bims-traimu 2026-02-01 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–02–01
fifteen papers selected by
Yantong Wan, Southern Medical University

Monocyte/macrophage-mediated trained immunity in disease prevention and immunotherapy.
Butyrate-induced trained immunity enhances bacterial killing ability of head kidney macrophages in turbot (Scophthalmus maximus L.).
Induction of trained immunity in myeloid cells and their progenitors from thyroid cancer patients.
Mucosal Adenovirus-Vectored Rv2299c Vaccine Protects Against Tuberculosis by Inducing Trained Immunity in Dendritic Cells and Polyfunctional T Cells.
The effect of BCG vaccination on systemic inflammation in neonates.
Trained Immunity in Bladder ILC3s Enhances Mucosal Defense Against Recurrent Urinary Tract Infections.
Leveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to enhance colorectal cancer vaccine response.
Macrophage membrane-biomimetic DNA nanocages deliver taurine to reprogram trained immunity for periodontitis therapy.
Sepsis induces long-term reprogramming of human HSPCs and drives myeloid dysregulation in sepsis survivors.
A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.
Enterococcus faecalis-derived lactic acid suppresses macrophage activation to facilitate persistent and polymicrobial wound infections.
Fasting-mimicking diet induces IFNβ secretion in tumor-associated macrophages via NRF1-mediated ubiquitin-dependent proteolysis of Trex1.
Gambogenic acid ameliorates inflammation by inhibiting HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis.
Environmentally driven immune imprinting protects against allergy.
Cross-disease analysis identifies the inflammatome as a transcriptional program of inflammation.

Bioact Mater. 2026 May;59 745-762

Monocyte/macrophage-mediated trained immunity in disease prevention and immunotherapy.

Xiao Zhang, Xinlian Wang, Miaomiao Xu, Jing Yuan, Ying Liu.

  Trained immunity refers to a functional reprogramming of the innate immune system that enhances its ability to respond to secondary stimuli. Monocytes and macrophages are central effectors of innate immunity with broad therapeutic relevance. Their capacity to acquire trained immunity enhances host defense and shapes immune homeostasis through epigenetic, metabolic, and functional changes. Unlike previous reviews that primarily focus on molecular mechanisms or vaccine-induced training, this review emphasizes the distinct roles of monocyte/macrophage-mediated trained immunity, originating from both central and peripheral sources. We further discuss how nanomaterials can be harnessed to precisely modulate this process, offering new opportunities for infection control, tumor immunotherapy, and the regulation of chronic inflammatory diseases. This dual-perspective framework provides a foundation for translating trained immunity into targeted clinical interventions.

Keywords:  Innate immune memory; Macrophage; Monocyte; Nanomaterials; Trained immunity

DOI:  https://doi.org/10.1016/j.bioactmat.2025.12.044
Fish Shellfish Immunol. 2026 Jan 27. pii: S1050-4648(26)00069-0. [Epub ahead of print] 111165

Butyrate-induced trained immunity enhances bacterial killing ability of head kidney macrophages in turbot (Scophthalmus maximus L.).

Shu Zhao, Jinjin Zhang, Wentao Wang, Shufei Liang, Mengqi Chen, Rui Shao, Xinmeng Liao, Qinghui Ai, Kangsen Mai, Min Wan.

  Trained immunity represents an evolutionarily conserved form of innate immune memory established through epigenetic and metabolic reprogramming. This study has demonstrated for the first time that butyrate, a key gut microbiota-derived metabolite, induces trained immunity in teleost macrophages. Our results revealed that priming head kidney macrophages (HKMs) from turbot (Scophthalmus maximus L.) with 1 μM of sodium butyrate (NaB) for 24 hours followed by a 5-day training period, established a durable memory phenotype of HKMs. Importantly, the bactericidal capacity against Edwardsiella tarda (E.tarda) infection was significantly enhanced in butyrate-trained HKMs, accompanied by the elevated pro-inflammatory response with significantly elevated expression of il1β and tnfα. Mechanistically, butyrate training activated the HIF-1α signaling pathway, modulated a late-phase metabolic shift towards anaerobic glycolysis and TCA cycle, evidenced by altered citrate metabolism and glutamine pathway activation. Furthermore, the gene expression of acly, acss1 and acss2 was increased, while the expression of acc1 was suppressed, leading to the increased acetyl-CoA pools. On the other hand, butyrate induced persistent epigenetic remodeling, evidenced by increased expression of histone acetyltransferase CBP/P300, HDAC3 suppression, and a robust accumulation of H3K27 acetylation. Remarkably, in vivo pretreatment with butyrate at a low dose conferred a 20% survival advantage against a lethal E. tarda challenge in juvenile turbot after 14 days post-exposure to butyrate compared to that in control group. These findings have established that butyrate drives innate immune memory in fish, offering novel insights and a promising candidate for prophylactic strategies against pathogenic infection in aquaculture.

