bims-traimu 2025-07-06 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–07–06
eighteen papers selected by
Yantong Wan, Southern Medical University

The double-edged nature of trained immunity.
IFNγ-induced memory in human macrophages is not sustained by epigenetic changes but the durability of the cytokine itself.
Current insights into insect immune memory.
Epigenetic and metabolic regulation of macrophage responsiveness and memory.
Central trained immunity in the context of bladder cancer immunotherapy.
Covalent Organic Frameworks-Delivered Reuterin Drives Trained Immunity in Tumor-Associated Macrophages to Enhance Melanoma Immunotherapy via Glycerophospholipid Metabolism.
Unleashing the power of the BCG vaccine in modulating viral immunity through heterologous protection: A scoping review.
Long-term immune changes after COVID-19 and the effect of BCG vaccination and latent infections on disease severity.
Does immune priming in Galleria mellonella reveal plastic mechanisms for survival?
Microglial immune memory in Parkinson's and Huntington's diseases: epigenetics, triggers, and therapies.
Engineered Bacteria-Nanoparticle Conjugate Reprograms Immunosuppressive Niche via Dendritic Cell-Centric Innate-Adaptive Immune Coupling.
VCPIP1 potentiates innate immune responses by non-catalytically reducing the ubiquitination of IRAK1/2.
The trapping of live neutrophils by macrophages during infection.
Thermal proteome profiling of itaconate interactome in macrophages.
Modeling heterogeneous signaling dynamics of macrophages reveals principles of information transmission in stimulus responses.
Acod1 Promotes PAD4 Ubiquitination via UBR5 Alkylation to Modulate NETosis and Exert Protective Effects in Sepsis.
Deubiquitinase-dependent transcriptional silencing controls inflammation.
Immune mechanisms and signatures in lethal and non-lethal sepsis revealed by single-cell transcriptomics.

Elife. 2025 Jul 03. pii: e107787. [Epub ahead of print]14

The double-edged nature of trained immunity.

Chrissy M Leopold Wager, Larry S Schlesinger.

  Trained immunity in alveolar macrophages can lead to damaging lung inflammation, confirming the importance of context in this phenomenon.

Keywords:  acute lung injury; alveolar macrophage; beta-glucan; immunology; inflammation; mouse; trained immunity

DOI:  https://doi.org/10.7554/eLife.107787
bioRxiv. 2025 Jun 17. pii: 2025.06.12.659073. [Epub ahead of print]

IFNγ-induced memory in human macrophages is not sustained by epigenetic changes but the durability of the cytokine itself.

Aleksandr Gorin, Noa Harriott, Vyas Koduvayur, Quen J Cheng, Alexander Hoffmann.

Macrophages, as key sentinel cells of the innate immune system, can retain memory of prior stimulus exposure. Interferon gamma (IFNγ) plays a central role in maintaining trained immunity in vivo and can induce potent memory in macrophages. Such memory is associated with the formation of de novo enhancers that alter gene expression responses to subsequent stimuli. However, how such enhancers are maintained after cytokine exposure remains unclear. We report that durable IFNγ-induced enhancers can last for days after cytokine washout, yet the underlying persistence mechanism is not cell-intrinsic. IFNγ-treated macrophages continue to exhibit JAK/STAT signaling days after cytokine removal. Blocking IFNγ signaling with a JAK inhibitor or anti-IFNγ neutralizing antibodies after cytokine removal is sufficient to reverse IFNγ-induced enhancers and erase the potentiated state of the treated macrophages. Our findings suggest that epigenetic changes in macrophages do not inherently encode innate immune memory or a "potentiated" macrophage state, but in fact are themselves dependent on ongoing cytokine signaling. These findings suggest new possibilities for pharmacologic interventions to reverse aberrantly trained immune states associated with pathology.

DOI: https://doi.org/10.1101/2025.06.12.659073
Elife. 2025 Jul 01. pii: e105011. [Epub ahead of print]14

Current insights into insect immune memory.

