyperglycemia, can induce trained immunity, and both experimental and clinical studies have linked it to graft survival. Although trained immunity reflects responses to nonspecific stimuli, innate allogeneic memory shows that innate immune cells can recognize nonself and mount donor-specific memory responses. This review covers the current knowledge on both forms of innate immune memory in the context of solid organ transplantation.

Keywords:  epigenesis, genetic; graft rejection; graft survival; organ transplantation; trained immunity

DOI:  https://doi.org/10.1161/ATVBAHA.125.323925
Cell Rep. 2026 Jul 15. pii: S2211-1247(26)00768-0. [Epub ahead of print]45(7): 117690

A core transcriptional signature of human trained immunity.

Katherine A Boden, Tafadzwa T J Kufazvinei, Jason Chai, Shreyas Adhikari, Injung Jang, Naveed Akbar, Robin P Choudhury.

  "Trained immunity" describes long-term functional reprogramming of innate immune cells that enhances responses to secondary challenge. However, the extent to which diverse training stimuli converge on shared transcriptional programs remains unclear. Here, we systematically analyzed publicly available RNA-sequencing datasets from diverse human trained-immunity models to define both baseline and restimulated responses of trained cells. Cross-dataset comparisons identified shared transcriptional and functional programs, indicative of common baseline and trained immune states. By integrating gene-expression data across models, we derived a consensus signature of human trained-immunity, which was validated in independent bulk and single-cell datasets. Enrichment analyses showed activation of pro-inflammatory and metabolic programs, including modulation of cellular iron homeostasis and robust increases in chemokine CCL7 expression, alongside suppression of anti-inflammatory, resolution-associated genes. These findings indicate that diverse training stimuli converge on core, shared gene-expression programs and support a two-layer model in which durable baseline reprogramming precedes exaggerated inflammatory responses upon restimulation.

Keywords:  CP: immunology; RNA-sequencing; gene signature; innate immune memory; trained immunity; transcriptional signature

DOI:  https://doi.org/10.1016/j.celrep.2026.117690
Inflamm Bowel Dis. 2026 Jul 17. pii: izag119. [Epub ahead of print]

Trained immunity: An unexplored component of IBD pathogenesis.

Michael Doulberis, Stergios A Polyzos, Abbas Yadegar, Jannis Kountouras.

  Trained immunity (TI) describes the capability of the innate immune system and its tissue-resident cells to acquire long-lasting functional adaptations following an initial inflammatory or microbial insult. These changes are maintained through coordinated immunometabolic rewiring and epigenetic remodeling, resulting in amplified or altered responses upon subsequent challenges. Inflammatory bowel disease (IBD) is a chronic, relapsing disorder of the gastrointestinal tract, and TI offers a useful framework for understanding disease persistence, relapse proneness, and incomplete resolution despite effective targeting of adaptive immune pathways. While TI has been extensively studies in various chronic inflammatory disorders, its role in IBD remains rather underexplored and largely confined to early preclinical evidence. Within this narrative review, we aim to address this gap by providing current insights into the potential pathogenetic mechanisms underpinning TI in IBD. We examine how the shaping of the behavior of monocytes, macrophages, and their bone marrow progenitors and how steady exposure to microbial ligands, dysbiotic metabolites, and metabolic stressors within the intestinal lumen may establish a sustained proinflammatory "memory" in the context of IBD. From a translational perspective, we consider how TI may favor relapse even during clinical remission and discuss its potential relevance for patient stratification, biomarker identification, and the development of novel therapeutic strategies. Ultimately, integration of TI into IBD pathophysiology may corroborate more lasting, mechanism-based approaches to remission.

Keywords:  Crohn’s disease; IBD; inflammatory bowel disease; innate immunity; trained immunity; ulcerative colitis

DOI:  https://doi.org/10.1093/ibd/izag119
Nat Aging. 2026 Jul 16.

Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.

Wei-Chieh Mu, Marine Barthez, Yufan Feng, Yibing Chen, Chih Ling Wang, Jing-Yi Huang, Jie Li, Paul Lanhart, Clair Tsui, Yang Joon Kim, Eric Verdin, Mihai G Netea, Danica Chen.

