bims-traimu 2025-05-04 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–05–04
eleven papers selected by
Yantong Wan, Southern Medical University

Innate immune training in the neonatal response to sepsis.
Integrating Subacute Ruminal Acidosis, Lipopolysaccharide, and Trained Immunity: A Comprehensive Review.
Dissecting inflammation in the immunemetabolomic era.
Heat-inactivated Mycobacterium bovis and P22PI protein immunocomplex: Two candidates for use as immunostimulants of innate immune response.
Targeting Splenic Myeloid Cells with Nanobiologics to Prevent Postablative Pancreatic Cancer Recurrence via Inducing Antitumor Peripheral Trained Immunity.
A neuroimmune pathway drives bacterial infection.
An atlas of ferroptosis-induced secretomes.
LPS-induced extracellular AREG triggers macrophage pyroptosis through the EGFR/TLR4 signaling pathway.
Modulation of brain immune microenvironment and cellular dynamics in systemic inflammation.
[Sepsis-trained macrophages promote antitumoral tissue-resident T cells].
Fasting-induced ketogenesis sensitizes bacteria to antibiotic treatment.

Mol Med. 2025 Apr 30. 31(1): 159

Innate immune training in the neonatal response to sepsis.

Jaimar C Rincon, Dayuan Wang, Valerie E Polcz, Evan L Barrios, Marvin L Dirain, Ricardo F Ungaro, Dina C Nacionales, Leilani Zeumer-Spataro, Feifei Xiao, Philip A Efron, Lyle L Moldawer, Guoshuai Cai, Shawn D Larson.

  Neonates, especially those born prematurely, are highly vulnerable to infection-induced mortality. Numerous observational and immunological studies in newborns have shown that live attenuated vaccines have beneficial, non-specific effects (NSEs) against secondary infections to unrelated pathogens. These beneficial effects have been attributed to trained immunity, and emergency granulopoiesis plays an essential role. However, trained immunity has been shown to affect multiple myeloid subsets and how trained immunity influences the host protective response is still undefined. Here we show that Bacillus-Calmette-Guérin (BCG) vaccination improves survival to polymicrobial sepsis by simultaneously reprogramming broad aspects of myelopoiesis. Specifically, BCG vaccination expands multiple myeloid subsets, including the lineage (Lin)-Sca- 1+c-kit+ (LSK) and granulocytic-macrophage progenitors (GMPs), and increases CD11b+Gr1+ cell number, as well as their oxidative metabolism and capacity to stimulate T-cell proliferation in response to sepsis. Single-cell RNA sequencing of neonatal splenocytes suggests that BCG-vaccination changes the broad transcriptional landscape of multiple myeloid subsets. The result is the maturation of various neutrophil and monocyte subsets, stimulation of antimicrobial processes, and suppression of inflammatory pathways and myeloid-derived suppressor cell transcription. These findings reveal that BCG administration early after birth fundamentally reorganizes the myeloid landscape to benefit the subsequent response to polymicrobial infection.

Keywords:  BCG; Myeloid-derived suppressor cells; Neonatal sepsis; Single-cell RNA sequencing; Trained immunity

DOI:  https://doi.org/10.1186/s10020-025-01179-5
Int J Biol Sci. 2025 ;21(6): 2806-2823

Integrating Subacute Ruminal Acidosis, Lipopolysaccharide, and Trained Immunity: A Comprehensive Review.

Guobin Hou, Jingjun Wang, Shuai Liu, Duo Gao, Yiming Xu, Yimin Zhuang, Wenzhuo Dong, Yi Yue, Jinni Bai, Shangru Li, Jiaying Ma, Mengmeng Li, Wei Wang, Yajing Wang, Shengli Li, Zhijun Cao.

