bims-traimu 2026-03-15 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–03–15
eight papers selected by
Yantong Wan, Southern Medical University

Persistent viral control status is associated with enhanced innate immune responses in people with HIV-1.
Human iPSC-derived alveolar macrophages reveal macrophage subtype functions of itaconate in M. tuberculosis defense.
Cytoskeletal remodeling promotes tunneling nanotube formation and drives cardiac resident cell mitochondrial transfer in sepsis.
Stochastic modeling of epigenetic memory.
DPEP2 suppresses hyperinflammation via metabolic reprogramming of macrophages in sepsis.
Neutrophil extracellular traps prime the ZBP1-cGAS sensor complex, triggering necroptosis and inflammatory injury in acute pancreatitis.
Respiratory viral infections prime accelerated lung cancer growth.
Preventive Aerobic Training Protects Against Doxorubicin-Induced Cardiotoxicity by Preserving Redox Status and Attenuating Cardiac Stress-Related Signaling.

iScience. 2026 Mar 20. 29(3): 114807

Persistent viral control status is associated with enhanced innate immune responses in people with HIV-1.

Jéssica C Dos Santos, Albert L Groenendijk, Suzanne D E Ruijten, Rainer Knoll, Nadira Vadaq, Rob Ter Horst, Ezio T Fok, Wojciech Witkowski, Marc J T Blaauw, Louise E van Eekeren, Wilhelm A J W Vos, Maartje Cleophas-Jacobs, Stephan Reichl, Twan Otten, Joost H A Martens, Arnold van der Meer, Han Koninkx, Marien I de Jonge, Marc D Beyer, Jan van Lunzen, Leo A B Joosten, Christoph Bock, Casper Rokx, Annelies Verbon, Linos Vandekerckhove, Anna C Aschenbrenner, Joachim L Schultze, Vasiliki Matzaraki, Andre J A M van der Ven, Mihai G Netea.

  The mechanisms mediating elite and persistent HIV control in people living with HIV (PLHIV) are only partially understood and largely attributed to adaptive T cell responses, but whether innate immunity also contributes remains unclear. Using samples from the 2000HIV study, we examined the transcriptional and functional profiles of monocytes from spontaneous HIV controllers and normal progressors on long-term antiretroviral therapy. HIV controllers displayed enhanced cytokine production after bacterial and viral stimulation, alongside antiviral and interferon-inducible transcriptional signatures and reduced inflammatory gene expression. Persistent controllers further showed increased capacity for trained immunity, with H3K4me3 profiling indicating the epigenetic priming of innate immune genes. Remarkably, relatives of persistent controllers also exhibited stronger innate and trained immune responses than relatives of normal progressors. These findings suggest that robust innate immunity, particularly monocyte function, may precede infection and contribute to sustained HIV control, offering new avenues for therapies that induce similar innate antiviral responses.

Keywords:  Clinical finding; Disease; Health sciences; Immunology; Medicine

DOI:  https://doi.org/10.1016/j.isci.2026.114807
JCI Insight. 2026 Mar 09. pii: e198342. [Epub ahead of print]11(5):

Human iPSC-derived alveolar macrophages reveal macrophage subtype functions of itaconate in M. tuberculosis defense.

Adam S Krebs, Tomi Lazarov, Anthony T Reynolds, Kimberly A Dill-McFarland, Abigail Xie, James M Bean, Muxue Du, Olivier Levy, John A Buglino, Aaron Zhong, Anna-Lena Neehus, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, Elouise E Kroon, Marlo Möller, Thomas R Hawn, Ting Zhou, Lydia Ws Finley, Marc Antoine Jean Juste, Dan W Fitzgerald, Frederic Geissmann, Michael S Glickman.

