bims-traimu 2025-07-20 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–07–20
nine papers selected by
Yantong Wan, Southern Medical University

Targeting alveolar macrophages in tuberculosis: Exploiting trained immunity for novel therapeutic approaches.
Respiratory syncytial virus infection confers heterologous protection against SARS-CoV-2 via induction of γδ T cell-mediated trained immunity and SARS-CoV-2 reactive mucosal T cells.
Interferon gamma rebalances immunopathological signatures in Chronic Granulomatous Disease through metabolic rewiring.
Itaconate suppresses neonatal intestinal inflammation via metabolic reprogramming of M1 macrophage.
The NF-κB-SLC7A11 axis regulates ferroptosis sensitivity in inflammatory macrophages.
Ablation of macrophage transcriptional factor FoxO1 protects against ischemia-reperfusion injury-induced acute kidney injury.
Cytokine Storm Induction Linked to Multi-Organ Failure in Fatal Jellyfish Stings.
Phosphorylated Toll-like receptor 3 nuclear translocation in cancer cell promotes metastasis and chemoresistance.
Endolysosomal damage surveillance enables rapid inflammasome sensing of pathogens.

Int Immunopharmacol. 2025 Jul 12. pii: S1567-5769(25)01201-9. [Epub ahead of print]163 115211

Targeting alveolar macrophages in tuberculosis: Exploiting trained immunity for novel therapeutic approaches.

Huilin Fang, Yan Xiong, Beibei Fu, Haibo Wu.

  Tuberculosis (TB) is an airborne infectious disease caused by the Mycobacterium tuberculosis (Mtb) complex organism. Alveolar macrophages (AMs) play key roles in immune defense, antigen presentation, immune regulation, and immune secretion during Mtb infection. Notably, AMs exhibit context-dependent dual functions: protective and pathogenic. This duality is driven by the heterogeneous composition of AM subsets and their distinct immune profiles. On one hand, they fight against Mtb through a series of mechanisms to protect the host; on the other hand, certain AM subsets may provide a permissive niche that facilitates Mtb survival and persistence. Mtb possesses unique cell surface lipids and secreted protein effectors that enable it to evade the killing effects of innate immune cells and preferentially establish an ecological niche within AMs. AMs not only strengthen their antibacterial capabilities through mechanisms such as training immune memory, metabolic reprogramming, cytokine production, and autophagy, but also collaborate with other immune cells to jointly maintain immune balance within the body. Once this balance is disrupted, tuberculosis infection may run rampant. Furthermore, this article summarizes the potential role of different methods for inducing trained immune AMs in the treatment of tuberculosis, including existing bacille Calmette-Guérin (BCG) vaccination and emerging strategies such as lipopolysaccharide (LPS)-mediated Toll-like receptor 4 (TLR4) activation and Influenza A virus (IAV)-induced host trained immunity activation, providing new ideas for the treatment of tuberculosis.

Keywords:  Alveolar macrophages; Antibacterial; Mycobacterium tuberculosis; Trained immunity

DOI:  https://doi.org/10.1016/j.intimp.2025.115211
bioRxiv. 2025 Jul 07. pii: 2025.07.02.662833. [Epub ahead of print]

Respiratory syncytial virus infection confers heterologous protection against SARS-CoV-2 via induction of γδ T cell-mediated trained immunity and SARS-CoV-2 reactive mucosal T cells.

Awadalkareem Adam, Wenzhe Wu, Madison C Jones, Haiping Hao, Aditi, Parimal Samir, Xiaoyong Bao, Tian Wang.

The respiratory viruses can concurrently or sequentially infect a host and influence the trajectory of each other. The underlying immune mechanisms are not well understood. Here, we investigated whether respiratory syncytial virus (RSV) infection affects host vulnerability to subsequent SARS-CoV-2 infection in two murine models of SARS-CoV-2 infection. We found that prior RSV infection-induced heterologous protection against subsequent SARS-CoV-2 infection was dose and time dependent. RNA-seq and immunological analyses revealed that RSV triggered the activation of lung antigen presenting cells (APC)s and SARS-CoV-2 reactive mucosal T cells at day 9, which declined at 1 month. RSV also induced the expansion of lung γδ T cells and the upregulation of their cellular metabolic pathways. Furthermore, RSV infection in TCRδ -/- mice, which are deficient of γδ T cells, resulted in a reduced SARS-CoV-2 reactive mucosal T cell response and subsequent increased viral loads and higher levels of virus-induced inflammatory responses in the lung upon SARS-CoV-2 challenge compared to the wild-type mice. In summary, our findings suggest that RSV infection provides heterologous protection against the subsequent SARS-CoV-2 infection via induction of γδ T cell-mediated trained immunity in the lung and SARS-CoV-2 reactive mucosal T cell responses.

DOI: https://doi.org/10.1101/2025.07.02.662833
Blood Adv. 2025 Jul 17. pii: bloodadvances.2025016213. [Epub ahead of print]

Interferon gamma rebalances immunopathological signatures in Chronic Granulomatous Disease through metabolic rewiring.