  Subacute ruminal acidosis (SARA) has emerged as a prevalent digestive disorder that significantly affects the overall health of ruminants, with notable links to various inflammatory diseases. Throughout the progression of SARA, elevated lipopolysaccharide (LPS) levels in the rumen play a crucial role in initiating the innate immune response. In this review, we evaluate the recent insights into the pathways associated with SARA-induced inflammatory responses, with a specific focus on LPS. It is important to recognize the variation in the immune response activation potential of LPS derived from different bacterial sources. This variability aligns with the widespread detection of LPS in the rumens of ruminants with SARA. Nonetheless, trained immunity is expected to become a novel strategy for the prevention and control of SARA. This mechanism offers a rapid response to secondary stimuli, including LPS, effectively preventing inflammation. Ultimately, this review establishes a comprehensive system integrating SARA, LPS, and trained immunity. Through this integrated approach, we aim to provide innovative solutions to the challenges associated with SARA.

Keywords:  inflammation; lipopolysaccharide; ruminant; subacute ruminal acidosis; trained immunity

DOI:  https://doi.org/10.7150/ijbs.104074
Cell Mol Life Sci. 2025 Apr 28. 82(1): 182

Dissecting inflammation in the immunemetabolomic era.

Patricia P Ogger, Peter J Murray.

  The role of immune metabolism, specific metabolites and cell-intrinsic and -extrinsic metabolic states across the time course of an inflammatory response are emerging knowledge. Targeted and untargeted metabolomic analysis is essential to understand how immune cells adapt their metabolic program throughout an immune response. In addition, metabolomic analysis can aid to identify pathophysiological patterns in inflammatory disease. Here, we discuss new metabolomic findings within the transition from inflammation to resolution, focusing on three key programs of immunity: Efferocytosis, IL-10 signaling and trained immunity. Particularly the tryptophan-derived metabolite kynurenine was identified as essential for efferocytosis and inflammation resolution as well as a potential biomarker in diverse inflammatory conditions. In summary, metabolomic analysis and integration with transcriptomic and proteomic data, high resolution imaging and spatial information is key to unravel metabolic drivers and dependencies during inflammation and progression to tissue-repair.

Keywords:  Chronic inflammatory disease; Efferocytosis; IL-10; Kynurenine; Metabolomics; Spatial resolution; Trained immunity

DOI:  https://doi.org/10.1007/s00018-025-05715-8
Vet Microbiol. 2025 Apr 21. pii: S0378-1135(25)00162-2. [Epub ahead of print]305 110527

Heat-inactivated Mycobacterium bovis and P22PI protein immunocomplex: Two candidates for use as immunostimulants of innate immune response.

Irene Agulló-Ros, Mercedes M Burucúa, Felipe A Cheuquepán, Mercedes Domínguez, Iker A Sevilla, Remigio Martínez, Natalia Plá, María A Risalde, Maia S Marin.

  Tuberculosis (TB), caused by members of the Mycobacterium tuberculosis complex, remains a critical global health challenge, affecting humans and a wide range of domestic and wild animals. Despite the availability of anti-TB drugs, cure rates remain suboptimal, exacerbated by the rise of multidrug-resistant TB strains. The Bacille Calmette-Guérin (BCG) vaccine, the only licensed vaccine against TB, has demonstrated efficacy in reducing lesion severity and bacterial burden in animals, as well as lowering TB-related and all-cause mortality in infants. However, BCG presents several safety concerns inherent to live vaccines. To overcome these limitations, exploring alternative vaccine candidates that do not incorporate live mycobacteria is crucial. This study aimed to evaluate and compare the immunostimulatory potential of two candidates based in mycobacteria inactivated or their derivatives, heat-inactivated Mycobacterium bovis (HIMB) and P22PI protein immunocomplex (P22PI), in bovine foetal lung cells. To assess the expression of innate immune components, including Toll-like receptors (TLRs), cathelicidins, and cytokines, bovine foetal lung were exposed to different concentrations of HIMB and P22PI immunostimulants, starting at 7.8 × 10⁶ CFU/ml and 10 µg/ml, respectively. These initial concentrations were subsequently diluted to 1/2 and 1/10 to evaluate dose-dependent effects. Our findings reveal that both HIMB and P22PI significantly stimulate innate immune mechanisms, as evidenced by the upregulation of TLR2 and TLR4, alongside the induction of BMAP28 cathelicidin, tumour necrosis factor alpha (TNFA) and interferons (IFNs). These results suggest their potential to orchestrate a robust innate immune response providing valuable insights into the immunological mechanisms underlying the protective effects of these immunostimulants. This underscores their potential role in in vivo studies as vaccine candidates. Furthermore, their ability to enhance antigen recognition via TLR and induce pro-inflammatory cytokines also indicates broader applications in immune modulation, potentially extending protection against heterologous pathogens through trained immunity.

