bims-traimu 2026-01-04 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–01–04
seven papers selected by
Yantong Wan, Southern Medical University

A CLOCK-targeting lncRNA induces trained immunity against tuberculosis.
Innate immune cell function in statin-treated patients with severe hypercholesterolemia is comparable to normocholesterolemic individuals: A cross-sectional study.
Systemically inducing trained immunity overcomes solid tumors' immunosuppressive microenvironment.
Innate Immune Tolerance Regulates Microglia Response to Aβ Oligomers.
A Novel Trained Immunity Adjuvant Derived From Commensal Bacteria Potentiates Liposome-Hydrogel Cancer Vaccine Against Breast Tumors.
Aromatic microbial metabolite hippuric acid enhances inflammatory responses in macrophages via TLR-MyD88 signaling and lipid remodeling.
Neutrophils Extracellular Traps Impair Lung Endothelial Proliferation in Sepsis via PLK1 Inhibition and Cell Cycle Arrest.

Cell Host Microbe. 2025 Dec 30. pii: S1931-3128(25)00521-9. [Epub ahead of print]

A CLOCK-targeting lncRNA induces trained immunity against tuberculosis.

Shanshan Yu, Qiyao Chai, Zhe Lu, Changgen Qiu, Yanzhao Zhong, Yiru Wang, Zehui Lei, Lihua Qiang, Yingxu Fang, Xinwen Zhang, Bingxi Li, Mengqiu Gao, Lingqiang Zhang, Gong Cheng, Jing Wang, Cui Hua Liu, Yu Pang.

  Trained immunity confers innate immune memory via metabolic and epigenetic reprogramming, yet the intercellular mediators regulating this process in host defense remain largely elusive. Here, through plasma exosomal profiling of tuberculosis (TB)-resistant individuals, we identify a trained immunity-inducing long non-coding RNA (lncRNA), termed tuberculosisresister-derived CLOCK regulator 1 (TRCR1). Mechanistically, exosome-derived TRCR1 collaborates with the RNA-binding protein FXR2 to stabilize CLOCK mRNA by forming lncRNA-protein-mRNA complexes in monocytes, thus enhancing circadian regulator CLOCK expression and promoting CLOCK-mediated histone H3 acetylation (K9/K14) at immune gene promoters, ultimately establishing epigenetic memory-mediated antimicrobial activity. We further reveal that Mycobacterium tuberculosis (Mtb)-secreted protein MPT53 induces lung epithelial cells to release TRCR1-enriched exosomes. In mice, TRCR1 training strengthens host anti-Mtb immunity and improves Bacille Calmette-Guérin (BCG) vaccine efficacy. Collectively, our findings unveil an intercellular TRCR1-FXR2-CLOCK axis driving trained immunity at the lung-systemic immune interface, providing a strategy for refining BCG vaccination and preventing infectious diseases.

Keywords:  CLOCK; exosome; long non-coding RNA; resister; trained immunity; tuberculosis

DOI:  https://doi.org/10.1016/j.chom.2025.12.002
Atheroscler Plus. 2025 Dec;62 53-61

Innate immune cell function in statin-treated patients with severe hypercholesterolemia is comparable to normocholesterolemic individuals: A cross-sectional study.

Harsh Bahrar, Kim Steward, Liesbeth van Emst, Nils Rother, Jeanine E Roeters van Lennep, Mihai G Netea, Siroon Bekkering, Niels P Riksen.

