bims-traimu 2025-12-21 papers

Issue of 2025–12–21
six papers selected by
Yantong Wan, Southern Medical University

Front Immunol. 2025 ;16 1665099

The significance of trained immunity in cancer.

Junxing Qu, Xinya Guo, Xinru Wang, Huiwen Meng, Peizhi Li, Zhiheng Sun.

Trained immunity (TI) represented a unique state of innate immune activation, characterized primarily by persistent epigenetic modifications in immune cells. This phenomenon was first observed during pathogen infections and vaccinations, where it manifested as enhanced defensive responses in innate immune effector cells-such as those of the mononuclear phagocyte system and natural killer cells-upon re-stimulation. Cancer was a disease with complex mechanisms, marked by the loss of normal growth regulation in cells due to genetic mutations or epigenetic dysregulation, leading to abnormal proliferation and dissemination. With hundreds of subtypes, cancer could arise in virtually any human tissue or organ. The primary cause of cancer-related mortality was metastasis, which referred to the spread of cancer cells from their original site to distant organs and accounted for approximately 90% of cancer deaths worldwide. The induction of TI involved multiple immune components including myeloid cells, natural killer cells, pattern recognition receptors, and various cytokines. Notably, the enhanced response observed during secondary stimulation remained non-specific to particular pathogens. Compared to conventional therapeutic approaches, TI demonstrated superior systemic immune activation. Simple pharmacological stimuli such as β-glucan or Bacillus Calmette-Guérin (BCG) not only triggered innate immune responses but also conferred benefits to adaptive immunity, resulting in more rapid immune activation and enhanced efficacy. TI enhanced the capacity of immune cells to recognize and eliminate cancer cells, playing a critical role in countering metastasis. In this review, we summarized existing knowledge in the field, focusing on the mechanisms underlying TI induction and its significance in combating cancer.

Keywords: colorectal cancer; gastric cancer; liver cancer; lung cancer; trained immunity

DOI: https://doi.org/10.3389/fimmu.2025.1665099

Int Immunopharmacol. 2025 Dec 12. pii: S1567-5769(25)02010-7. [Epub ahead of print]169 116021

CD11c+CD69+ trained APCs in lungs mediate allergic asthma through increased H3K27ac.

Wenjian Li, Junhai Wang, Hanglin Li, Boyang Zheng, Beibei Qin, Xiaoying Wang, Ling Zhang, Jiaqi Liang, Jiao Li, Yueling Wang, Yuqing Deng, Xiaoqing Zheng, Ruihong Zeng.

OBJECTIVE: Investigating the impact and mechanism of trained antigen-presenting cells (APCs) in asthma in ovalbumin (OVA)-sensitized mouse model and discovering targets for treating asthma.
METHODS: BALB/c and C57BL/6 J wild-type mice and TNF-α-/- mice were exposed to OVA. CD11c+CD69+ APCs induced by OVA were re-stimulated by lipopolysaccharide to investigate trained immunity. The effect of histone acetylation in CD11c+CD69+ trained APCs were determined in vivo and in vitro. Epigenetic inhibitors, TNF-α-/- mice, and adoptive transfer were used to explore the development and function of these cells in mice.
RESULTS: OVA induced CD11c+CD69+ trained APCs, which showed stronger responses and lipid metabolic reprogramming characterized by increased acetylcarnitine, a source of acetyl, compared with CD11c+CD69- APCs in mice. CD11c+CD69+ trained APCs showed the histone acetylation marker H3K27achigh. H3K27ac was enriched at the CD69 gene in CD11c+CD69+ trained APCs, which supported CD69 expression. Histone acetyltransferase inhibitor inhibited development of CD11c+CD69+ trained APCs. Functionally, CD11c+CD69+ trained APCs promoted Th2-type response. Adoptively transferred CD11c+CD69+ trained APCs, but not CD11c+CD69- APCs, induced asthma. Inhibition of histone acetyltransferase prevented asthma. Further, TNF-α expression increased in asthmatic mice or patients. H3K27ac maintained TNF-α production in the trained APCs. TNF-α-/- mice showed attenuated asthma, whereas adoptive transfer of the trained APCs restored asthma, suggesting a key role of TNF-α for the function of the trained APCs.
CONCLUSION: We discovered a crucial role of CD11c+CD69+ trained APCs in asthma, and demonstrated that histone acetylation supported CD11c+CD69+ trained APCs to mediate asthma. The result may provide a potential target for the treatment of asthma.

Keywords: Allergic asthma; H3K27ac; Metabolic reprogramming; TNF-α; Trained APCs

DOI: https://doi.org/10.1016/j.intimp.2025.116021

J Transl Med. 2025 Dec 17. 23(1): 1404

Exercise-induced hypertrophic preconditioning alleviates myocardial ischemic injury through trained immunity of macrophages.

Jichen Liu, Zhihong Li, Xinnan Wei, Dongxiao Xie, Qi Chen, Kaitong Chen, Cankun Zheng, Mingjue Li, Mingyuan He, Mengjia Shen, Lu Chen, Chiyu Liu, Wangjun Liao, Jianping Bin, Ziyun Guan, Qiancheng Wang, Yulin Liao, Hairuo Lin.

Keywords: Energy metabolism; Exercise; Exercise-induced hypertrophic preconditioning; Macrophages; Myocardial ischemia/Reperfusion; Survival; Trained immunity

DOI: https://doi.org/10.1186/s12967-025-07359-5

Cell Death Dis. 2025 Dec 18.

Heme drives cardiac endothelial senescence in sepsis via STING activation.