Keywords:  Butyrate; Epigenetic modification; Macrophages; Metabolic reprogramming; Trained immunity; Turbot

DOI:  https://doi.org/10.1016/j.fsi.2026.111165
Front Immunol. 2025 ;16 1706496

Induction of trained immunity in myeloid cells and their progenitors from thyroid cancer patients.

Pepijn van Houten, Prashant Changoer, Liesbeth van Emst, Han J Bonenkamp, Johannes H W de Wilt, Willemijn Hobo, Manita E J Bremmers, Mieke W H Roeven, Janneke E W Walraven, Petronella B Ottevanger, Willem J M Mulder, Mihai G Netea, Martin Jaeger, Romana T Netea-Maier.

   Background: The prognosis of patients with cancer in which tumor-associated macrophages with a pro-tumoral phenotype are abundant is poor. This includes aggressive forms of non-medullary thyroid carcinoma (NMTC). Trained immunity describes long-term epigenetic and metabolic reprogramming in innate immune cells and their bone marrow progenitors, leading to improved responsiveness, which is currently being explored as a potential new treatment approach in cancer. We aimed to assess whether trained immunity can be induced in myeloid cells of patients with NMTC to enhance the anti-tumor immune response, and whether this effect is tumor-specific or can be elicited in other forms of cancers sharing the immune-mediated pathophysiology, such as colorectal carcinoma (CRC).
Methods: Peripheral blood and bone marrow were obtained from 53 NMTC patients (39 differentiated and 14 poorly differentiated/anaplastic NMTC) and 13 healthy controls. Peripheral monocytes and bone marrow progenitors were isolated ex vivo, and trained immunity was induced using different stimuli. Cytokine production upon restimulation and expression of cell membrane activation markers were used as biomarkers of cellular activation. In addition, trained immunity was assessed in peripheral monocytes from seven CRC patients.
Results: Training of circulating monocytes with β-glucan or interleukin-4 resulted in amplified cytokine production upon restimulation, a hallmark of trained immunity responses. Fold changes of increase in cytokine production were comparable between the NMTC subtypes, CRC, and healthy controls. Flow cytometry showed that training of bone marrow progenitors resulted in macrophages with lower CD206 and CD163 and higher CD86 expression, a profile associated with a less immunosuppressive and more anti-tumoral phenotype.
Conclusion: Ex vivo training of monocytes and bone marrow progenitors from patients with NMTC and CRC results in macrophages with increased proinflammatory cytokine production and differentiation toward an anti-tumoral phenotype. This suggests that trained immunity may be exploited as a potential novel treatment strategy for cancer.

Keywords:  innate immunity; macrophages; monocytes; non-medullary thyroid carcinoma; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1706496
Vaccines (Basel). 2026 Jan 02. pii: 55. [Epub ahead of print]14(1):

Mucosal Adenovirus-Vectored Rv2299c Vaccine Protects Against Tuberculosis by Inducing Trained Immunity in Dendritic Cells and Polyfunctional T Cells.

Huiling Wang, Shiqi Xie, Shaoqiong Huang, Xuejiao Huang, Ying Zhang, Juan Wu, Xiao-Yong Fan, Zhidong Hu.