Gabriela Krejčová, Adam Bajgar.

  Traditionally, insects have been thought to be entirely dependent on their innate immune system, which has little capacity for the acquisition of experience from previous infections. However, much experimental evidence has challenged this view, showing that insects can develop long-term, pathogen-specific immune memory, which in some cases can be transmitted to offspring. Although significant progress has been made in this area, the underlying mechanism is still not fully understood, and a number of fundamental questions remain unanswered. In this review, we present an overview of documented cases of insect immune memory and summarize the experimental evidence in support of the prevailing hypotheses on the mechanism of antiviral and antibacterial immune memory in insects. We also highlight key questions that remain unanswered and discuss Drosophila melanogaster as a powerful model organism for investigating the mechanisms of innate immune memory formation. Finally, we evaluate the significance of this research and explore the potential for insect vaccination.

Keywords:  Dscam; evolutionary biology; hemocytes; immune memory; immunology; inflammation; insect immunity; insect vaccination; trained immunity

DOI:  https://doi.org/10.7554/eLife.105011
J Immunol. 2025 Jul 01. pii: vkaf135. [Epub ahead of print]

Epigenetic and metabolic regulation of macrophage responsiveness and memory.

Maria G Daskalaki, Ioanna Lapi, Avery Ellen Hurst, Ahmed Al-Qahtani, Eleni Vergadi, Christos Tsatsanis.

  Macrophages, the central mediators of innate immune responses, can adapt and build nonspecific memory, also known as innate immune memory or trained immunity. Training of macrophages occurs through epigenetic changes and metabolic rewiring, which fuels macrophage responsiveness. In addition to training in response to infectious insults, macrophage responsiveness can be modulated by pathogenic de-regulation of hormones, cytokines, or adipokines, which similarly induce epigenetic changes in inflammatory genes. Sex specific differences in macrophage responsiveness to TLR ligands have been described, with sex hormones playing a crucial role in shaping the epigenetic landscape and regulating inflammatory responses. Chronic metabolic disorders, such as obesity and type 2 diabetes, also affect macrophage responsiveness. In particular, insulin resistance impairs Akt signaling in macrophages in an Akt isoform-specific manner, altering their metabolism, their responsiveness to inflammatory insults and their capacity to eliminate pathogens. These functional impairments are underpinned by changes in the epigenetic landscape of macrophages. Given the short half-life of macrophages in the periphery, these long-lasting alterations in their responsiveness originate in the bone marrow at the level of hematopoietic stem and progenitor cells. Recent studies have demonstrated that exposure to TLR ligands induces immunological memory driven by changes in hematopoietic stem and progenitor cells. These changes include epigenetic alterations in histones and DNA. Herein we discuss recent evidence on the epigenetic and metabolic regulation of macrophage memory, highlight sex hormone-driven changes, describe changes driven by metabolic factors and obesity, and explore the therapeutic potential of targeting epigenetic regulators for the treatment of inflammatory diseases.

Keywords:  Akt; epigenetics; gender; innate immunity; macrophages; memory; metabolism; obesity; sex; trained immunity

DOI:  https://doi.org/10.1093/jimmun/vkaf135
Cancer Cell. 2025 Jun 27. pii: S1535-6108(25)00260-0. [Epub ahead of print]

Central trained immunity in the context of bladder cancer immunotherapy.

Julia Chronopoulos, Maria Crespo, Triantafyllos Chavakis.

Two articles in Immunity and Cancer Cell describe that bladder cancer immunotherapy with Bacillus Calmette-Guerin (BCG) alone or in combination with β-glucan, another agonist of trained immunity (TRIM), involves reprogramming of bone marrow (BM) hematopoiesis. These findings provide additional evidence of the therapeutic potential of BM-mediated TRIM against cancer.