Mariolina Bruno, Charlotte Kröger, Anaísa V Ferreira, Bowen Zhang, Rutger J Röring, Ruiqi Liu, Caspar I van der Made, Norman van Rhijn, Lazslo Groh, Viola Klück, Nico A F Janssen, Wenchao Li, Diletta Rosati, Ahmed Alaswad, Helin Tercan, Jorge Saiz, Carolina Gonzalez-Riano, Martina van Uelft, Orsi Gaal, Sophie Müller, Humberto J Ferreira, Stefanie Warnat-Herresthal, Matthias Becker, Lisa Holsten, Michael Kraut, Jonas Schulte-Schrepping, Lorenzo Bonaguro, Kristian Händler, Cristina Cunha, Manfred Schmolz, Joachim L Schultze, Leo Joosten, Coral Barbas, Mihai G Netea, Yang Li, Anna C Aschenbrenner, Agostinho Carvalho, Frank L van de Veerdonk.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent life-threatening infections and hyperinflammatory complications. It is caused by mutations in the NADPH oxidase complex and the consequent loss of reactive oxygen species (ROS) production. Recombinant human interferon gamma (rIFN-γ) prophylaxis reduces the risk of severe infections, but the mechanisms behind its efficacy in CGD are still an open question, as it does not restore NADPH oxidase-dependent ROS production. Here, we show that innate immune cells of CGD patients are transcriptionally and functionally reprogrammed to a hyperactive inflammatory status, displaying an impaired in vitro induction of trained immunity. CGD monocytes have reduced intracellular amino acids concentrations and profound functional metabolic defects, both at the level of glycolysis and mitochondrial respiration. Ex vivo and in vivo treatment with IFN-γ restored these metabolic defects and reduced excessive IL-1β and IL-6 production in response to fungal stimuli in CGD monocytes. These data suggest that prophylactic rIFN-γ modulates the metabolic status of innate immune cells in CGD. These data shed light on the effects of NADPH-oxidase-derived ROS deficiency to the metabolic programs of immune cells and pose the basis for targeting this immunometabolic axis, potentially beyond CGD, with IFN-γ immunotherapy.

DOI: https://doi.org/10.1182/bloodadvances.2025016213
Clin Transl Med. 2025 Jul;15(7): e70419

Itaconate suppresses neonatal intestinal inflammation via metabolic reprogramming of M1 macrophage.

Shuchen Huangfu, Chaoting Lan, Sitao Li, Huijuan Wang, Chun Yan, Yuling Yang, Bowen Tian, Yide Mu, Peizhi Zhao, Yan Tian, Yijia Wang, Wei Zhong, Limei Zhong, Yongyan Shi, Yufeng Liu.

   BACKGROUND: Necrotizing enterocolitis (NEC) is a rapidly progressive and severe gastrointestinal disorder in neonates that is marked by an inflammatory cascade initiated by mechanisms that remain incompletely understood, resulting in intestinal necrosis and systemic infections. This study demonstrated that itaconate (ITA) exerts a protective effect in NEC by regulating macrophage reprogramming.
METHODS: Changes in ITA expression were investigated using immunofluorescence staining and liquid chromatography-mass spectrometry, and their effect on immune cell differentiation was verified through single-cell sequencing. In vivo experiments were performed using ACOD1-/- and ACOD1fl/flLysMcre NEC mouse models.
RESULTS: We detected changes in ITA expression in clinical NEC samples and confirmed the effect of these changes on immune cell differentiation. In vivo experiments confirmed the therapeutic role of ITA in regulating macrophage differentiation in NEC, and we further investigated the mechanism by which ITA regulates macrophage metabolic reprogramming. The depletion of ITA in NEC correlates with an increased frequency of pro-inflammatory macrophage polarization, thereby exacerbating intestinal inflammatory injury. Importantly, our in vivo experiments revealed that treatment with 4-octyl itaconate (4OI) significantly mitigated intestinal symptoms associated with NEC in murine models. Mechanistic investigations showed that 4OI effectively suppressed M1 macrophage polarization by rescuing mitochondrial function and upregulating oxidative phosphorylation in macrophages.
CONCLUSIONS: Our results highlight ITA as a metabolic checkpoint of macrophage differentiation in NEC and suggest the therapeutic efficacy of 4OI in NEC.
KEY POINTS: Itaconate alleviates NEC by reprogramming M1 macrophage metabolism ACOD1 deficiency exacerbates NEC severity 4OI maintains intestinal barrier integrity. 4OI rescues NEC by regulating macrophage mitochondrial activity.

Keywords:  itaconate; macrophage; metabolic reprogramming; necrotizing enterocolitis; oxidative phosphorylation

DOI:  https://doi.org/10.1002/ctm2.70419
Cell Insight. 2025 Aug;4(4): 100257

The NF-κB-SLC7A11 axis regulates ferroptosis sensitivity in inflammatory macrophages.