Trained immunity is a state of heightened immune response that is initiated in hematopoietic stem cells (HSCs) and mediated mainly by their myeloid progeny. Aging-associated inflammation drives many aging-related diseases, yet its biological origin is largely unknown. Here we show that SIRT3, a mitochondrial deacetylase highly expressed in HSCs but reduced during aging, suppresses the HSC response to aging that drives maladaptive trained immunity, chronic inflammation and tissue functional decline in mice. Overexpression of SIRT3 in HSCs not only ameliorates aging-associated HSC decline, but also improves the function of distant tissues, including attenuation of age-related declines in cognition and motility, via myeloid cells with modulated inflammatory programs. These findings reveal that HSC aging is a driver of aging-associated inflammation through maladaptive trained immunity and broaden the possible clinical applications of targeting HSCs from hematological diseases to include countering aging-associated physiological decline and improving healthspan.

DOI: https://doi.org/10.1038/s43587-026-01175-2
J Inflamm Res. 2026 ;19 598095

Microglial Epigenetic Memory is Associated with Accelerated Resolution of Inflammatory Pain Induced by Prophylactic Macrophage-Derived Small Extracellular Vesicles.

Xuan Luo, Jason R Wickman, Jason T DaCunza, Yuzhen Tian, Ahmet Sacan, Seena K Ajit.

   Introduction: Small extracellular vesicles (sEVs) are cell-released lipid vesicles that facilitate intercellular communication by transferring bioactive cargo to recipient cells. We previously showed that a single intrathecal administration of RAW 264.7 macrophage-derived sEVs, given two weeks prior to complete Freund's adjuvant (CFA)-induced inflammation, resulted in earlier recovery from mechanical and thermal hypersensitivity. How this long-term memory develops, and how sEVs regulate immune responses, are unknown. Recent studies have shown that priming microglia with inflammatory stimuli can enhance or suppress responses to a delayed secondary insult via epigenetic modifications. We hypothesized that prophylactic intrathecal administration of macrophage-derived sEVs confers accelerated resolution of inflammatory pain by reprogramming epigenetic memory in spinal microglia.
Methods: Microglia were ablated using the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 prior to sEV administration. Pain behaviors were assessed following CFA-induced inflammation. Chromatin immunoprecipitation sequencing (ChIP-seq) was performed on spinal microglia isolated 14 days after sEV administration. The role of epigenetic modification was evaluated by pharmacological inhibition of the H3K4 mono-methyltransferase SETD7.
Results: Prophylactic sEV administration accelerated the resolution of inflammatory pain hypersensitivity. This effect was abolished in mice treated with PLX5622, indicating that microglia are required during sEV exposure. ChIP-seq analysis revealed enrichment of H3K4me1-marked loci in spinal microglia 14 days after sEV administration, consistent with induction of innate immune memory. Inhibition of SETD7 eliminated the protective effect of sEVs, demonstrating a requirement for H3K4 mono-methylation.
Discussion: Macrophage-derived sEVs induce a microglia-dependent, epigenetically mediated form of pain prophylaxis. These findings support a model in which sEVs establish a primed, memory-like state in spinal microglia, characterized by enhancer-associated chromatin changes that confer latent regulatory potential and enhance resolution of subsequent inflammatory pain. This work links extracellular vesicles to microglial epigenetic remodeling and suggests a potential strategy for non-addictive, preventive pain therapeutics.

Keywords:  H3K4me1; SETD7; epigenetics; exosomes; extracellular vesicles; inflammatory pain; microglia

DOI:  https://doi.org/10.2147/JIR.S598095
Ecancermedicalscience. 2026 ;20 2142

BCG in the fight against cancer: exploring its applications in diverse tumour types and future directions.

P Ignacio A Bianco, O Jeismar M Carballo, P Isaac R Blanca, Ana Federica Convit.

  Bacillus Calmette-Guérin (BCG), originally a tuberculosis vaccine, is a standard immunotherapy for non-muscle-invasive bladder cancer (NMIBC). This review summarises BCG biology, including trained immunity, and evaluates clinical and translational evidence for BCG across solid tumours. We aim to distinguish guideline-supported indications from investigational uses and identify contexts where BCG may remain clinically relevant or trial-ready. Evidence is strongest in NMIBC, where outcomes depend on induction plus maintenance schedules and appropriate patient selection. Outside the bladder, intralesional and vaccine-adjuvant approaches show signals in selected melanoma and vaccine settings, while historical lung and colorectal trials largely failed to translate into durable benefit. Emerging preclinical work in hepatocellular carcinoma and breast cancer suggests potential synergy with modern immunotherapy strategies. BCG should be framed as a platform immunomodulator whose value beyond NMIBC requires mechanism-guided trials, clear safety boundaries and clinically anchored endpoints.