  Background: The development of effective tuberculosis (TB) vaccines beyond BCG remains an urgent global health priority, especially for prevention of pulmonary TB in adults. While most current strategies focus on enhancing T-cell immunity, the potential of trained immunity to broadly augment both innate and adaptive responses remains underexplored in TB vaccinology. Given the central role of dendritic cells (DCs) as bridges between innate and adaptive immunity, we hypothesized that inducing trained immunity in DCs could optimize subsequent T-cell responses. Previous studies have identified Rv2299c as a promising adjuvant of other antigens by promoting DC maturation; however, whether it could be used as a standalone protective antigen of TB vaccine remains unclear. Methods: We constructed a chimpanzee adenovirus-vectored TB vaccine candidate expressing Rv2299c (rAd-Rv2299c), and evaluated its immunogenicity and protective efficacy in murine models. Results: rAd-Rv2299c vaccine effectively induced a trained immunity phenotype in DCs, as evidenced by upregulated MHC-II and CD86 expression and increased pro-inflammatory cytokine (TNF-α, IL-6, IL-1β and IL-12p70) secretion. Moreover, its immunization promoted the generation of antigen-specific polyfunctional T cells, and robustly enhanced both Th1 and Th17-type immune responses. In a murine challenge model, vaccination significantly reduced bacterial loads in the lung and spleen and attenuated pulmonary inflammation, which was associated with robust recall T-cell immune responses. Conclusions: rAd-Rv2299c confers anti-TB protection by inducing trained immunity in DCs and promoting polyfunctional T-cell responses, thereby offering valuable experimental evidence and conceptual insights for the development of next-generation TB vaccines.

Keywords:  dendritic cells; polyfunctional T cells; trained immunity; tuberculosis; vaccine

DOI:  https://doi.org/10.3390/vaccines14010055
Vaccine. 2026 Jan 26. pii: S0264-410X(26)00048-4. [Epub ahead of print]75 128241

The effect of BCG vaccination on systemic inflammation in neonates.

Valerie A C M Koeken, Thomas N Nissen, Nina M Birk, Collins K Boahen, Reinout van Crevel, Vinod Kumar, Yang Li, Peter Aaby, Christine S Benn, Mihai G Netea.

   OBJECTIVES: To assess the impact of BCG vaccination on systemic inflammation in neonates, focusing on sex-specific differences and the relationship between circulating inflammatory proteins and immune responses, including cytokine production and antibody levels.
METHODS: A randomized clinical trial was conducted in Denmark involving newborns who were randomized to receive BCG vaccine or not. Blood samples were collected at 4 days, 3 months and 13 months post-randomization. In the current sub-study within the randomized clinical trial, ninety-two inflammatory proteins in plasma were measured using a proximity extension assay. We analysed the changes in these inflammatory markers and examined their association with immune markers.
RESULTS: Before BCG vaccination, girls had slightly higher inflammatory marker levels than boys. Post-vaccination, a moderate decrease in circulating inflammatory markers was noted in BCG-vaccinated children, especially in girls, with the strongest effects observed at 3 months. By 13 months, following routine vaccinations, there was no longer any measurable effect of BCG vaccination. BCG seemed to modify the associations between inflammatory proteins and immune responses.
CONCLUSIONS: This sub-study suggests that BCG vaccination could temporally reduce systemic inflammation in neonates, with the strongest effect observed in girls, who had the highest baseline levels. These findings seemingly replicate observations in adults, showing that BCG has a pronounced inflammation-dampening effect in those with higher pre-vaccination levels. The results further show that BCG vaccination could alter circulating inflammatory proteins in a time-dependent manner and potentially modulate the associations between inflammatory markers and immune function. These insights highlight the importance of sex-specific immune modulation by BCG in early life and underscore the value of personalised vaccination strategies that considers both timing and sex differences in immune responses.

Keywords:  BCG; Inflammatory proteins; Sex-specific immune effects; Trained immunity; Vaccination

DOI:  https://doi.org/10.1016/j.vaccine.2026.128241
Biomedicines. 2025 Dec 30. pii: 78. [Epub ahead of print]14(1):

Trained Immunity in Bladder ILC3s Enhances Mucosal Defense Against Recurrent Urinary Tract Infections.

Qiaoqiao Pei, Jiaqi Liu, Ziwen Tang, Jiaqing Tan, Xu Han, Xinrong Hu, Zhou Liang, Feng Li, Changjian Zhu, Ruoni Lin, Ruilin Zheng, Jiani Shen, Qinghua Liu, Haiping Mao, Kefei Wu, Wei Chen, Yi Zhou.