  Mycobacterium tuberculosis (Mtb) survives within multiple macrophage populations during infection, including alveolar macrophages (AMs) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1-mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to Mtb infection. The role of itaconate in human macrophages is less clear, and it is unknown whether itaconate mediates distinct effects in macrophage subtypes. Here, we investigated the role of itaconate in macrophages derived from human induced pluripotent stem cells (iPSCs), induced by either GM-CSF to resemble AMs (AM-like cells, hereafter ipAM-Ls) or M-CSF to resemble monocyte-derived macrophages (MDM-like cells, hereafter ipMDM-Ls). Both human macrophage types produced substantially less itaconate than mouse macrophages, and ipAM-Ls produced 4-fold less itaconate than ipMDM-Ls. Surprisingly, ACOD1-deficient ipAM-Ls, but not ipMDM-Ls, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb-induced inflammatory response in ipMDM-Ls, but not ipAM-Ls, affecting both the type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to tuberculosis, with distinct roles in different macrophage subsets. These results also show that genetically tractable iPSC-derived macrophages are a useful model to dissect cellular host-pathogen interactions in human macrophages.

Keywords:  Cytokines; Immunology; Infectious disease; Macrophages; Pulmonology; Tuberculosis

DOI:  https://doi.org/10.1172/jci.insight.198342
Sci Adv. 2026 Mar 13. 12(11): eadz3266

Cytoskeletal remodeling promotes tunneling nanotube formation and drives cardiac resident cell mitochondrial transfer in sepsis.

Rui Song, Cheng Huang, Yinrui Ma, Zhenhua Zhang, Yifei Liu, Bing Chen, Xi Zhang, Shuai Hao, He Huang, Milad Ashrafizadeh, João Conde, Chenyang Duan.

Sepsis-induced cardiac dysfunction arises from complex intercellular communication networks that extend beyond direct cardiomyocyte damage, yet the nanoscale mechanisms governing these interactions remain poorly understood. Here, we identify tunneling nanotubes (TNTs) as dynamic biological nanostructures facilitating intercellular mitochondrial transfer, revealing their critical role in septic cardiac remodeling. Using a murine cecal ligation and puncture (CLP) model and single-cell RNA sequencing, we demonstrate that sepsis reprograms cardiac endothelial cells, fibroblasts, and macrophages, generating metabolically impaired subpopulations with dysfunctional mitochondrial respiration. We uncover a Drp1-driven cytoskeletal remodeling process that orchestrates TNT biogenesis, wherein Drp1 interacts with Filamin and Kinesin to regulate TNT formation and extension, enabling long-range organelle trafficking. Cardiac-specific Drp1 knockout disrupts TNT-mediated mitochondrial exchange, halting metabolic deterioration and reversing cellular reprogramming. These findings establish Drp1-mediated TNT networks as nanoscale conduits of organelle communication, offering insights into biological nanotube engineering, cellular-scale nanotechnology, and potential therapeutic interventions for mitochondrial dysfunction in sepsis.

DOI: https://doi.org/10.1126/sciadv.adz3266
NPJ Syst Biol Appl. 2026 Mar 11.

Stochastic modeling of epigenetic memory.

Simone Bruno, Domitilla Del Vecchio.

Here, we review mathematical models of epigenetic memory, focusing on chromatin modifications as key mechanisms to achieve long-term maintenance of epigenetic states. After reviewing the main stochastic modeling frameworks, we focus on stochastic models of chromatin modifications to analyze residence time in memory states, which underpins the long-term maintenance of epigenetic information. We review these concepts through increasingly complicated chromatin modification circuits, including histone modifications, DNA methylation, and their combination.

DOI: https://doi.org/10.1038/s41540-026-00664-9
Nat Commun. 2026 Mar 09.

DPEP2 suppresses hyperinflammation via metabolic reprogramming of macrophages in sepsis.

Wenchen Luo, Wei Xu, Qimeng Yin, Jieqiong Song, Jie Wang, Yian Guan, Jian Huang, Jian Yu, Kefeng Zou, Danfeng Jin, Chao Xu, Min Qiu, Zhixin Qiu, Jing Zhong.