DOI: https://doi.org/10.1016/j.ccell.2025.06.010
Adv Sci (Weinh). 2025 Jun 30. e04784

Covalent Organic Frameworks-Delivered Reuterin Drives Trained Immunity in Tumor-Associated Macrophages to Enhance Melanoma Immunotherapy via Glycerophospholipid Metabolism.

Jian-Gang Zhang, Xiao-Mei Zhang, Xi Wu, Cheng-Kai Zhou, Zhen-Zhen Liu, Xue-Yue Luo, Liang Zhang, Wei Chen, Yong-Jun Yang.

  The gut microbiota is increasingly recognized as a promising therapeutic target in cancer treatment. However, the specific mechanisms by which gut bacteria and their metabolites exert therapeutic effects in melanoma remain poorly understood. In this study, it is unexpectedly demonstrated that prophylactic supplementation with Limosilactobacillus reuteri exhibits significant tumor-suppressive properties, primarily mediated by its secreted metabolite, reuterin. This metabolite induces trained immunity through macrophage metabolic reprogramming, thereby enhancing antitumor immune responses. Mechanistically, this process involves stabilizing HIF-1α via the AHR-ROS signaling pathway, enhancing glycerophospholipid metabolism, and elevating arachidonic acid levels, thereby amplifying the trained immunity response. Similar to reuterin, arachidonic acid also induces trained immunity and facilitates macrophage-mediated tumor cell killing. To enhance its therapeutic efficacy, reuterin is encapsulated in covalent organic frameworks (COFs). COF-Reuterin demonstrates superior effects in tumor-associated macrophages (TAMs), remodulating intratumor bacteria and directly facilitating tumor cell killing. Notably, COF-Reuterin demonstrates superior therapeutic efficacy compared to cisplatin. Furthermore, COF-Reuterin reprogrammed TAMs from an M2 to an M1 phenotype, increasing CD8+ T cell infiltration and decreasing myeloid-derived suppressor cells (MDSCs), reshaping the immunosuppressive tumor microenvironment. These findings highlight the potential of probiotics and their metabolites in the metabolic reprogramming of TAMs, offering a promising cancer therapeutic approach.

Keywords:  Limosilactobacillus reuteri; intratumor bacteria; melanoma; reuterin; trained immunity; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/advs.202504784
Hum Vaccin Immunother. 2025 Dec;21(1): 2521190

Unleashing the power of the BCG vaccine in modulating viral immunity through heterologous protection: A scoping review.

Thales A Campelo, Natália S Oliveira, Pedro F N Souza, Denis F G de-Oliveira, Cristiane C Frota, Paulo R Z Antas.

  The Bacillus Calmette-Guérin (BCG) vaccine, used against tuberculosis for a century, shows promise in protecting against viral infections through trained/innate immunity. This review maps clinical and preclinical studies on both parental (WT) and recombinant BCG (rBCG) against 17 common viruses. From 68 studies, BCG strains were found to enhance innate immune responses by reprogramming myeloid cells, leading to stronger responses to related infections. Sixteen rBCG candidates expressed viral antigens, activating CD4+ and CD8+ T cells, and stimulating antibody production specific to the viral antigens. However, challenges like genetic stability and varied efficacy among BCG strains remain. The review highlights the potential of BCG, especially rBCG, as a multivalent vaccine platform for immunization campaigns, with significant public health implications. More translational studies and clinical trials are needed to confirm these findings.

Keywords:  Recombinant BCG; immunity; innate immune response; trained immunity; viral diseases

DOI:  https://doi.org/10.1080/21645515.2025.2521190
Clin Transl Immunology. 2025 ;14(7): e70041

Long-term immune changes after COVID-19 and the effect of BCG vaccination and latent infections on disease severity.

Kamila Bendíčková, Ioanna Papatheodorou, Gabriela Blažková, Martin Helán, Michaela Haláková, Petr Bednář, Erin Spearing, Lucie Obermannová, Julie Štíchová, Monika Dvořáková Heroldová, Tomáš Tomáš, Roman Panovský, Vladimír Šrámek, Marco De Zuani, Marcela Vlková, Daniel Růžek, Marcela Hortová-Kohoutková, Jan Frič.