Keywords:  Bacillus Calmette Guérin vaccine; cancer vaccines; immunotherapy; intralesional injections; trained immunity; urinary bladder neoplasms

DOI:  https://doi.org/10.3332/ecancer.2026.2142
Int Immunopharmacol. 2026 Jul 17. pii: S1567-5769(26)00962-8. [Epub ahead of print]186 117116

Diabetic cardiomyopathy: Target immune cell from mechanism to treatment.

Jingyi Lv, Xiaoyi Bao, Xiaolu Jiao, Yue Jiang, Maoning Lin, Wenbin Zhang, Min Wang.

  Diabetic cardiomyopathy (DCM) is a specific cardiac complication of diabetes that occurs independently of hypertension and coronary artery disease. Beyond metabolic disturbance, chronic hyperglycemia triggers immune dysfunction, contributing to myocardial inflammation, remodeling, and contractile impairment. This review highlights the critical roles of multiple immune cell populations-including monocytes, macrophages, mast cells, neutrophils, and T lymphocytes-in the pathogenesis of DCM, and frames DCM as an immunometabolic disorder driven in part by trained immunity. Hyperglycemia enhances glycolysis in macrophages and neutrophils, leading to the accumulation of acetyl-CoA that serves as a substrate for histone acetyltransferases. The resulting hyperacetylation of histone H3 locks immune cells into a pro-inflammatory state even after glucose levels normalize and amplifies inflammasome activation via the NLRP3 pathway, thereby coupling metabolic reprogramming to epigenetic reprogramming and sustaining chronic inflammation. In parallel, hyperglycemia-induced metabolic changes promote reactive oxygen species (ROS) production and upregulate S100A8/A9 expression. The S100A8/A9 heterodimer engages the receptor for advanced glycation end products (RAGE) on myeloid progenitors, driving the expansion of monocytes/macrophages and pro-inflammatory neutrophils and further fueling adverse cardiac remodeling. We also summarize emerging immunomodulatory therapies, including anti-cytokine strategies, inhibitors of inflammatory signaling pathways, mesenchymal stromal cell (MSC)-based interventions, other cellular treatments, and nanotechnology-enabled delivery platforms, which have shown promising anti-inflammatory and cardioprotective effects in preclinical models and early clinical studies. Targeting trained immunity and immunometabolic pathways may offer novel opportunities to halt or even reverse DCM progression.

Keywords:  Diabetic cardiomyopathy; Hyperglycemia; Immune cells; Inflammation; Trained immunity

DOI:  https://doi.org/10.1016/j.intimp.2026.117116
Front Cardiovasc Med. 2026 ;13 1839374

Emerging insights into inflammation-driven atherosclerosis: immune cell mechanisms.

Abdullahi Osman Mohamud, Zhiyin Dai.

  Atherosclerosis is a chronic inflammatory disease marked by the deposition of lipids, fibrous components, and calcification in the major arteries. The process is initiated by endothelial activation, which increases vascular permeability, promotes leukocyte adhesion, and leads to the migration of inflammatory cells into the arterial wall. These events trigger vascular constriction and activate inflammatory pathways, together promoting atheromatous plaque development. This review integrates emerging concepts in the immune cascade, detailing how recruited immune cells such as macrophages, T cells, B cells, dendritic cells (DCs), and neutrophils interact to sustain inflammation within developing plaques, as revealed by single-cell omics approaches. In addition, we discuss novel ideas, such as phenotypic switching of vascular smooth muscle cells into macrophage-like foam cells and the systemic effects of clonal haematopoiesis. Finally, we explore how systemic and environmental factors, including gut microbiota, epigenetic changes, hypertension, diabetes, obesity, and smoking, maintain a state of trained immunity and meta-inflammation that exacerbates disease, thus providing a conceptual framework for targeting inflammatory axes in future therapeutic strategies.

Keywords:  atherosclerosis; clonal haematopoiesis; gut microbiota; meta-inflammation.; single-cell omics; trained immunity

DOI:  https://doi.org/10.3389/fcvm.2026.1839374
EMBO Mol Med. 2026 Jul 16.

RXRα suppression drives hepatic metabolic and immune dysfunction in sepsis.