  Background: Urinary tract infections (UTIs) rank among the most prevalent infectious diseases globally, with recurrent UTIs (rUTIs) posing substantial therapeutic challenges due to the lack of durable protective immunity. While trained immunity augments innate immune responses, its induction and functional significance in bladder-resident group 3 innate lymphoid cells (ILC3s) remain unknown. This study investigates whether ILC3s develop trained immunity following uropathogenic Escherichia coli (UPEC) exposure and how they contribute to mucosal defense against rUTIs. Methods: The ILC3 counts were detected in bladder sections from UTI patients and health controls (HC). A recurrent UTI mouse model was established through primary and secondary urethral UPEC inoculation. Bacterial loads in tissues were assessed, and single-cell suspensions were analyzed via flow cytometry. Bladder naïve- and UPEC-trained ILC3s were adoptively transferred, with evaluations of histopathology, epithelial barrier function, inflammation, and antimicrobial peptides. The in vitro ILC3 cell line MNK-3 was detected for IL-17A and IL-22 production following primary and secondary UPEC lysate stimulation. Results: We demonstrate that primary UPEC infection triggers ILC3 expansion in both human and murine bladders. Upon secondary challenge, these ILC3s develop trained immunity, characterized by enhanced proliferation, amplified IL-17A and IL-22 production, and improved pathogen clearance. Mechanistically, trained ILC3s reinforce urothelial barrier integrity through upregulation of antimicrobial peptides (Reg3b/Reg3g) and attenuate inflammatory pathology by suppressing pro-inflammatory cytokines (IL-6, TNF-α). Conclusions: We uncover an endogenous defense mechanism wherein UPEC primes bladder ILC3s via trained immunity, enabling amplified IL-17A- and IL-22-mediated protection against recurrent infections. These findings establish ILC3-trained immunity as a novel conceptual foundation, providing a basis for developing immunotherapies against rUTIs.

Keywords:  group 3 innate lymphoid cells; innate immune memory; trained immunity; urinary tract infection; uropathogenic Escherichia coli

DOI:  https://doi.org/10.3390/biomedicines14010078
Nat Commun. 2026 Jan 28.

Leveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to enhance colorectal cancer vaccine response.

Firas Hamdan, Sara Gandolfi, Federica D'Alessio, Yvonne Giannoula, Julia Kolikova, Manlio Fusciello, Elisa Zaghen, Alessandra Napolano, Salvatore Russo, Ozan Izci, Paolo Bottega, Jacopo Chiaro, Kirsi-Marja Alanen, Gabriella Antignani, Michaela Feodoroff, Virpi Stigzelius, Milda Sakalauskaite, Janita Sandberg, Anni I Nieminen, Nicola Zambrano, Ove Eriksson, Satu Mustjoki, Toni T Seppälä, Mikaela Grönholm, Vincenzo Cerullo.

Colorectal cancer (CRC) remains refractory to most immunotherapies, with cancer vaccines failing due to an immunosuppressive tumor microenvironment. Here, we show that β-glucan-induced trained immunity overcomes these barriers by reprogramming macrophages through H3K4me3-dependent epigenetic modifications and metabolic rewiring. In female mice vaccinated with peptide-coated adenovirus-based vaccine PeptiCrad, training enhances glycolysis with creatine metabolism sustaining CXCL9/10 production, enabling macrophages to recruit NK cells via CXCR3. In turn, NK cells produce CCL5, driving cDC1 infiltration and antigen presentation, which together amplify effector memory CD8⁺ T cell responses. Moreover, with human peripheral blood mononuclear cells and CRC patient-derived organoids, trained macrophages boost NK migration, antigen-specific T cell activation, and tumor killing. These findings highlight trained immunity as a powerful adjuvant to reinvigorate colorectal cancer vaccination.

DOI: https://doi.org/10.1038/s41467-026-68466-5
J Control Release. 2026 Jan 26. pii: S0168-3659(26)00065-9. [Epub ahead of print] 114664

Macrophage membrane-biomimetic DNA nanocages deliver taurine to reprogram trained immunity for periodontitis therapy.

Ya Cui, Xiaojing Li, Shebin Hong, Kaili Lin, Lixia Mao, Xudong Wang.