Sepsis-induced excessive inflammation contributes to mortality, but restricting hyperinflammation in sepsis remains challenging. Here, we identify dipeptidase 2 (DPEP2) as an immunotherapeutic target in sepsis by integrating single-cell and bulk RNA sequencing data from septic patients. In patients with sepsis, peripheral monocytes/macrophages have reduced DPEP2 expression, with DPEP2 levels negatively correlating with inflammation severity, disease progression, and clinical outcomes. In vitro, Dpep2 knockdown enhances macrophage-mediated inflammation, while in septic mice in vivo, macrophage-specific Dpep2 loss decreases survival by exacerbating inflammation and organ damage. Mechanistically, sepsis-induced EGR1 represses Dpep2 transcription, leading to reduced DPEP2-mediated enzymatic cleavage of leukotriene D4 (LTD4). Increased LTD4 redirects the metabolic flux toward prostaglandin E2 overproduction, amplifying NF-κB activation and lipopolysaccharide-induced inflammatory cytokine production. Lastly, lipid nanoparticle (LNP)-mediated delivery of Dpep2 mRNA expression to monocytes/macrophages mitigates inflammation and organ damage in septic mice. Our findings thus suggest a protective function for DPEP2 in sepsis-induced hyperinflammation via immunometabolic regulation, and also present LNP-mediated Dpep2 mRNA delivery as a potential therapy for septic hyperinflammation.

DOI: https://doi.org/10.1038/s41467-026-70466-4
Int J Biol Sci. 2026 ;22(5): 2398-2417

Neutrophil extracellular traps prime the ZBP1-cGAS sensor complex, triggering necroptosis and inflammatory injury in acute pancreatitis.

Haoyu Zhang, Zheng Wang, Jiongdi Lu, Jie Li, Yuchen Jia, Xiaozhou Xie, Yixuan Ding, Feng Cao, Fei Li.

  Severe acute pancreatitis (SAP) involves dynamic interactions between immune dysregulation and inflammatory infiltration. Although elevated levels of neutrophil extracellular traps (NETs) are associated with SAP, the downstream mechanisms by which NETs exacerbate the inflammatory injury remain unclear. In this study, we demonstrate that NETs levels positively correlate with SAP severity, and pharmacological inhibition of NETs reduces pancreatic injury, and acinar cell death. Mechanistically, NETs activate the ZBP1-cGAS complex via mitochondrial DNA (mtDNA), triggering downstream necroptosis and inflammatory pathways, thereby driving pancreatic inflammatory injury. Specifically, NETs induce mitochondrial damage in acinar cells, leading to cytosolic accumulation of mtDNA. This recruits ZBP1 to form a complex with cGAS dependent on the RHIM domain, wherein ZBP1 stabilizes Z-form mtDNA and potentiates cGAS recognition of Z-mtDNA, thereby cooperatively promoting necroptosis and inflammation. Furthermore, cyclosporine A inhibits mtDNA release, thereby suppressing NETs-induced ZBP1-cGAS complex formation and mitigating pancreatic injury. Our findings establish the mtDNA-ZBP1-cGAS axis as a pivotal mechanism by which NETs exacerbate pancreatic inflammation, revealing new therapeutic targets for SAP.

Keywords:  Necroptosis; ZBP1; acute pancreatitis; cGAS; mitochondrial DNA; neutrophil extracellular traps

DOI:  https://doi.org/10.7150/ijbs.122290
Cell. 2026 Mar 11. pii: S0092-8674(26)00220-5. [Epub ahead of print]

Respiratory viral infections prime accelerated lung cancer growth.

Wei Qian, Xiaoqin Wei, Andrew J Barros, Xiangyu Ye, Haibo Zhang, Qing Yu, Samuel P Young, Eric V Yeatts, Yury Park, Chaofan Li, Sijie Hao, Gislane Almeida-Santos, Jinyi Tang, Harish Narasimhan, Nicole A Kirk, Valeria Molinary, Ying Li, Li Li, Bimal N Desai, Peter Chen, Kwon-Sik Park, Anny Xiaobo Zhou, Jeffrey M Sturek, Wei Chen, In Su Cheon, Jie Sun.