   Background and aims: Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease. Innate immune cells, including monocytes and neutrophils, play important roles in the pathophysiology of atherosclerosis. We previously reported that monocytes from patients with severely elevated low-density lipoprotein (LDL) cholesterol (LDL-c > 4.9 mmol/l) have a hyperresponsive phenotype, which persists even after three months statin treatment. This long-term hyperresponsive innate immune phenotype is termed trained immunity (innate immune memory), and is mediated by persistent enrichment of activating histone modifications leading to higher chromatin accessibility. In this study we investigated the monocyte and neutrophil phenotype of patients with severe hypercholesterolemia treated for 12 months with statins, compared to normocholesterolemic controls.
Methods: In a multicentric cross-sectional study, treatment-naïve patients with severe hypercholesterolemia (defined as LDL-cholesterol >4.9 mmol/L) requiring statin treatment were included. Blood was drawn after 12 months of lipid lowering therapy with statins (n = 15) and compared to healthy normocholesterolemic controls (LDL-c<3.5 mmol/l; n = 18).We assessed monocyte phenotype with flow cytometry, cytokine production capacity of PBMCs, and H3K4me3 expression on the TNFA promotor. In addition, we assessed the neutrophil phenotype and function.
Results: Treatment lowered LDL-c from 5.8 to 2.7 mmol/L. PBMC cytokine production capacity, as well as the expression of H3K4me3 histone mark on the TNFA promotor did not differ from the controls (LDL-c 2.6 mmol/L). Although neutrophil CD11b, CD66b, and CD62L expression was the same, production of several granular proteins was lower in patients.
Conclusions: Previous studies reported hyperresponsive monocytes in treatment-naïve patients with LDL-c > 4.9 mmol/l. We now demonstrate that in an independent cohort of patients with LDL-c > 4.9 who are treated for 12 months with lipid-lowering drugs, the monocyte phenotype and function was similar to that of normocholesterolemic controls. In addition, neutrophils phenotype was similar, while the secretion of several granular proteins was lower in the patients.

Keywords:  Cytokine production; Hypercholesterolemia; Inflammation; Innate immune cells; Lipid lowering treatment; Statins; Trained immunity

DOI:  https://doi.org/10.1016/j.athplu.2025.11.004
Sci Adv. 2026 Jan 02. 12(1): eadu0292

Systemically inducing trained immunity overcomes solid tumors' immunosuppressive microenvironment.

Bram Priem, Lisa Willemsen, Tom Anbergen, Yuri van Elsas, Jeroen Deckers, David P Schrijver, Stijn R J Hofstraat, Iris V Messing, Jazz Munitz, Dionne Honing, Geoffrey Prévot, Yohana C Toner, Judit Morla, William Wang, Anna Ranzenigo, Isabella Sirchia, Tomas Post, Raphaël Duivenvoorden, Ewelina Kluza, Glenn A O Cremers, Joost H C M Kreijtz, Carlos Pérez-Medina, Mandy M T van Leent, Abraham J P Teunissen, Roy van der Meel, Yi Zhou, Chris Glass, Jordi Ochando, Leo A B Joosten, Zahi A Fayad, Romana T Netea-Maier, Mihai G Netea, Menno P J de Winther, Thijs J Beldman, Arjan W Griffioen, Willem J M Mulder.

Hematopoietic bone marrow progenitors are increasingly implicated as an origin of immunosuppression in cancer. We have previously shown that trained immunity induction using nanomedicine potentiates checkpoint blockade therapy. Here, we studied how this approach's induction of trained immunity systemically overcomes the immunosuppressive tumor microenvironment. We found changes in the tumor microenvironment to mirror functional changes in the hematopoietic system in a melanoma mouse model. Single cell sequencing methods disclosed a shift in the tumor-associated macrophage population from immunosuppressive to antitumorigenic. Uniquely, a trained immunity and checkpoint blockade combination therapy mobilized natural killer cells which, in conjunction with the functional changes in the myeloid cell compartment, effectively activated T cells. Last, we established the effectiveness of our approach in mouse models of breast, lung, and pancreatic cancer. Collectively, our data show that the systemic induction of trained immunity rebalances the immune system for effective checkpoint blockade therapy.

DOI: https://doi.org/10.1126/sciadv.adu0292
J Neurochem. 2026 Jan;170(1): e70341

Innate Immune Tolerance Regulates Microglia Response to Aβ Oligomers.

Rafaela Rodrigues Valerio, Áquila Rodrigues Santos, Ana Helena Larangeira Nóbrega, Raquel Martins, Fernanda G De Felice, Sergio T Ferreira, Wilson Savino, Adriana Bonomo, Andressa Bernardi, Rudimar Luiz Frozza.