   Objectives: Several years after the COVID-19 pandemic, the impact of SARS-CoV-2 on immunity and the potential protective role of Bacillus Calmette-Guérin (BCG) vaccination through trained immunity remain a subject of investigation. This study aimed to determine the long-term impact of SARS-CoV-2 on immune cells and the association between BCG vaccination, latent infections and COVID-19 severity and sepsis progression.
Methods: We conducted a prospective analysis of patients who recovered from mild/severe/critical COVID-19 (n = 97, 3-17 months after COVID-19) and sepsis patients (n = 64). First, we assessed the impact of COVID-19 and its severity on immune cell frequencies and expression of functional markers. Further, we analysed plasma titres of anti-Toxoplasma gondii/cytomegalovirus/BCG antibodies and their association with COVID-19 severity and sepsis outcome. To examine monocyte responses to secondary challenge, monocytes isolated from COVID-19 convalescent patients, BCG vaccinated and unvaccinated volunteers were stimulated with SARS-CoV-2 and LPS.
Results: Post-COVID-19 patients showed immune dysregulation regardless of disease severity characterised by altered expression of activation and functional markers in myeloid (CD39, CD64, CD85d, CD11b) and lymphoid cells (CD39, CD57, TIGIT). Strikingly, post-critical COVID-19 patients showed elevated expression of CD57 in CD8+ T cells compared to other severity groups. A trend toward improved outcomes in BCG-seropositive COVID-19/sepsis patients was observed, although this may be confounded by age differences between groups. In contrast, the monocyte response to stimulation appeared unaffected by COVID-19 severity.
Conclusion: These findings highlight the long-term alterations of immune cells in post-COVID-19 patients, emphasising the substantial impact of COVID-19 on immune function.

Keywords:  Bacillus Calmette–Guérin (BCG) vaccination; COVID‐19; Toxoplasma; cytomegalovirus; immune cells; sepsis

DOI:  https://doi.org/10.1002/cti2.70041
Dev Comp Immunol. 2025 Jun 27. pii: S0145-305X(25)00096-5. [Epub ahead of print]169 105407

Does immune priming in Galleria mellonella reveal plastic mechanisms for survival?

Fátima Terán-Murillo, Enakshi Ghosh, Markus J Rantala, Indrikis Krams, Ronald Krams, Jorge Contreras-Garduño.

  Immune priming enhances protection in invertebrates upon secondary exposure to specific pathogens. Despite significant advances in understanding this phenomenon, it remains unclear whether the elevated defense observed through priming arises from identical or distinct effector-mediated responses within the same species. To address this, we used the model species Galleria mellonella from two geographically distinct origins (Siberia and Mexico), both of which exhibited immune priming with enhanced survival. We measured five immune effectors in primed individuals to investigate whether the mechanisms behind immune priming were conserved. Remarkably, we identified distinct effector responses associated with immune priming between the two groups. Individuals of Siberian origin exhibited an increased total hemocyte count, and a higher number of live hemocytes in primed individuals. In contrast, individuals of Mexican origin demonstrated a higher lytic activity and a higher level of hydrogen peroxide production in the priming group compared with control. Phenoloxidase activity did not significantly differ across treatments in either group. Our findings suggest that G. mellonella from different origins achieve similar survival through different physiological effectors. These results highlight the diversity of immune priming mechanisms within a single species and support the idea that the immune priming mechanisms in invertebrates may be plastic within and across species.

Keywords:  Bacteria; Ecoimmunology; Host-parasite relationship; Immune priming; Innate memory; Invertebrates; Trained immunity

DOI:  https://doi.org/10.1016/j.dci.2025.105407
Epigenomics. 2025 Jul 01. 1-14

Microglial immune memory in Parkinson's and Huntington's diseases: epigenetics, triggers, and therapies.