Matyas Jelinek, Jolien Vandewalle, Marah Heyerick, Tineke Vanderhaeghen, Céline Van Dender, Steven Timmermans, Madeleine Hellemans, Daria Fijalkowska, Hilde De Rooster, Martin Guilliams, Karolien De Bosscher, Claude Libert.

Sepsis is a life-threatening condition in which a dysregulated host response to infection leads to organ dysfunction and metabolic and immune failure. We identify hepatocyte retinoid X receptor α (RXRα) as a key integrator of host resilience during polymicrobial sepsis. RXRα is transcriptionally regulated by hepatocyte nuclear factor 4α (HNF4α), and sepsis rapidly decreases RXRα mRNA and protein levels. Transcriptomic analyses show that the septic liver becomes partially resistant to pharmacological activation of RXRα with bexarotene. Prophylactic- but not therapeutic- bexarotene improves survival by preserving metabolic stability and enhancing bacterial clearance. In hepatocyte-specific inducible RXRα-deficient mice, this protection is lost, confirming dependence on hepatocyte RXRα. Loss of RXRα in hepatocytes reduces Kupffer cell numbers, resulting in bacterial dissemination and mortality, a phenotype reproduced in a genetic model of selective Kupffer cell ablation. Overall, RXRα maintains the hepatic macrophage niche, linking hepatocellular transcriptional competence to systemic antibacterial defense.

DOI: https://doi.org/10.1038/s44321-026-00480-y
Nat Metab. 2026 Jul 14.

Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.

Jiayin Tang, Gerard Pernes, Brenda Nakagaki, Nhien Tran, Laura Bokor, Fran Prenen, Mingyang Yi, Avery E Robertson, Rachel Cronin, Mohamad Sarmini, Jacob Pierscianowski, Victoria Roberts, Birgitta A Ryback, Carl D Novina, Karine Auclair, Haopeng Xiao, Evanna L Mills.

Thermogenic brown and beige adipose tissues are important in maintaining metabolic health because of their distinct ability to catabolize stored fat and circulating glucose in futile cycles1,2. Macrophages, present in brown adipose tissue, have been reported to both positively and negatively regulate thermogenic adipocyte function through mechanisms that are incompletely understood3-14. Here we show that the macrophage-derived metabolite, itaconate, acts as a paracrine signal to repress adipose tissue thermogenesis in mice. Mechanistically, itaconate inhibits thermogenesis by antagonizing uptake of the pro-thermogenic metabolite, succinate, into brown adipose tissue. These findings reveal an unexpected mechanism for local control of thermogenesis in vivo that relies on paracrine itaconate signalling and demonstrate that the important signalling roles of itaconate extend beyond immunological processes to the regulation of energy balance.

DOI: https://doi.org/10.1038/s42255-026-01572-2
Mol Cell Biochem. 2026 Jul 15.

Transcriptomic profiling reveals transcriptomic remodeling linked to inflammatory activation and cell cycle-related gene expression in the early hours of macrophage activation.

Ding Li, Qinsong Ye, Tiantian Liu, Diqi Ying, Song Ye, Jishan Zheng, Zhiqiang Sun.

  Macrophages undergo rapid transcriptional reprogramming upon LPS stimulation, but the early regulatory mechanisms (≤6 hours) remain poorly understood. This study investigates the immediate molecular responses in the RAW264.7 murine macrophage cell line, focusing on the interplay between immune activation, cell cycle modulation, and metabolic-epigenetic crosstalk. The metabolic and epigenetic crosstalk mentioned in this study is only inferred from transcriptomic data, and no direct experimental verification was performed. Transcriptomic profiling (RNA-seq) was performed on LPS-stimulated (6-hour) and control macrophages. Differentially expressed genes (DEGs) were analyzed via GO/KEGG enrichment and protein-protein interaction (PPI) networks. Key findings were validated by qPCR and Western blot. Identified 2,715 DEGs (716 upregulated, 1,999 downregulated), with Ikbke identified as a multi-pathway gene (14 pathways). LPS triggered activation of inflammatory pathways (NF-κB, TNF) and downregulation of cell cycle regulators. Ikbke and C5ar1 co-enriched in COVID-19 and viral infection pathways, reflecting their involvement in general innate immune signaling pathways. Transcriptomic findings were validated by qPCR and Western blot, confirming a 6.2-fold induction of Ikbke and significant downregulation of Ezh2. This study identifies Ikbke as a potential correlational candidate of early macrophage responses, linking TLR signaling, metabolic shifts, and viral defense mechanisms. All conclusions in this study are limited to the RAW264.7 immortalized murine macrophage cell line and require further verification in primary cells and in vivo models. These findings in the RAW264.7 cell model provide potential molecular targets for further investigating the modulation of early hyperinflammatory responses.

