bims-traimu 2025-01-19 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–01–19
ten papers selected by
Yantong Wan, Southern Medical University

Role of Trained Immunity in Heath and Disease.
Early and delayed STAT1-dependent responses drive local trained immunity of macrophages in the spleen.
Friends to remember: innate immune memory regulation by the microbiota.
Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis.
Menin orchestrates macrophage reprogramming to maintain the pulmonary immune homeostasis.
Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1.
Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity.
Inhibition of Interleukin-40 prevents multi-organ damage during sepsis by blocking NETosis.
Training the synergy between Bacillus Calmette-Guérin and immune checkpoint-blocking antibodies in bladder cancer.
In vivo itaconate tracing reveals degradation pathway and turnover kinetics.

Curr Cardiol Rep. 2025 Jan 13. 27(1): 18

Role of Trained Immunity in Heath and Disease.

Shibali Das, Kory J Lavine.

   PURPOSE OF REVIEW: This review aims to explore the role of immune memory and trained immunity, focusing on how innate immune cells like monocytes, macrophages, and natural killer cells undergo long-term epigenetic and metabolic rewiring. Specifically, it examines the mechanisms by which trained immunity, often triggered by infection or vaccination, could impact cardiac processes and contribute to both protective and pathological responses within the cardiovascular system.
RECENT FINDINGS: Recent research demonstrates that vaccination and infection not only activate immune responses in circulating monocytes and tissue macrophages but also affect immune progenitor cells within the bone marrow environment, conferring lasting protection against heterologous infections. These protective effects are attributed to epigenetic and metabolic reprogramming, which enable a heightened immune response upon subsequent encounters with pathogens. However, while trained immunity is beneficial in combating infections, it has been linked to exacerbated inflammation, which may increase susceptibility to cardiovascular diseases, including atherosclerosis and heart failure. Our review highlights the dual nature of trained immunity: while it offers protective advantages against infections, it also poses potential risks for cardiovascular health by promoting chronic inflammation. Understanding the molecular mechanisms underlying immune memory's impact on cardiac processes could lead to new therapeutic strategies to mitigate cardiovascular diseases, such as atherosclerosis, heart failure, and diabetes. These insights build the grounds for future research to balance the benefits of trained immunity with its potential risks in cardiovascular disease management.

Keywords:  Atherosclerosis; Epigenetics; Immune memory; Trained immunity; Vaccine

DOI:  https://doi.org/10.1007/s11886-024-02167-7
Elife. 2025 Jan 16. pii: RP100922. [Epub ahead of print]13

Early and delayed STAT1-dependent responses drive local trained immunity of macrophages in the spleen.

Aryeh Solomon, Noa Bossel Ben-Moshe, Dotan Hoffman, Sébastien Trzebanski, Dror Yehezkel, Leia Vainman, Mihai G Netea, Roi Avraham.

  Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling of the cellular architecture within the tissue during TI remains underexplored. Here, we study the effects of peritoneal Bacillus Calmette-Guérin (BCG) administration to find TI-mediated protection in the spleen against a subsequent heterologous infection by the Gram-negative pathogen Salmonella Typhimurium (S.Tm). Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealing both early and delayed myeloid subsets with time-dependent, cell-type-specific STAT1 signatures. Using lineage tracing, we find that tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Early inhibition of STAT1 activation, using specific JAK-STAT inhibitors, reduces both RPM loss and recruitment of trained monocytes. Our study suggests a temporal window soon after BCG vaccination, in which STAT1-dependent activation of long-lived resident cells in the tissue mediates localized protection.

Keywords:  BCG; Salmonella; immunology; inflammation; macrophages; mouse

DOI:  https://doi.org/10.7554/eLife.100922
Trends Microbiol. 2025 Jan 09. pii: S0966-842X(24)00318-4. [Epub ahead of print]

Friends to remember: innate immune memory regulation by the microbiota.

Aize Pellon, Ainhoa Palacios, Leticia Abecia, Héctor Rodríguez, Juan Anguita.

  Innate immune memory (IIM) is the process by which, upon a primary challenge, innate immune cells alter their epigenetic, transcriptional, and immunometabolic profiles, resulting in modified secondary responses. Unlike infections or other immune-system-related diseases, the role of IIM in nonpathogenic contexts is less understood. An increasing body of research has shown that normal microbiota members or their metabolic byproducts induce alternative memory phenotypes, suggesting that memory cells contribute to homeostasis in mucosal areas. In this review, we discuss the newest insights in the emerging field of IIM to the microbiota and the potential of manipulating these long-term responses to promote better mucosal health.