Keywords:  Cathelicidins; Cytokines; HIMB; Innate immunity; P22PI; Toll-like receptors

DOI:  https://doi.org/10.1016/j.vetmic.2025.110527
Adv Sci (Weinh). 2025 Apr 28. e2413562

Targeting Splenic Myeloid Cells with Nanobiologics to Prevent Postablative Pancreatic Cancer Recurrence via Inducing Antitumor Peripheral Trained Immunity.

Shengbo Wu, Weichen Xu, Xuexia Shan, Liping Sun, Shuo Liu, Xixi Sun, Shaoyue Li, Xiaodong Hou, Xiaowan Bo, Chengzhong Peng, Bin Huang, Huixiong Xu, Wenwen Yue.

  Minimally invasive irreversible electroporation ablation shows promise for pancreatic cancer (PCa), but the high recurrence and metastasis rates pose a therapeutic challenge for loco-regional ablation treatment. Immunotherapy holds promise for preventing tumor recurrence, however, its efficacy against PCa remains limited. Here, using a preclinical model of PCa, it is identified that tumor development dramatically restructures the splenic immune landscape characterized by increased frequency of myeloid cells. Further, nanobiologics with high affinity for splenic myeloid cells using erythrocyte membrane fused with apoA1-modified liposomes are presented. Biocompatible CaCO3 nanoparticles are incorporated to serve as a release reservoir of immunomodulatory therapeutics (muramyl dipeptide, MDP). The nanobiologics, MDCa@RBC-Alipo, induce antitumor-trained immunity by epigenetically and metabolically rewiring splenic myeloid cells, thereby overcoming the immunosuppressive tumor microenvironment in residual PCa following irreversible electroporation ablation. This approach enhances the therapeutic efficacy of aPD-L1 and significantly inhibits tumor recurrence and hemorrhagic ascites development. The trafficking of MDP directly to the spleen highlights a previously uncharacterized pathway for inducing peripheral trained immunity, thereby presenting a novel therapeutic approach for locally advanced PCa treatment.

Keywords:  irreversible electroporation; nanomaterials; pancreatic cancer; trained immunity

DOI:  https://doi.org/10.1002/advs.202413562
Sci Adv. 2025 May 02. 11(18): eadr2226

A neuroimmune pathway drives bacterial infection.

Nian Wang, Jiao Liu, Runliu Wu, Feng Chen, Ruoxi Zhang, Chunhua Yu, Herbert Zeh, Xianzhong Xiao, Haichao Wang, Timothy R Billiar, Ling Zeng, Jianxin Jiang, Daolin Tang, Rui Kang.

Pathogen-induced septic death presents a substantial public health challenge, with its neuroimmune mechanisms largely unexplored. Our study investigates neurotransmitter modulation of ACOD1 expression, a regulator of immunometabolism activated by bacterial lipopolysaccharide (LPS). Screening neurotransmitters identifies dopamine as a potent inhibitor of LPS-induced ACOD1 expression in innate immune cells. Mechanistically, DRD2 forms a complex with TLR4, initiating MAPK3-dependent CREB1 phosphorylation and subsequent ACOD1 transcription. Conversely, dopamine disrupts TLR4-MYD88 interaction via DRD2 without affecting the formation of the LPS-induced TLR4-MD2-CD14 complex. Enhanced ACOD1 expression induces CD274/PD-L1 production independently of itaconate, precipitating inflammation-associated immunosuppression in sepsis. Delayed administration of pramipexole, a dopamine agonist, mitigates lethality in bacterial sepsis mouse models. Conversely, the dopamine antagonist aripiprazole exacerbates sepsis mortality. Dysregulation of the dopamine-ACOD1 axis correlates with sepsis severity in patients, indicating a potential therapeutic target for modulating this neuroimmune pathway.