  Microglia are the main innate immune cells residing in the brain parenchyma. Their activation and resulting neuroinflammation have emerged as major pathogenic mechanisms in neurodegenerative disorders, particularly in Alzheimer's disease (AD). The accumulation of amyloid-β oligomers (AβOs) and microglia activation play crucial roles in the pathogenesis of AD. In a second vein, the development of innate immune memory in response to different stimuli is a vital mechanism that enables microglia to adjust their response to subsequent inflammatory challenges. While there is increasing evidence that repeated bouts of peripheral inflammation lead to training or tolerance in microglia, the impact of tolerance on the inflammatory response induced by AβOs remains to be determined. In this study, we investigated whether lipopolysaccharide (LPS)-induced tolerance affects microglial responses to AβOs. For that, organotypic hippocampal cultures were repeatedly challenged with LPS before being exposed to AβOs. We measured cytokine levels and evaluated changes in microglial activation and morphology following exposure of cultures to AβOs. A significant decrease in cytokine production was observed when hippocampal slice cultures were repeatedly challenged with LPS. Interestingly, microglial activation and the resulting inflammatory response induced by AβOs were prevented when these cultures had been previously challenged with LPS. Moreover, the changes in microglial morphology and cytokine production resulting from repeated LPS stimulation were associated with reduced activation of nuclear factor kappa B (NF-κB). These results indicate that preconditioning microglia with LPS induces a physiological immune tolerance response rather than pathological inflammation, which may have implications for developing therapeutic strategies for AD aimed at modulating innate immune memory.

Keywords:  Alzheimer's disease; cytokines; immune tolerance; innate immune memory; microglia; neuroinflammation

DOI:  https://doi.org/10.1111/jnc.70341
Adv Healthc Mater. 2025 Dec 29. e04705

A Novel Trained Immunity Adjuvant Derived From Commensal Bacteria Potentiates Liposome-Hydrogel Cancer Vaccine Against Breast Tumors.

Cheng-Kai Zhou, Jian-Gang Zhang, Zi-Ran Peng, Xue-Yue Luo, Liang Zhang, Tie-Lin Wang, Wei-Qiang Wan, Han-Xi Yang, Wei Chen, Yong-Jun Yang.

  Traditionally, vaccines rely on adaptive immunity to confer protection, yet emerging evidence highlights the importance of trained immunity in enhancing innate immune responses for broad-spectrum defense. The M28 family peptidase (M28), secreted by the commensal bacterium Peribacillus frigoritolerans, acts as a novel inducer of trained immunity with adjuvant potential. In studies using ovalbumin (OVA) as model antigen, both free M28 and M28-loaded liposome (M28-Lipo) significantly enhanced antigen-specific IgG production, stimulated splenic CD4+/CD8+ T cell proliferation, and induced balanced Th1/Th2 immunity, with M28-Lipo demonstrating superior efficacy. Building on these findings, a biphasic-release breast cancer vaccine (Zfp142-Lipo + M28@ sodium alginate (ALG)) was developed by co-delivering the tumor-specific neoantigen Zfp142 and M28 using a hydrogel-liposome hybrid system. This formulation enabled sustained antigen release and targeted accumulation in lymph nodes and tumor tissues. Prophylactic administration completely inhibited 4T1 tumorigenesis and pulmonary metastasis, whereas therapeutic administration significantly suppressed tumor progression and dissemination. Mechanistic analysis revealed enhanced infiltration of CD4⁺ and CD8⁺ T cells, reduction of regulatory T cells, and M2-to-M1 macrophage repolarization within the tumor microenvironment. These findings establish M28 as a safe and potent adjuvant that reprograms the tumor microenvironment and effectively bridges innate and adaptive immunity, providing a versatile platform for cancer immunotherapy.

Keywords:  M28 family peptidase; adjuvant; breast tumor nanovaccine; microenvironment; trained immunity

DOI:  https://doi.org/10.1002/adhm.202504705
Cell Rep. 2025 Dec 30. pii: S2211-1247(25)01521-9. [Epub ahead of print]45(1): 116749

Aromatic microbial metabolite hippuric acid enhances inflammatory responses in macrophages via TLR-MyD88 signaling and lipid remodeling.