  The COVID-19 pandemic has highlighted the long-term consequences of viral pneumonia, yet its impact on cancer development remains unclear. Here, we show that patients previously hospitalized with severe COVID-19 have an increased risk of subsequent lung cancer. Across multiple murine models, severe respiratory viral infections accelerated lung cancer growth, whereas vaccination mitigated infection-enhanced tumor progression. Mechanistically, prior viral pneumonia reprogrammed the lung into a pro-tumor microenvironment marked by the sustained accumulation of tumor-associated neutrophils and heightened immunosuppression. We observed persistent chromatin remodeling at key cytokine loci in immune and structural cells, linking inflammatory memory to tumor-promoting signals. Therapeutically, combined blockade of neutrophil recruitment and programmed death-ligand 1 (PD-L1) restored CD8+ T cell function and suppressed tumor growth. Together, these findings establish a causal link between prior viral pneumonia and lung tumorigenesis, underscoring the need for enhanced surveillance and targeted interventions to reduce post-COVID cancer risk.

Keywords:  COVID-19; epigenetic imprinting; influenza; lung cancer; respiratory viral infection; tumor-associated neutrophils

DOI:  https://doi.org/10.1016/j.cell.2026.02.013
Cells. 2026 Feb 26. pii: 408. [Epub ahead of print]15(5):

Preventive Aerobic Training Protects Against Doxorubicin-Induced Cardiotoxicity by Preserving Redox Status and Attenuating Cardiac Stress-Related Signaling.

Paola Victória da Costa Ghignatti, Rafael Aguiar Marschner, Rafael Teixeira Ribeiro, Vitor Gayger-Dias, Vanessa-Fernanda Da Silva, Luciele Varaschini Teixeira, Simone Wajner, Maximiliano Isoppo Schaun, Carlos-Alberto Gonçalves, Patrícia Sesterheim.

  Doxorubicin (DOX) is a highly effective chemotherapeutic agent whose clinical use is limited by dose-dependent cardiotoxicity associated with oxidative stress, inflammation, and cellular stress responses. Here, we investigated whether preventive aerobic training could protect against DOX-induced cardiac injury in Wistar rats. Animals were assigned to sedentary control (C), sedentary DOX (D), trained control (CT), and trained DOX (DT) groups. The moderate-intensity (~50-80% maximal exercise test) treadmill protocol (40 min/day, 4 days/week for 4 weeks) was performed before intraperitoneal administration of DOX (4 mg/kg, weekly for 4 weeks) or saline. Preventive training markedly improved exercise capacity (p < 0.001) and attenuated oxidative damage, maintaining antioxidant enzyme activity (GR, SOD) at control levels (p > 0.05). DOX significantly upregulated cardiac IL-6 and IL-1β expression (p < 0.01), while trained animals preserved IL-1β expression similar to controls (p > 0.99). In parallel, DOX increased cardiac HIF-1 expression (p < 0.05), indicating activation of hypoxia- and stress-related signaling pathways, an effect that was attenuated by preventive training (p > 0.99). DOX-induced cardiac atrophy was evidenced by reduced left ventricular mass (p < 0.001), which was partially prevented by training (p < 0.05). Although hematological toxicity persisted, preventive aerobic exercise effectively counteracted DOX cardiotoxicity by restoring redox homeostasis, dampening inflammation, and limiting apoptotic signaling. Collectively, these findings highlight exercise preconditioning as a promising non-pharmacological strategy in cardio-oncology to mitigate chemotherapy-associated cardiac injury.

Keywords:  aerobic training; cardiotoxicity; doxorubicin; heart; oxidative stress

DOI:  https://doi.org/10.3390/cells15050408