Keywords:  immunometabolism; innate immune memory; microbiota; tolerance; trained immunity

DOI:  https://doi.org/10.1016/j.tim.2024.12.002
Sci Rep. 2025 Jan 15. 15(1): 2059

Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis.

Blake A Caldwell, Susanti Ie, Amy Lucas, Liwu Li.

  Sepsis is a leading cause of death worldwide, with most patient mortality stemming from lingering immunosuppression in sepsis survivors. This is due in part to immune dysfunction resulting from monocyte exhaustion, a phenotype of reduced antigen presentation, altered CD14/CD16 inflammatory subtypes, and disrupted cytokine production. Whereas previous research demonstrated improved sepsis survival in Ticam2-/- mice, the contribution of TICAM2 to long-term exhaustion memory remained unknown. Using a cecal slurry injection sepsis model, we monitored the establishment and recovery of monocyte exhaustion in Ticam2-/- mice. After one week of recovery, we profiled bone marrow and splenic reservoir monocytes in Ticam2-/- mice and found that, in contrast to the persistent exhaustion observed in wild-type monocytes, Ticam2-/- monocytes largely resembled healthy controls. To determine the impact of TICAM2 ablation on innate epigenetic memory in sepsis, we measured genome-wide DNA methylation in bone marrow monocytes and found that Ticam2-/- cells exhibit a unique profile of altered methylation at CEBPE binding sites and regulatory features for key immune genes such as Dmkn and Btg1. Bearing human translational relevance, a case study of time course blood samples collected from a sepsis patient presenting with SIRS and a positive qSOFA revealed a similar effect in human monocytes, which steadily transition into an exhausted memory characterized by a CD38high; CX3CR1low; HLA-DRlow state within four days of hospital admittance. Together, our data reveal the chronic preservation of monocyte exhaustion, partially controlled by TICAM2.

Keywords:  Innate immune memory; Monocyte exhaustion; Sepsis; Ticam2

DOI:  https://doi.org/10.1038/s41598-025-86103-x
Cell Rep. 2025 Jan 15. pii: S2211-1247(24)01570-5. [Epub ahead of print]44(1): 115219

Menin orchestrates macrophage reprogramming to maintain the pulmonary immune homeostasis.

Xingwen Zhu, Bin Xu, Aobo Lian, Xiaoqian Zhang, Yiting Wang, Yuan Zhang, Li Zhang, Jie Ma, Shubin Gao, Guanghui Jin.

  Menin is a scaffold protein encoded by the Men1 gene, and it interacts with a variety of chromatin regulators to activate or repress cellular processes. The potential importance of menin in immune regulation remains unclear. Here, we report that myeloid deletion of Men1 results in the development of spontaneous pulmonary alveolar proteinosis (PAP). This is strongly correlated with impaired development of alveolar macrophages (AM) through inactivation of the granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) pathway caused by Men1 deficiency. Mechanistically, menin directly interacts with the SET domain containing 2 (SETD2) through the N-terminal domain (NTD) and Palm domains to maintain protein stability and chromatin recruitment. SETD2 and menin collectively maintain CSF2 expression through H3K36me3, which orchestrates AM reprogramming and pulmonary immune homeostasis. Targeting H3K36me3 remodeling mitigated the aberrant activation of macrophages caused by lipopolysaccharide (LPS). Our results point to a nonredundant role of menin in the control of macrophage lineage maintenance via reinforcement of the H3K36me3 transcriptional program.

Keywords:  CP: Immunology; CSF2; Men1; SETD2; alveolar macrophages; pulmonary alveolar proteinosis

DOI:  https://doi.org/10.1016/j.celrep.2024.115219
Cell Metab. 2025 Jan 03. pii: S1550-4131(24)00480-7. [Epub ahead of print]

Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1.

Yizeng Fan, Weichao Dan, Yuzhao Wang, Zhiqiang Ma, Yanlin Jian, Tianjie Liu, Mengxing Li, Zixi Wang, Yi Wei, Bo Liu, Peng Ding, Yuzeshi Lei, Chendong Guo, Jin Zeng, Xiaolong Yan, Wenyi Wei, Lei Li.

  Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.

Keywords:  IRG1; PD-L1; SLC13A3; immunotherapy; itaconate

DOI:  https://doi.org/10.1016/j.cmet.2024.11.012
Cell Metab. 2025 Jan 10. pii: S1550-4131(24)00482-0. [Epub ahead of print]

Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity.