  As one of the most burdensome oral diseases, periodontitis frequently leads to tooth loss and heightens the risk of systemic diseases. A major clinical challenge is that current strategies often fail to resolve chronic inflammation and bone resorption characteristic of its refractory state. Recent research implicates maladaptive trained immunity (TRIM) as a core mechanism, which promotes myeloid cell skewing and amplifies inflammatory responses and bone loss. Single-cell sequencing of peripheral blood mononuclear cells from periodontitis patients identified an elevated inflammatory stress state. Taurine, a sulfur-containing amino acid with known anti-inflammatory properties, offers therapeutic potential, but its application is limited by low oral bioavailability and a lack of target specificity. To address these challenges, a novel therapeutic strategy based on precisely engineered DNA nanocages carrying taurine has been developed. These nanocages are camouflaged with hybrid cell membranes harvested from M2-polarized and trained-immunosuppressive macrophages for targeted monocytes. This biomimetic system is designed to therapeutically correct the dysregulated TRIM state in monocytes and macrophages, effectively inhibiting inflammation and bone destruction. Concurrently, it restores the osteogenic differentiation and mitochondrial function of periodontal ligament cells via immune modulation, establishing a novel strategy for the precise immunotherapy of chronic periodontitis.

Keywords:  Biomimetic delivery system; Immunotherapy; Macrophage; Periodontitis; Taurine

DOI:  https://doi.org/10.1016/j.jconrel.2026.114664
J Inflamm (Lond). 2026 Jan 27.

Sepsis induces long-term reprogramming of human HSPCs and drives myeloid dysregulation in sepsis survivors.

Marco De Zuani, Petra Lázničková, Marcela Hortová Kohoutková, Veronika Bosáková, Ivana Andrejčinová, Natália Vadovičová, Veronika Tomášková, Alexandra Mýtniková, Julie Štíchová, Tomáš Tomáš, Jiří Hrdý, Kristýna Boráková, Stjepan Uldrijan, Marcela Vlková, Vladimír Šrámek, Martin Helán, Kamila Bendíčková, Jan Frič.

   BACKGROUND: Sepsis is a life-threatening condition characterised by an overwhelming immune response and high fatality. While most research has focused on its acute phase, many sepsis survivors remain immunologically weakened leaving them susceptible to serious complications from even mild infections. The mechanisms underlying this prolonged immune dysregulation remain unclear, limiting effective interventions. Here, we analysed whether sepsis induced long-term "training" in hematopoietic stem and progenitor cells (HSPCs), imprinting changes that persist in their myeloid progeny.
RESULTS: Peripheral blood analysis of 8 sepsis survivors, 12 patients with septic shock, and 10 healthy donors revealed a significant expansion of CD38 + progenitors in survivors, with increased megakaryocyte-erythroid progenitors and a near significant reduction in mature neutrophil counts. This shift suggests impaired granulopoiesis, favouring immature, immunosuppressive granulocytes. Differentiated macrophages from survivors' HSPCs exhibited impaired metabolic pathways after lipopolysaccharide stimulation, with downregulation of tricarboxylic acid cycle and glycolysis genes, indicating altered immune metabolism. Pathway analysis revealed enhanced type-I interferon (IFN) and JAK-STAT signalling in survivors' macrophages, reflective of potentially tolerance-prone reprogramming. Finally, exposing healthy donor HSPCs to IFNβ during macrophage differentiation reduced HSPC proliferation, increased apoptosis, and induced a metabolic shift towards glycolysis over mitochondrial respiration.
CONCLUSIONS: Together, these findings suggest that sepsis induces lasting reprogramming in HSPCs leading to myeloid progeny with altered immune memory that might drive immune dysregulation in survivors. These data open avenues to explore potential targets to better manage long-term immune alterations in sepsis survivors.

Keywords:  Dysregulation; Hematopoietic stem and progenitor cell; Macrophage; Metabolic impairment; Reprogramming; Sepsis; Sepsis survivor; Septic shock; Signalling

DOI:  https://doi.org/10.1186/s12950-025-00483-5
Immunity. 2026 Jan 28. pii: S1074-7613(25)00566-7. [Epub ahead of print]

A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.

Gillian Dunphy, Irene Adán-Barrientos, Irene Fernández-Delgado, Carolina Villarroya-Beltri, Ignacio Heras-Murillo, Elena Moya-Ruiz, Miguel Sánchez-Álvarez, Aitor Jarit-Cabanillas, Miguel A Del Pozo, Susana Guerra, Francisco Sánchez-Madrid, David Sancho.