DOI: https://doi.org/10.1126/sciadv.adr2226
Cell Death Differ. 2025 Apr 25.

An atlas of ferroptosis-induced secretomes.

F Isil Yapici, Eric Seidel, Alina Dahlhaus, Josephine Weber, Christina Schmidt, Adriano de Britto Chaves Filho, Ming Yang, Maria Nenchova, Emre Güngör, Jenny Stroh, Ioanna Kotouza, Julia Beck, Ali T Abdallah, Jan-Wilm Lackmann, Christina M Bebber, Ariadne Androulidaki, Peter Kreuzaler, Almut Schulze, Christian Frezza, Silvia von Karstedt.

Cells undergoing regulated necrosis systemically communicate with the immune system via the release of protein and non-protein secretomes. Ferroptosis is a recently described iron-dependent type of regulated necrosis driven by massive lipid peroxidation. While membrane rupture occurs during ferroptosis, a comprehensive appraisal of ferroptotic secretomes and their potential biological activity has been lacking. Here, we apply a multi-omics approach to provide an atlas of ferroptosis-induced secretomes and reveal a novel function in macrophage priming. Proteins with assigned DAMP and innate immune system function, such as MIF, heat shock proteins (HSPs), and chaperones, were released from ferroptotic cells. Non-protein secretomes with assigned inflammatory function contained oxylipins as well as TCA- and methionine-cycle metabolites. Interestingly, incubation of bone marrow-derived macrophages (BMDMs) with ferroptotic supernatants induced transcriptional reprogramming consistent with priming. Indeed, exposure to ferroptotic supernatants enhanced LPS-induced cytokine production. These results define a catalog of ferroptosis-induced secretomes and identify a biological activity in macrophage priming with important implications for the fine-tuning of inflammatory processes.

DOI: https://doi.org/10.1038/s41418-025-01517-4
Front Immunol. 2025 ;16 1549749

LPS-induced extracellular AREG triggers macrophage pyroptosis through the EGFR/TLR4 signaling pathway.

Gang Yuan, Qudi Qiao, Aolin Jiang, Zehui Jiang, Haihua Luo, Lin Huang, Jieyan Wang, Yong Jiang.

  Amphiregulin (AREG), a member of the EGF family, exists as a transmembrane protein anchored to the cell surface. In response to external stimuli, its extracellular domain is released into the extracellular matrix through paracrine or autocrine signaling. However, its role in septic macrophage pyroptosis remains poorly understood. This study aims to investigate the role of extracellular AREG in septic macrophages, mice, and patients. We found that high expression of extracellular AREG was regulated by RPLP1 at the translation level, which increased the expression of IL-6, CCL2, and CCL3 protein, as well as Caspase 1, IL-1β, and Nlrp3 mRNA expression, resulting in macrophage pyroptosis. Mechanistically, macrophage pyroptosis was aggravated by extracellular AREG pretreatment, which was triggered by extracellular AREG and ATP (adenosine 5'-triphosphate). The AREG-neutralizing antibody reduced LPS-induced epidermal growth factor receptor (EGFR) activation, TLR4 expression, and pyroptosis. Extracellular AREG-induced macrophage pyroptosis decreased with EGFR and NF-κB inhibition, as well as TLR4 and Myd88 knockout. Additionally, DTT-pretreated extracellular AREG suppressed macrophage pyroptosis. In vivo, extracellular AREG attenuates systemic inflammation infiltration and delays survival in a septic mouse model. Furthermore, extracellular AREG mediates sepsis in humans, and genes involved in the AREG-mediated pyroptosis signaling pathway were highly expressed in patients with severe sepsis compared with those with general or moderate sepsis. Overall, LPS-induced extracellular AREG aggravated or triggered macrophage pyroptosis through the EGFR/TLR4/Myd88/NF-κB signaling pathway, providing promising treatment strategies for sepsis.