Shihao Zhang, Zenghui Cui, Danni Zhang, Deyu Zhang, Ke Jin, Zemeng Li, Bo Li, Boyi Cong, Juan Liu, Lei Wang, Mingyue Wen, Xuetao Cao.

  Bacterial infection reprograms cellular metabolism and epigenetic status, but how the metabolic-epigenetic crosstalk empowers host antibacterial defense remains unclear. Here, we report that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is a sensor for metabolite adenine to launch an antimicrobial innate response through increasing Il1b transcription. Myeloid cell-specific Hnrnpa2b1-cKO mice are more susceptible to bacterial infection, while interleukin 1 beta (IL-1β) supplementation rescues the phenotype. Through a large-scale metabolites-hnRNPA2B1 interaction screen, we reveal that adenine directly binds and activates hnRNPA2B1 to mediate innate antibacterial response. Mechanistically, adenine directly recruits hnRNPA2B1 to Il1b enhancers, and hnRNPA2B1 increases Il1b enhancer chromatin accessibility through binding and recruiting nucleolin and fat mass and obesity-associated protein (FTO) to mediate Il1b enhancer DNA N6-methyladenosine (6mA) demethylation. Furthermore, bacterial infection elevates nuclear adenine at the early stage of infection, and in vivo adenine administration protects mice from death upon bacterial infection through the hnRNPA2B1-IL-1β circuit. Our findings offer new insights into metabolic-epigenetic crosstalk relevant to antibacterial innate immunity and indicate potential approaches for treating bacterial infections.

Keywords:  DNA N(6)-methyladenosine; adenine; antibacterial immunity; hnRNPA2B1; interleukin 1; nucleolin

DOI:  https://doi.org/10.1016/j.cmet.2024.11.014
Crit Care. 2025 Jan 16. 29(1): 29

Inhibition of Interleukin-40 prevents multi-organ damage during sepsis by blocking NETosis.

Shijie Cai, Xiao Li, Chen Zhang, Yuqian Jiang, Yonghui Liu, Zhi He, Shuo Ma, Yuming Yao, Chun-Kwok Wong, Guoqiu Wu, Xun Gao.

  Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to the lack of precise biomarkers for patient stratification and therapeutic guidance. Interleukin 40 (IL-40), a novel cytokine with immune regulatory functions in human diseases, was elevated at admission in two independent cohorts of patients with sepsis. High levels of secreted IL-40 in septic patients were positively correlated with PCT, CRP, lactate (LDH), and Sequential Organ Failure Assessment (SOFA) scores, in which IL-40 levels were used to stratify the early death of critically ill patients with sepsis. Moreover, genetic knockout of IL-40 (IL-40-/-) improved outcomes in mice with experimental sepsis, as evidenced by attenuated cytokine storm, multiple-organ failure, and early mortality, compared with those of wild-type (WT) mice. Mechanistically, single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) have revealed that S100A8/9hi neutrophil influx into the peritoneal cavity along with neutrophil extracellular trap (NETs) formation accounts predominantly for the IL-40-mediated worsening of sepsis outcomes. Clinically, the IL-40 level was positively correlated with the NET-related MPO/dsDNA ratio in septic patients. Finally, with antibiotics (gentamycin), genetic knockout of IL-40 prevented polymicrobial sepsis fatalities more efficiently than without gentamycin treatment. In summary, these data reveal a novel prognostic strategy for sepsis and that IL-40 may serve as a novel therapeutic target for sepsis.

Keywords:  IL-40; NETs; Prognostic; Sepsis; Theranostic

DOI:  https://doi.org/10.1186/s13054-025-05257-2
Cancer Commun (Lond). 2025 Jan 10.

Training the synergy between Bacillus Calmette-Guérin and immune checkpoint-blocking antibodies in bladder cancer.

Renate Pichler, Martin Thurnher.

DOI: https://doi.org/10.1002/cac2.12647
bioRxiv. 2025 Jan 02. pii: 2025.01.02.629617. [Epub ahead of print]

In vivo itaconate tracing reveals degradation pathway and turnover kinetics.

Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.

Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized via tricarboxylic acid (TCA) metabolism downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation, and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13 C itaconate tracing, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine, and fuels TCA cycle metabolism specifically in the liver and kidneys. These studies further revealed that itaconate is converted into acetyl-CoA, mesaconate, and citramalate in mitochondria. Itaconate administration also influenced branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase (SDH) and methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered a previously unknown aspect of the itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.

DOI: https://doi.org/10.1101/2025.01.02.629617