  Macrophage metabolism is intricately linked to cellular function. Contrasting with Toll-like receptor (TLR) stimulation, cytosolic nucleic acid sensing induced a decrease in mitochondrial membrane potential (MMP) while maintaining mitochondrial respiration. Interferon α/β (IFN-I) receptor (IFNAR) signaling was necessary and sufficient for this metabolic response. IFNAR signaling induced interferon-stimulated gene 15 (ISG15) expression and ISGylation of mitochondrial proteins, including subunits of mitochondrial complex V, increasing ATP production and decreasing MMP, thus enhancing macrophage efferocytic capacity. Moreover, the IFNAR-ISG15-mediated drop in MMP activated the mitochondrial protease OMA1, inducing mitochondrial fission and decreasing endoplasmic reticulum-mitochondria communication, thus dampening IFN-stimulated gene (ISG) induction. Loss of ISG15 or OMA1 enhanced histone acetylation and ISG induction upon IFN-I stimulation, in a manner dependent on mitochondrial calcium uptake. This increase in ISG induction provided protection against acute viral infections. These data indicate that IFNAR-ISG15 signaling boosts efferocytosis while limiting ISG induction, thereby promoting the resolution of inflammation.

Keywords:  efferocytosis; interferon-stimulated genes; macrophage; metabolism; mitochondrial endoplasmic reticulum contacts; mitochondrial fission; mitochondrial membrane potential; oxidative phosphorylation; type I interferon; viral infection

DOI:  https://doi.org/10.1016/j.immuni.2025.12.010
Cell Host Microbe. 2026 Jan 27. pii: S1931-3128(26)00002-8. [Epub ahead of print]

Enterococcus faecalis-derived lactic acid suppresses macrophage activation to facilitate persistent and polymicrobial wound infections.

Ronni A G da Silva, Brenda Yin Qi Tien, Patrick Hsien Neng Kao, Haris Antypas, Cenk Celik, Ai Zhu Casandra Tan, Muhammad Hafiz Ismail, Guangan Hu, Kelvin Kian Long Chong, Guillaume Thibault, Jianzhu Chen, Kimberly A Kline.

  Macrophage activation is essential for innate immunity and antimicrobial defense. We show that Enterococcus faecalis suppresses macrophage activation through lactic-acid-mediated acidification of the extracellular environment, enabling pathogen persistence. E. faecalis-derived lactic acid acts via the lactate transporter monocarboxylate transporter 1 (MCT-1) and the sensor GPR81 to initiate complementary mechanisms that collaboratively reduce nuclear factor κB (NF-κB) activity. Lactic acid acts through MCT-1 to inhibit extracellular signal-regulated kinase and STAT3 phosphorylation, leading to reduced levels of the adaptor MyD88 involved in NF-κB activation. Lactic acid signaling to GPR81 induces phosphorylation of the transcription factor YAP, ultimately attenuating NF-κB signaling. A bacterial mutant lacking lactate dehydrogenase is unable to acidify the environment and thus fails to inhibit NF-κB. In a murine wound infection model, lactic-acid-driven immunosuppression enables prolonged E. faecalis persistence and enhances the fitness of co-infecting bacteria such as Escherichia coli. These findings reveal how bacterial lactic acid subverts innate immunity to support chronic and polymicrobial infections.

Keywords:  E. faecalis; NF-κB inhibition; lactic acid; lactic acid signaling; lactic-acid-mediated immune evasion; macrophage immunosuppression; macrophages; polymicrobial wound infections; recalcitrant wound infections

DOI:  https://doi.org/10.1016/j.chom.2026.01.002
Br J Cancer. 2026 Jan 29.

Fasting-mimicking diet induces IFNβ secretion in tumor-associated macrophages via NRF1-mediated ubiquitin-dependent proteolysis of Trex1.

Jiakun Li, Wenjiao Jiang, Guowei Tu, Ziwen Zhong, Zhe Luo, Tiffany Horng, Changhong Miao.