Tingting Li, Peilin Zhu, Jialing Wang, Tao Zhang, Joseph Adams, Fei Tu, Chloe Garbe, Xiaojin Zhang, Li Liu, Krishna Singh, David L Williams, Chuanfu Li, Xiaohui Wang.

Sepsis-induced cardiac dysfunction is a major contributor to sepsis-related mortality, and many patients continue to experience long-term cardiac complications after recovery. Here, we demonstrate that cardiac senescence is a key feature of sepsis-associated cardiac dysfunction, with endothelial cells identified as the predominant senescent population in septic cardiac tissue. However, the pathogenic drivers of endothelial senescence in sepsis remain poorly characterized. Among potential mediators, we found that elevated levels of heme, a byproduct of hemolysis, strongly correlate with increased endothelial senescence and impaired cardiac function. Mechanistic studies revealed that heme acts as a novel ligand for STING, exacerbating bacterial infection-induced STING polymerization and activation, thereby promoting endothelial senescence. Notably, either STING inhibition or enhanced heme clearance via increased hemopexin expression significantly alleviated cardiac endothelial senescence and facilitated cardiac functional recovery in septic mice. These findings identify heme as a critical pathogenic driver of endothelial senescence and highlight heme clearance as a promising therapeutic strategy for mitigating sepsis-induced cardiac dysfunction.

DOI: https://doi.org/10.1038/s41419-025-08370-w

J Clin Invest. 2025 Dec 15. pii: e194310. [Epub ahead of print]135(24):

DLL4+ neutrophils promote Notch1-mediated endothelial PANoptosis to exacerbate acute lung injury in sepsis.

Hui Jin, Saoirse Holland, Alok Jha, Gaifeng Ma, Jingsong Li, Atsushi Murao, Monowar Aziz, Ping Wang.

Neutrophils play a critical role in sepsis-induced acute lung injury (ALI). Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, promotes neutrophil heterogeneity. While delta-like ligand 4 (DLL4) expression has been studied in various cell populations, its expression in neutrophils and impact on inflammation remain unknown. Here, we discovered that eCIRP induces DLL4+ neutrophils. These neutrophils trigger PANoptosis, a novel proinflammatory form of cell death initiated by Z-DNA-binding protein-1 (ZBP1) in pulmonary vascular endothelial cells (PVECs). In sepsis, DLL4+ neutrophils increase in the blood and lungs, upregulating ZBP1, cleaved gasdermin D, cleaved caspase-3, and phosphorylated MLKL, all of which are markers of PANoptosis, exacerbating ALI. DLL4 binds to Notch1 on PVECs and activates Notch1 intracellular domain to increase ZBP1-mediated endothelial PANoptosis. We discovered what we believe to be a novel Notch1-DLL4 inhibitor (NDI), derived from Notch1 to specifically block this interaction. Our findings reveal that NDI reduced endothelial PANoptosis in vitro and in vivo, attenuated pulmonary injury induced by DLL4+ neutrophils, and decreased lung water content and permeability, indicating improved barrier function. NDI also reduced serum injury and inflammatory markers and improved survival rate in sepsis. These findings underscore the Notch1-DLL4 pathway's critical role in DLL4+ neutrophil-mediated ALI. Targeting the Notch1-DLL4 interaction with an NDI represents a promising therapeutic strategy for sepsis-induced ALI.

Keywords: Immunology; Inflammation; Neutrophils

DOI: https://doi.org/10.1172/JCI194310

J Control Release. 2025 Dec 12. pii: S0168-3659(25)01159-9. [Epub ahead of print] 114545

Biomimetic siRNA therapeutics attenuate mitochondrial DNA damage and cytokine storm in sepsis.

Sijia Jiang, Yang Zhou, Chenglong Ge, Renxiang Zhou, Mengyao Ren, Lichen Yin, Jiang Zhu.

During the progression of severe sepsis, the oxidized mitochondrial DNA (mtDNA) in macrophages is cleaved by flap-structure-specific endonuclease 1 (FEN1) into small fragments, which are subsequently released into the cytosol and extracellular space to activate multiple pro-inflammatory signaling pathways such as NLRP3 inflammasome, cGAS-STING, and TLR9-NF-κB. Herein, biomimetic nanocomplexes (NCs) partially cloaked with macrophage membrane (MM) are developed to efficiently deliver FEN1 siRNA (siFEN1) into macrophages for sepsis management. To construct the NCs, membrane-penetrating, helical polypeptide (PG) first condenses siFEN1 and forms the cationic inner core, which is further coated with MM. By optimizing the membrane protein/siFEN1 weight ratios, partial membrane coating can be achieved, which enables the formation of NCs with both enhanced serum stability and efficient macrophage uptake efficiency. After systemic administration in cecal ligation and puncture-induced sepsis mice, the NCs exhibit prolonged blood circulation time and effective accumulation to the inflamed tissues, facilitated by MM-mediated charge neutralization of the cationic nanocore and inflammation homing. Subsequently, the NCs are efficiently internalized by macrophages through the interaction between the partially exposed polycationic core and the target cell membranes, provoking robust FEN1 silencing to suppress mtDNA fragmentation and leakage. Consequently, the NCs effectively restore immune homeostasis in sepsis mice, thereby mitigating cytokine storm and alleviating multiple organ failure.

Keywords: Cytokine storm; Macrophage membrane coating; Mitochondrial DNA fragmentation; Sepsis; siRNA delivery

DOI: https://doi.org/10.1016/j.jconrel.2025.114545