Keywords:   C5ar1 ; Ikbke ; Cell cycle-related gene expression; Early immune response; Macrophage activation; Transcriptomics

DOI:  https://doi.org/10.1007/s11010-026-05643-6
Cell Rep Med. 2026 Jul 16. pii: S2666-3791(26)00336-8. [Epub ahead of print] 102919

Alterations of the host-lung microbiome metasystem in systemic inflammatory response syndrome is associated with secondary pneumonia.

Debajyoti Sinha, Melanie Petrier, Florian Pierre Martin, Cecile Poulain, Delphine Flattres Duchaussoy, Chiara Alberti, Stefanie Kreutmair, Jonas Schmid, Susanne Unger, Athanasios Ziogas, Despoina Koulenti, Laia Fernández-Barat, Antoni Torres, Cecile Braudeau, Regis Josien, Burkhard Becher, Mihai G Netea, Robert P Dickson, Emmanuel Montassier, Jeremie Poschmann, Antoine Roquilly.

  Host-respiratory microbiome interplay is vital to lung homeostasis. Systemic inflammatory response syndrome (SIRS) is an intense alteration in host status that necessitates rapid microbiome adaptation to avoid respiratory complications. Using longitudinal multi-omic data from patients with SIRS, we confirm that the respiratory microbiome, blood metabolome, and immune cells form a dynamic metasystem and define a metacluster with distinct T/B cell trafficking, anaerobic bacteria, high tyrosine metabolism, and low fatty acid biosynthesis. This metacluster status can serve to classify the severity of alterations in host-lung microbiome interactions as moderate or severe and to predict pneumonia and mortality. We demonstrate the robustness of these findings in an independent, randomized controlled trial and propose that interferon-γ treatment may benefit patients with severe metacluster alterations but harm those with moderate alterations. Our study supports the concept of the host-respiratory microbiome as a dynamic metasystem, in which specific alterations are associated with pneumonia and responses to interferon-γ treatment.

Keywords:  SIRS; immune therapy; interferon; metabolome; pneumonia; precision medicine; respiratory microbiome; sepsis

DOI:  https://doi.org/10.1016/j.xcrm.2026.102919
Adv Sci (Weinh). 2026 Jul 13. e76424

CXCL10/SLC11A1 Axis Exacerbates Septic Liver Injury by Regulating Neutrophil Extracellular Traps Formation to Drive Macrophage Pro‑Inflammatory Polarization.

Haiping Lin, Shicong Zheng, Pei Song, Jie Chang, Zewei Chen, Cang Li, Min Yu, Lude Wang, Shian Yu.

  Intra-abdominal infection frequently progresses to sepsis, where the liver is an early and commonly injured organ. In a cecal ligation and puncture (CLP) mouse model combined with bulk and single‑cell RNA sequencings, we observed marked neutrophil infiltration in the liver that correlated with injury severity. Sepsis‑associated neutrophils displayed a pro‑inflammatory phenotype and specifically upregulated the divalent metal transporter solute carrier family 11 member 1 (SLC11A1). Conditional knockout of Slc11a1 in neutrophils (Ly6G-Cre+ Slc11a1f/f) significantly alleviated liver injury and improved survival. Mechanistically, SLC11A1 drives intracellular Fe2 + accumulation and reactive oxygen species production via the Fenton reaction, promoting the formation of neutrophil extracellular traps (NETs). Hepatocytes were found to secrete C-X-C motif chemokine ligand 10 (CXCL10) through nuclear factor kappa B (NF‑κB) activation, which both recruit neutrophils and stimulates the JAK/STAT1/SLC11A1 axis, thereby enhancing NETs‑mediated pro‑inflammatory macrophage polarization. Clinically, peripheral blood CXCL10 levels correlated with liver injury markers in sepsis patients. Neutralization of CXCL10 using an anti-CXCL10 antibody or liver-specific knockdown of CXCL10 via Adeno-Associated Virus (AAV) reduced NETs formation and attenuated liver damage in CLP mice. This study delineates a "CXCL10-SLC11A1-NETs" signaling axis that exacerbates sepsis‑induced liver injury, offering a novel target for therapeutic intervention.