Reema Chowdhury, Anna Hendlinger, Olaf Riess, Julia Schulze-Hentrich.

  Neurodegenerative disorders, like Parkinson's and Huntington's disease, have a profound global impact but currently lack effective treatments. Accumulations of misfolded proteins of α-synuclein and huntingtin are a common pathological hallmark in these diseases, respectiveley. Recently, the role of microglia and innate immune memory in modulating neurodegenerative diseases has been studied in more detail. This review explores the mechanisms of microglial activation in Parkinson's and Huntington's, emphasizing innate immune memory, epigenetic reprogramming, and the influence of external triggers such as lipopolysaccharides (LPS) and high-fat diets (HFD). The review also examines therapeutic strategies targeting microglia to mitigate neurodegeneration, including shifting microglial phenotypes from pro-inflammatory to anti-inflammatory states using epigenetic interventions. To support this review, a structured literature search was conducted using PubMed, Scopus, and Web of Science. Keywords included microglia, innate immune memory, epigenetics, neuroinflammation, and disease-specific terms. Future research should focus on improving animal models, investigating environmental stressors, and developing reliable biomarkers to strengthen translational approaches for neuroinflammatory-driven neurodegenerative diseases.

Keywords:  Huntington's disease; Parkinson's disease; epigenetics; innate immune memory; microglia

DOI:  https://doi.org/10.1080/17501911.2025.2518909
ACS Nano. 2025 Jul 02.

Engineered Bacteria-Nanoparticle Conjugate Reprograms Immunosuppressive Niche via Dendritic Cell-Centric Innate-Adaptive Immune Coupling.

Xiaoxi Wang, Gaoli Shi, Xueqin Zhu, Zimai Liu, Meiyi Liu, Zixian Wu, Zonghong He, Kai Li, Tiantian Zhang, Hui Liu, Jiao Lu, Yuanyuan Wei, Qianxi Lu, Pingping Zhu, Yongchao Wang, Zhenzhen Chen.

  The immunosuppressive tumor microenvironment (TME) represents a critical barrier to effective T cell activation, contributing to immunotherapy resistance. Dendritic cells (DCs), essential initiators of T cell-mediated adaptive immunity, frequently display both quantitative defects and functional impairments within the TME. Compounding this challenge, emerging evidence highlights the indispensable role of innate immunity in sustaining T cell activity and establishing durable immunological memory. To address these limitations, we engineered M-CHNP/D: a bacteria-nanoparticle hybrid platform integrating Escherichia coli with acid-responsive calcium carbonate nanoparticles encapsulating the programmed cell death ligand-1 blocking peptide DPPA-1. Leveraging the motility and targeting capabilities of bacteria, M-CHNP/D achieves a deep tumor penetration and neutralizes the acidic TME. M-CHNP/D induced tumor-cell-derived CCL3 upregulation, driving DC recruitment and spatial redistribution within the tumor parenchyma. This intervention enhanced DCs' antigen-presenting capacity, ultimately potentiating adaptive immune responses. Furthermore, M-CHNP/D administration significantly increased the population of innate immune cells and induced their phenotypic reprogramming toward antitumor functional states. By reshaping the immune "hot" network, M-CHNP/D combined with radiotherapy effectively inhibited tumor growth and recurrence. M-CHNP/D demonstrates significant potential in modulating both innate and adaptive immunity, offering a robust strategy for improving cancer immunotherapy outcomes.

Keywords:  adaptive immunity; bacteria-based drug delivery system; functional DCs; immunosuppressive microenvironment; trained immunity

DOI:  https://doi.org/10.1021/acsnano.5c03960
Cell Rep. 2025 Jun 27. pii: S2211-1247(25)00702-8. [Epub ahead of print]44(7): 115931

VCPIP1 potentiates innate immune responses by non-catalytically reducing the ubiquitination of IRAK1/2.