BACKGROUND: Fasting-mimicking diet (FMD) is a safe and effective strategy in clinical oncology via metabolically restricting tumour growth and remodelling the immunity. To date, few studies have investigated the impact of on tumour-associated macrophages (TAMs), which are a crucial component of immune cells in the tumour microenvironment. Fasting can induce the ubiquitin-proteasome system (UPS) to regulate intracellular protein turnover homoeostasis, while Nuclear Factor Erythroid 2-like 1 (NRF1; encoded by the gene Nfe2l1), which controls proteasome gene transcription, may potentially be induced by fasting. However, whether NRF1 is induced by FMD/fasting, and how NRF1-mediated protein turnover works on TAMs remain unknown. This study investigated the hypothesis that FMD activates the anti-tumour immunity of TAMs by ubiquitinated protein metabolism.
METHODS: Subcutaneous MC38 tumour models were established in WT and myeloid-specific NRF1 knockout (Mye-NFE2L1-/-) C57BL/6 mice, treated with FMD alone or combined with intraperitoneal Trex1 inhibitor (Trex1-IN-1). TAMs were isolated from tumour tissues using CD11b+ magnetic bead sorting. In vitro, bone marrow-derived macrophages (BMDMs) were co-cultured with MC38 in fasting medium, with MC38 proliferation assessed by CCK8 assay. BMDM-derived TAMs (B-TAMs) were induced by MC38 supernatant under fasting conditions. IFNβ levels in serum and cell supernatant were measured by ELISA. RNA-seq was performed to compare WT and Mye-NFE2L1-/- BMDMs under fasting conditions. Protein levels of cGAS-Sting pathway components, ubiquitinated proteins, and nuclear NRF1 were analysed by Western blot, while Trex1 ubiquitination was assessed by Co-IP. qPCR quantified IFNβ-related gene expression and mitochondrial DNA (mtDNA) copy number. Trex1-mitochondria colocalization was examined by immunofluorescence, and Trex1-bound mtDNA levels were determined by ChIP-qPCR.
RESULTS: FMD/fasting triggers interferon-β (IFNβ) secretion in TAMs, which is driven by protein metabolism. In TAMs with FMD, an initial accumulation of ubiquitinated proteins occurs concomitantly with the induction of NRF1 in response to fasting-induced energy stress, leading to the ubiquitin/proteasome-dependent proteolysis of the three prime repair exonuclease 1 (Trex1) through UPS. Such a process engages type I interferon responses, which derepress the cGAS-Sting-IFNβ axis to promote anti-tumour effects of TAMs. In the absence of NRF1, Trex1 accumulates due to impaired UPS and binds to mtDNA, disrupting cGAS sensing of mtDNA to inhibit IFNβ secretion in TAMs, which attenuates anti-tumour effects of FMD/fasting.
CONCLUSION: In this study, we revealed for the first time that FMD/fasting coordinates NRF1-UPS and Trex1/Sting-mediated type I interferon responses in TAMs that contribute to suppressing tumour growth. Graphical abstract: FMD upregulates the entry of NRF1 into the TAM nucleus to promote gene expression of proteasome subunits, which induces the ubiquitin/proteasome-dependent proteolysis of Trex1, leading to derepression of the cGAS-Sting-IFNβ axis. On the other hand, FMD triggers increasing of mtDNA in TAMs, promoting the cGAS-Sting-IFNβ axis to release IFNβ. In myeloid NRF1 knockout TAMs, transcriptional levels of proteasome subunits are reduced, resulting in impaired proteolysis of Trex1 and its subsequent accumulation during fasting. Then, Trex1 binds to mtDNA, directing the inhibition of the cGAS-Sting-IFNβ axis and inhibiting IFNβ secretion of macrophages.

DOI: https://doi.org/10.1038/s41416-025-03319-4
Acta Pharm Sin B. 2026 Jan;16(1): 337-351

Gambogenic acid ameliorates inflammation by inhibiting HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis.

Huanhuan Pang, Honglin Chen, Peng Chen, Xu Wei, Hongda Liu, Xueling He, Yang Yang, Junzhe Zhang, Dianfei Li, Linlin Lou, Wen Xie, Chong Qiu, Fei Xia, Qiuyan Guo, Shengnan Shen, Qiaoli Shi, Weiguang Li, Guang Han, Xijun Wang, Jigang Wang, Chengchao Xu.