Keywords:  CXCL10; SLC11A1; macrophage polarization; neutrophil extracellular trap; septic liver injury

DOI:  https://doi.org/10.1002/advs.76424
Inflammation. 2026 Jul 16.

Propofol Inhibits Neutrophil Extracellular Traps Formation and Alleviates Sepsis-Induced Acute Lung Injury.

Wei Wang, Ran Xia, Chengmi Zhang, Muqiao Cheng, Yi Zheng, Haiying Ji, Fengying Xu, Shunan Lv, Nuo Xu, Yanfei Mao, Siyuan Li, Weiwei Li, Xueyin Shi.

BACKGROUND: Excessive neutrophil extracellular traps (NETs) formation contributes to lung tissue injury in sepsis-associated acute lung injury (ALI). Propofol, a commonly used sedative with anti-inflammatory and antioxidant properties, has been suggested to confer protection against ALI; however, its effects on NET sformation and the underlying mechanisms remain poorly defined.
METHODS AND RESULTS: At the cellular level, we established an in vitro model of lipopolysaccharide (LPS)-induced NET formation using human peripheral blood neutrophils to evaluate the effects of propofol. Pharmacological inhibition experiments in vitro suggested that propofol may suppress NET release by modulating Akt/mTOR signaling, with a concomitant reduction in neutrophil autophagic activity. In parallel, we established an LPS-induced sepsis model in mice and administered propofol by intraperitoneal pretreatment. Lung histopathology and NET quantification showed that propofol treatment was associated with attenuated sepsis‑induced lung injury and suppressed NET formation in vivo. These protective effects were associated with increased Akt/mTOR pathway activity in lung tissue; however, because in vivo pathway blockade was not performed, the functional contribution of Akt/mTOR signaling to organ protection in this setting remains to be directly validated.
CONCLUSIONS: Propofol attenuates sepsis-induced lung injury in association with suppressed NET formation. In vitro pharmacological inhibition experiments suggest that the Akt/mTOR axis may represent one pathway through which propofol suppresses NET release. However, direct in vivo validation of this mechanism (e.g., using pathway-specific inhibitors, conditional knockout models, or other loss-of-function approaches) remains necessary and should be addressed in future studies. Collectively, these findings identify a previously underappreciated mechanism of propofol action and support its potential adjunctive role in sepsis management.

DOI: https://doi.org/10.1007/s10753-026-02552-0
Methods Cell Biol. 2026 ;pii: S0091-679X(26)00125-1. [Epub ahead of print]209 67-89

Optimized strategies for necroptosis induction and evaluation.

Jie Lu, Haohao Lu, Sudan He.

  Necroptosis is a regulated form of cell death that relies on receptor-interacting serine/threonine-protein kinase 3 (RIPK3) -mediated phosphorylation of mixed-lineage kinase domain-like pseudokinase (MLKL). This phosphorylation drives MLKL oligomerization and membrane translocation, eventually leading to plasma membrane rupture and the release of damage-associated molecular patterns (DAMPs). Here, we outline methods to induce necroptosis by activating signaling pathways through the tumour necrosis factor receptor 1, Toll-like receptors (TLR3/4), and the interferon receptor. All pathways converge on the core event of RIPK3 activation, which further phosphorylates the effector MLKL to execute cell death. Furthermore, we describe key techniques and optimized protocols for detecting necroptotic activity and validating it with specific inhibitors, providing a comprehensive overview of both induction and evaluation strategies in necroptosis research.

Keywords:  Cell death; MLKL; Necroptosis; Necroptosis induction; RIPK1; RIPK3

DOI:  https://doi.org/10.1016/bs.mcb.2026.04.004
Science. 2026 Jul 16. 393(6808): eaea3075

Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.

Yuting Jessy Tan, Travis E Conley, Fuwen Yao, Fernando J García-Marqués, Damilola E Akinyemi, Van Vuong Dinh, Qian Wang, Abel Bermudez, Jieun Kim, Julia A Belk, Oliver Soehnlein, Sharon J Pitteri, Katrin I Andreasson.

Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE2) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.

DOI: https://doi.org/10.1126/science.aea3075