Gauri Mirji, Sajad Ahmad Bhat, Mohamed El Sayed, Sarah Kim Reiser, Siva Pushpa Gavara, Ying Ye, Taito Miyamoto, Wujuan Zhang, Peter Vogel, Joel Cassel, Qin Liu, Aaron R Goldman, Andrew Kossenkov, Nan Zhang, Rahul S Shinde.

  The gut microbiome produces diverse metabolites shaping immunity, yet their pro-inflammatory potential remains unclear. Using untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics, we identified hippuric acid-an aromatic, microbe-derived metabolite-as a potent enhancer of inflammatory responses during Escherichia coli infection. Hippuric acid administration heightened inflammation, activated innate immune cells, and reduced survival in infected mice. In vitro, hippuric acid selectively potentiated M1-like (lipopolysaccharide [LPS] or LPS+interferon gamma [IFNγ]) macrophage pro-inflammatory responses but had no effect on M2-like (interleukin [IL]-4) polarization. It enhanced responses to myeloid differentiation primary response 88 (MyD88)-dependent Toll-like receptor (TLR) ligands but not TRIF-, STING-, or NOD2-mediated stimuli. Genetic deletion of MyD88 abolished hippuric-acid-induced pro-inflammatory responses. Transcriptomic and lipidomic analyses revealed increased cholesterol biosynthesis and lipid accumulation, while reducing cellular cholesterol blunted the pro-inflammatory effects of hippuric acid. Notably, hippuric acid also enhanced pro-inflammatory responses in human macrophages, and its elevated levels correlated with sepsis mortality, linking microbial metabolism, lipid remodeling, and innate immunity.

Keywords:  CP: immunology; CP: metabolism; TLR-MyD88 signaling; biomarker; cholesterol biosynthesis; hippuric acid; inflammation and infection; lipid remodeling; macrophage polarization; macrophages; microbial metabolite; sepsis

DOI:  https://doi.org/10.1016/j.celrep.2025.116749
J Inflamm Res. 2025 ;18 18165-18180

Neutrophils Extracellular Traps Impair Lung Endothelial Proliferation in Sepsis via PLK1 Inhibition and Cell Cycle Arrest.

Chenyu Zhu, Mengdi Qu, Dan Wu, Yuxin Shi, Fu Zeng, Changhong Miao, Di Zhou.

   Purpose: Sepsis continues to pose a significant threat to global health, characterized by elevated mortality rates. Pulmonary complications frequently develop in septic patients, with endothelial dysfunction correlating with adverse clinical outcomes. While overproduction of neutrophil extracellular traps (NETs) is implicated in vascular damage, their specific influence on the regenerative potential of pulmonary endothelial cells requires further elucidation. Our investigation aims to address this critical knowledge gap.
Patients and Methods: Clinical samples from sepsis patients and healthy controls were analyzed to establish the correlation between NETs and pulmonary endothelial injury. An in vivo sepsis model was generated through cecal ligation and puncture (CLP) in mice, with sham surgery animals serving as reference group. Human umbilical vein endothelial cells (HUVECs) were employed for in vitro assessment of NETs-mediated cell cycle modulation.
Results: Elevated NETs formation was observed in septic patients, showing positive association with inflammatory damage. CLP-induced mice demonstrated substantially increased NETs levels, pronounced pulmonary vascular permeability, and notable endothelial cell depletion. DNase I-mediated NETs degradation alleviated pulmonary inflammation and promoted endothelial recovery. Both experimental models revealed that excessive NETs release during sepsis compromises endothelial proliferation via polo-like kinase 1 (PLK1) pathway inhibition and subsequent G2/M phase arrest.
Conclusion: This study establishes that NETs accumulation in septic pulmonary injury hinders endothelial regeneration and vascular repair through PLK1 signaling suppression and G2/M cell cycle blockade.

Keywords:  NETs; cell cycle; endothelial dysfunction; polo like kinase 1; sepsis

DOI:  https://doi.org/10.2147/JIR.S556891