  Sepsis is a life-threatening disease caused by the dysregulated host immune response to infection, which eventually leads to multi-organ failure. Current therapeutic strategies rely heavily on antibiotics. However, conventional antimicrobial therapy often leads to antibiotic abuse and resistance. Therefore, it is of utmost importance to develop new agents for treating sepsis. Here, we demonstrated that gambogenic acid (GNA) not only restricted the release of inflammatory cytokines in lipopolysaccharide (LPS)-stimulated macrophages but also attenuated the inflammatory response and organ damage in septic mice. By using the activity-based protein profiling (ABPP) strategy, we identified 30 potential target proteins of GNA. Among these potential targets, we found that GNA directly bound to the Cys684 residue of hexokinase 1 (HK1) and affected its enzyme activity and cellular localization. These findings were confirmed by the cellular thermal shift assay (CETSA), bio-layer interferometry (BLI), and single-site mutation experiments. Functionally, siHK1 alleviated the Warburg effect, suppressed the activation of NLRP3 inflammasome, and eventually suppressed the release of inflammatory cytokines. Taken together, our findings demonstrated that GNA could attenuate inflammation by alleviating HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis and could serve as a novel therapeutic agent for sepsis and inflammatory disorders.

Keywords:  Activity-based protein profiling (ABPP); Chemical proteomics; Gambogenic acid (GNA); Hexokinase 1 (HK1); Inflammation; Sepsis; Target identification; Warburg effect

DOI:  https://doi.org/10.1016/j.apsb.2025.10.020
Nature. 2026 Jan 28.

Environmentally driven immune imprinting protects against allergy.

S Erickson, B Lauring, J Cullen, R Medzhitov.

Allergic diseases are caused by overexuberant type II immune responses mounted against environmental antigens1. The allergic state is typified by the presence of allergen-reactive immunoglobulin E (IgE), which triggers mast cell degranulation upon allergen encounter, manifesting in pruritis, oedema and, in severe cases, anaphylaxis. Over the past century, the prevalence of allergic diseases has increased markedly, suggesting that environmental rather than genetic factors are mediating this change2. Although many hypotheses connecting environment to allergy exist3-6, the biological mechanisms that underpin environmentally mediated protection from allergy are unknown. Here we show, using a mouse model of allergic disease, that exposure to immunostimulatory environments generated cross-reactive adaptive immune memory, which tracked with obstructed type II immune responses upon allergen exposure. We found that engagement of cross-reactive adaptive immunity protected against future allergic sensitization and suppressed established allergic responses. Cross-reactivity in a tolerogenic context also prevented allergy, with the effect extending across antigenically complex exposures even at low protein sequence similarity. Our findings demonstrate a mechanistic relationship between environment and allergy, with general implications for adaptive immune function in natural settings.

DOI: https://doi.org/10.1038/s41586-025-10001-5
Cell Rep. 2026 Jan 27. pii: S2211-1247(25)01655-9. [Epub ahead of print]45(2): 116883

Cross-disease analysis identifies the inflammatome as a transcriptional program of inflammation.

Isabel Díaz-Pinés Cort, Oana Palasca, Luca Finn Gaessler, Tim Holm Jakobsen, Thomas Bjarnsholt, Lars Juhl Jensen.

  Inflammation is a complex biological process that upregulates numerous genes compared to homeostasis. These transcriptional changes can dominate the statistical signal in differential expression analyses and confound the detection of disease-specific effects. Here, we exploit inflammatory signals in public clinical transcriptomic datasets to derive the inflammatome, a comprehensive set of 2,000 genes consistently upregulated in various inflammatory diseases vs. healthy controls. Within this set, we define the inflammation signature, a high-confidence subset of 100 genes capturing the most consistent changes. We demonstrate how these gene sets can be used to identify and filter inflammation-associated changes in gene expression and protein abundance. Additionally, we introduce a sample-wise inflammation score derived from the inflammation signature and show its correlation with clinical disease severity. To support broad usability, we provide these functionalities in a user-friendly Shiny app. This resource will enable users to assess the effect of inflammation in future transcriptomic and proteomic studies.

Keywords:  CP: genomics; CP: immunology; confounder effects; gene signature; inflammation; inflammatome; inflammatory diseases; proteomics; transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2025.116883