Keywords:  EGFR/TLR4; amphiregulin; macrophage; pyroptosis; sepsis

DOI:  https://doi.org/10.3389/fimmu.2025.1549749
Theranostics. 2025 ;15(11): 5153-5171

Modulation of brain immune microenvironment and cellular dynamics in systemic inflammation.

Junhao Wang, Zhaoqian Zhong, Haihua Luo, Qizheng Han, Kan Wu, Aolin Jiang, Li Chen, Yanxia Gao, Yong Jiang.

  Background: Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, affecting approximately 70% of patients, leading to increased mortality and long-term cognitive impairments among survivors. However, there is a lack of comprehensive studies on the development of SAE, especially related to the cellular communication networks in the brain microenvironment. Methods: We evaluated the impact of myeloid cells on the brain's immune microenvironment through glial cell alterations using bulk and single-cell transcriptomics data from human and mouse models and validated this with correlative experiments. We also developed the DeconvCellLink R package to study neuroinflammation-associated cellular interaction networks. A dynamic brain immune microenvironment map showing temporal alterations in brain cellular network during systemic inflammatory reactions was constructed using time-series data. Results: While brain cellular alterations differed between human and animal models, a highly conserved set of sepsis-associated genes regulating immune microenvironment signalling was identified. The dynamic alterations in cellular interaction networks and cytokines revealed brain immune cells' temporal response to systemic inflammation. We also found that valproic acid could mitigate sepsis-induced neuroinflammation by regulating glial cell balance and modulating the neuroimmune microenvironment. Conclusion: Through dynamic cellular communication networks, the study revealed that, immune dysregulation in the inflamed brain in SAE involves overactivation of innate immunity, with neutrophils playing a crucial role, providing a scientific framework for developing novel therapeutic strategies and offering new insights into the mechanisms underlying sepsis-induced brain dysfunction.

Keywords:  Intercellular communication inferred; Multi-omics analysis; Neuroinflammatory microenvironment; Sepsis

DOI:  https://doi.org/10.7150/thno.107061
Med Sci (Paris). 2025 Apr;41(4): 321-323

[Sepsis-trained macrophages promote antitumoral tissue-resident T cells].

Jérémie Poschmann, Alexis Broquet, Antoine Roquilly.

DOI: https://doi.org/10.1051/medsci/2025056
Cell Metab. 2025 Apr 27. pii: S1550-4131(25)00216-5. [Epub ahead of print]

Fasting-induced ketogenesis sensitizes bacteria to antibiotic treatment.

Shujun Cui, Danyang Chong, Yi-Xin Wang, Huixian Tong, Minggui Wang, Guo-Ping Zhao, Liang-Dong Lyu.

  Fasting metabolism is a commonly observed motivational response to acute infections and is conceptualized as being beneficial for host survival. Here, we show that fasting potentiates antibiotic treatment for murine sepsis caused by Salmonella Typhimurium, Klebsiella pneumoniae, and Enterobacter cloacae, resulting in increased bacterial clearance and improved host immune responses and survival. This effect is mediated by fasting-induced ketogenesis and could be alternatively implemented by combination therapy with antibiotics and ketone bodies. We show that the ketone body acetoacetate is an effector that sensitizes bacteria to antibiotic treatment by increasing antibiotic lethality and outer and inner membrane permeability. Our results demonstrate that acetoacetate depletes bacterial amino acids, particularly positively charged amino acids and putrescine, leading to cell membrane malfunctions and redox-related lethality. This study reveals an unrecognized role of ketogenesis in antibiotic treatment and a potential ketone body-based treatment strategy for bacterial sepsis.

Keywords:  acetoacetate; anorexia; antibiotic treatment; antibiotics; drug susceptibility; fasting metabolism; ketogenesis; ketone body; sepsis

DOI:  https://doi.org/10.1016/j.cmet.2025.04.006