Liyan Lou, Jiangyun Shen, Jianzhao Zhang, Fuqi Mei, Deyu Deng, Deqi Wang, Yanqi Xu, Kangmin Chen, Baoli Cheng, Jinghua Liu, Xu Wang.

  The host innate immune system is efficiently activated after recognizing microbial components, such as lipopolysaccharide (LPS), by Toll-like receptors (TLRs). However, the molecular basis for the regulation of TLR-mediated signaling remains poorly understood. Here, we report that valosin containing protein interacting protein 1 (VCPIP1), a deubiquitinating enzyme, acts as a critical positive regulator of TLR4 signaling. TLR4 activation induces the upregulation and nuclear-to-cytoplasmic translocation of VCPIP1. The cytoplasmic VCPIP1 interacts with interleukin-1 receptor-associated kinase 1 and 2 (IRAK1/2) and maintains IRAK1/2 protein levels by reducing their degradation through the ubiquitin-proteasome system. Instead of directly deubiquitinating IRAK1/2 through the enzymatic activity, VCPIP1 blocks the K48 ubiquitination of IRAK1/2 in a non-catalytic manner. Ablation of VCPIP1 significantly attenuates LPS-induced inflammatory gene expression in macrophages. Consistently, VCPIP1-deficient mice are less susceptible to sepsis. Thus, this work reveals an essential role of VCPIP1 in TLR4 signaling and suggests that VCPIP1 may become a potential therapeutic target for inflammatory diseases.

Keywords:  CP: Cell biology; CP: Immunology; VCPIP1; innate immune response; sepsis; signal transduction; ubiquitination

DOI:  https://doi.org/10.1016/j.celrep.2025.115931
Cell Death Dis. 2025 Jul 03. 16(1): 488

The trapping of live neutrophils by macrophages during infection.

Kelley N Cooper, Marina Terekhova, Barbara Potempa, Ana D'Aubeterre, Jerome Timbol, Si An Chen, Antoine Dufour, Shunying Jin, Maxim N Artyomov, Jan Potempa, Juhi Bagaitkar.

Neutrophils are highly abundant in the oral mucosal tissues, and their balanced activation and clearance are essential for immune homeostasis. Here, we demonstrate that neutrophils infected with the bacterial pathogen Porphyromonas gingivalis (Pg) are captured alive by macrophages in a manner that bypasses all known receptor-ligand interactions involved in the phagocytosis of either live or dead cells. Mechanistically, upon interaction with Pg, or its protease RgpB (gingipains), live neutrophils undergo rapid remodeling of their proteomes, generating neoepitopes. N-terminomics-based proteomic profiling identified multiple RgpB cleavage sites on several azurophilic granule proteins that are translocated to the surface of live neutrophils via low-level degranulation and activate macrophage αMβ2 integrin receptors, thus mediating internalization of non-apoptotic neutrophils within macrophage phagosomes. Macrophages with entrapped live neutrophils exhibit phenotypic and transcriptional reprogramming, consistent with inflammatory outcomes in vitro and in vivo. In contrast to the immunosuppressive outcomes associated with efferocytosis of apoptotic neutrophils, live neutrophil entrapment failed to fully activate several catabolic and metabolic processes and exhibited a defective activation of PPAR-γ mediated pro-resolution pathways, thereby promoting bacterial persistence and hindering the resolution of inflammation. Thus, our data demonstrate a novel immune subversion strategy unique to Pg and reveal a previously unknown mode of live neutrophil sequestration into macrophages during an infection.

DOI: https://doi.org/10.1038/s41419-025-07808-5
Chem Sci. 2025 Jul 02.

Thermal proteome profiling of itaconate interactome in macrophages.

Yunzhu Meng, Tiantian Wei, Chenlin Zhang, Anqi Yu, Yuan Liu, Junyu Xiao, Chu Wang.

Itaconate (ITA) is an upregulated immunometabolite in macrophages during pathogen infection. It is known to influence oxidation stress, cellular metabolism, programmed cell death and many other biological processes to regulate the immune response via interaction with proteins. Previous studies capture covalently ITA-modified proteins by activity-based proteome profiling with bioorthogonal chemical probes; however, how itaconate interacts non-covalently with other proteins at the proteome level remains unexplored. Here we applied thermal proteome profiling (TPP) to globally identify a large number of ITA-interacting proteins in macrophage proteomes. Among these targets, we verified mitochondrial branched-chain aminotransferase (BCAT2) as a novel non-covalent binding target of itaconate via biochemical and structural experiments. The binding of itaconate could inhibit transamination activity of BCAT and regulate the metabolism of branched-chain amino acids (BCAAs) in lipopolysaccharide (LPS)-activated inflammatory macrophages. This study offers a valuable resource that helps decipher novel and comprehensive functions of ITA in macrophages during the immune response and other related biological processes.

DOI: https://doi.org/10.1039/d5sc02378e
Nat Commun. 2025 Jul 01. 16(1): 5986

Modeling heterogeneous signaling dynamics of macrophages reveals principles of information transmission in stimulus responses.

Xiaolu Guo, Adewunmi Adelaja, Apeksha Singh, Roy Wollman, Alexander Hoffmann.

Macrophages initiate pathogen-appropriate immune responses with the activation dynamics of transcription factor NFκB mediating specificity. Live-cell imaging revealed the stimulus-response specificity of NFκB dynamics among populations of heterogeneous cells. To study stimulus-response specificity beyond what is experimentally accessible, we develop mathematical model simulations that capture the heterogeneity of stimulus-responsive NFκB dynamics and the stimulus-response specificity performance of the population. Complementing experimental data, extended-dose response simulations improved channel capacity estimates. By collapsing parameter distributions, we locate information loss to receptor modules, while the negative-feedback-containing core module shows remarkable signaling fidelity. Further, constructing virtual single-cell networks reveals the stimulus-response specificity of single cells. We find that despite stimulus-response specificity limitations at the population level, the majority of single cells are capable of responding specifically to immune threats, and that the few instances of stimulus-pair confusion are highly uncorrelated. The diversity of blindspots enable small consortia of macrophages to achieve perfect stimulus distinction.

DOI: https://doi.org/10.1038/s41467-025-60901-3
Adv Sci (Weinh). 2025 Jun 30. e11652

Acod1 Promotes PAD4 Ubiquitination via UBR5 Alkylation to Modulate NETosis and Exert Protective Effects in Sepsis.

Huifan Liu, Guoqing Jing, Shujuan Wu, Min Yuan, Yingyue Dong, Xue Chen, Huimin Zhou, Hailong Gong, Jing Zuo, Xiaojing Wu, Xuemin Song.

  Neutrophil extracellular traps (NETs) are reticular structures released by neutrophils, and the process of their formation is called NETosis. NETs play a key role in the pathological process of sepsis. However, the specific regulatory mechanism has not been fully clarified. This study finds that the levels of NETs in peripheral blood are significantly elevated in clinical sepsis patients and cecal ligation and puncture (CLP) mouse models, and the expression of Acod1 is closely related to the generation of NETs. Acod1 knockout led to a further increase in NETs levels in CLP mice, aggravated the inflammatory response, worsened organ damage, and reduced the survival rate. Further studies indicate that E3 ubiquitin ligase UBR5 interacts with PAD4 (one of the core proteins for NETs generation). Acod1/itaconate (ITA) enhanced the enzymatic activity of UBR5 through alkylation modification, promoting the K48-linked polyubiquitination and degradation of PAD4, thereby inhibiting NETosis. In conclusion, this study combines transcriptomics, metabolomics, genetic engineering, and co-immunoprecipitation techniques to reveal the molecular mechanism of Acod1/ITA in regulating NETs, providing new potential targets and theoretical basis for the treatment of sepsis.

Keywords:  Acod1; Neutrophil extracellular traps; Neutrophils; Sepsis; Ubiquitination

DOI:  https://doi.org/10.1002/advs.202411652
Cell Res. 2025 Jul 03.

Deubiquitinase-dependent transcriptional silencing controls inflammation.

Yuxin Yi, Wenjie Xu, Pengcheng Mi, Siliang Ye, Li Chen, Neal M Alto, Zixu Liu.

Transcriptional control is crucial for the regulation of inflammation. While it is well-established that inducible transcriptional repressors are synthesized de novo through signal-dependent transcriptional upregulation, it remains unclear whether post-translational modification mechanisms, such as deubiquitination, also contribute to this process. We previously identified developmentally silenced sine oculis (SIX) transcription factors that are reactivated to control inflammatory gene transcription in differentiated immune cells under chronic microbial infections. However, the molecular mechanisms by which this transcriptional silencing process is regulated remain unclear. Here, we report that USP2, a deubiquitinase localized in the nucleus and induced by inflammatory signals, stabilizes SIX proteins through deubiquitination under inflammatory conditions. Consequently, the USP2-SIX complex acts in concert to control NF-κB-mediated inflammatory gene transcription by directly targeting gene promoters. Supporting this mechanism, Usp2-/- mice exhibit higher mortality during H1N1 infections, which phenocopies Six1-/- mice, attributed to elevated levels of life-threatening inflammatory mediators and exacerbated pathology. This study establishes a deubiquitinase-dependent transcriptional control of the inflammatory response to prevent immunopathology, offering new therapeutic avenues for combating infectious diseases.

DOI: https://doi.org/10.1038/s41422-025-01140-5
J Immunol. 2025 Jun 28. pii: vkaf140. [Epub ahead of print]

Immune mechanisms and signatures in lethal and non-lethal sepsis revealed by single-cell transcriptomics.

Xinyang Zhang, Yunshi Cao, Zihui Zhao, Lijie Tang, Baozhong Zhang, Chunyu Liao, Ganwu Li, Wentong Cai.

  Sepsis is a life-threatening inflammatory syndrome caused by systemic infections, potentially leading to multi-organ failure and death. Due to patient heterogeneity, early and accurate diagnosis of sepsis, as well as stratification of patients by severity and potential outcomes, remains a huge challenge. In this study, we leveraged the genetic homogeneity of inbred mice to develop Escherichia coli-induced lethal and non-lethal sepsis models. Using single-cell RNA sequencing, we analyzed dynamic transcriptomes of peripheral blood mononuclear cells and found a marked expansion of monocytes during sepsis. A specific monocyte subset, designated Mono2, exhibited heightened expression of cytokines, chemokines, and pro-inflammatory pathways compared to other subsets. Notably, we observed a clear increasing trend in the abundance of Mono2 population in the lethal groups, and a decreasing trend in the non-lethal groups over time. Genes enriched in pro-inflammatory pathways (eg TNF and NF-κB signaling pathways) showed opposing trends in the 2 models: decreasing as mice recovered in the non-lethal model and increasing as mice succumbed to infection in the lethal model. Furthermore, we identified gene signatures corresponding to different stages of infection in the mouse models. By utilizing publicly available patient data, we validated the diagnostic potential of several genes and gene sets, including ANXA1+FPR1 and BCL2A1 for distinguishing septic patients from healthy individuals, and GBP2 for differentiating survivors from non-survivors. Collectively, this study highlights critical cellular and molecular signatures while providing insights into host immune mechanisms underlying sepsis progression and outcomes, offering valuable resources for advancing sepsis diagnosis and therapeutic strategies.

Keywords:  cytologic and gene signature; immune mechanism; sepsis; single-cell RNA sequencing

DOI:  https://doi.org/10.1093/jimmun/vkaf140