Mengjie Yang, Xiaowei Chen, Xiran Hu, Hexiang Li, Hao Huang, Yingzhe Fang, Jue Jiang, Hudan Liu, Yuan Wang, Guoliang Qing.

  M1-polarized macrophages exhibit remarkable resistance to ferroptosis, a form of regulated cell death driven by excessive lipid peroxidation. Yet the underlying mechanisms remain to be defined. Through CRISPR-based functional screen of metabolic genes combining transcriptomics analysis, we herein identified the cystine/glutamate antiporter SLC7A11 as a pivotal mediator of ferroptosis resistance in M1 macrophages. Mechanistically, lipopolysaccharide (LPS) engagement with the Toll-like receptor 4 (TLR4) resulted in NF-κB activation, leading to RELA-dependent transcriptional upregulation of Slc7a11 expression. SLC7A11 in turn promoted cystine uptake and subsequent glutathione (GSH) synthesis. Genetic ablation of Slc7a11 reduced GSH production, sensitizing M1 macrophages to RSL3-induced ferroptosis. In aggregate, our findings unveil the RELA-SLC7A11 axis as a critical metabolic checkpoint dictating macrophage ferroptosis sensitivity, which might be employed to modulate macrophage functions in inflammatory diseases.

Keywords:  Ferroptosis; Immune metabolism; Macrophage; RELA; SLC7A11

DOI:  https://doi.org/10.1016/j.cellin.2025.100257
Acta Pharm Sin B. 2025 Jun;15(6): 3107-3124

Ablation of macrophage transcriptional factor FoxO1 protects against ischemia-reperfusion injury-induced acute kidney injury.

Yao He, Xue Yang, Chenyu Zhang, Min Deng, Bin Tu, Qian Liu, Jiaying Cai, Ying Zhang, Li Su, Zhiwen Yang, Hongfeng Xu, Zhongyuan Zheng, Qun Ma, Xi Wang, Xuejun Li, Linlin Li, Long Zhang, Yongzhuo Huang, Lu Tie.

  Acute kidney injury (AKI) has high morbidity and mortality, but effective clinical drugs and management are lacking. Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI and may serve as potential therapeutic targets. Emerging evidence has highlighted the importance of forkhead box protein O1 (FoxO1) in mediating macrophage activation and polarization in various diseases, but the specific mechanisms by which FoxO1 regulates macrophages during AKI remain unclear. The present study aimed to investigate the role of FoxO1 in macrophages in the pathogenesis of AKI. We observed a significant upregulation of FoxO1 in kidney macrophages following ischemia-reperfusion (I/R) injury. Additionally, our findings demonstrated that the administration of FoxO1 inhibitor AS1842856-encapsulated liposome (AS-Lipo), mainly acting on macrophages, effectively mitigated renal injury induced by I/R injury in mice. By generating myeloid-specific FoxO1-knockout mice, we further observed that the deficiency of FoxO1 in myeloid cells protected against I/R injury-induced AKI. Furthermore, our study provided evidence of FoxO1's pivotal role in macrophage chemotaxis, inflammation, and migration. Moreover, the impact of FoxO1 on the regulation of macrophage migration was mediated through RhoA guanine nucleotide exchange factor 1 (ARHGEF1), indicating that ARHGEF1 may serve as a potential intermediary between FoxO1 and the activity of the RhoA pathway. Consequently, our findings propose that FoxO1 plays a crucial role as a mediator and biomarker in the context of AKI. Targeting macrophage FoxO1 pharmacologically could potentially offer a promising therapeutic approach for AKI.

Keywords:  AKI; ARHGEF1; Chemotaxis; FoxO1; I/R injury; Inflammation; Macrophage; Migration

DOI:  https://doi.org/10.1016/j.apsb.2025.04.009
Adv Sci (Weinh). 2025 Jul 13. e01104

Cytokine Storm Induction Linked to Multi-Organ Failure in Fatal Jellyfish Stings.

Yichao Wang, Yi Wang, Fengling Yang, Jingbo Chen, Xiaoyu Geng, Qing Sun, Jinyu Zhang, Chang Liu, Jie Lv, Xiaochuan Hou, Yongfang Wang, Huiyan Lin, Jing Zhang, Lingxin Chen, Bing Yan, Liang Xiao.

  Fatal jellyfish stings often cause multi-organ failure. Until now, these fatal outcomes are attributed to the direct toxic effects of the venom. Here, a mouse model of delayed jellyfish envenomation syndrome (DJES) is established and showed that venom from Nemopilema nomurai jellyfish can trigger a deadly cytokine storm - a severe inflammatory reaction. Mice injected with the venom displayed acute multi-organ failure and significant upregulation of over 20 pro-inflammatory cytokines (including IL-6, TNF-α, CXCL2, and CCL4) in the heart, liver, and kidneys. Transcriptomic analyses identified NF-κB p65 subunit activation as central to the cytokine storm induction. Knockdown of p65 in macrophages reduced cytokine production and improved cell viability. Treatment with dexamethasone, an NF-κB inhibitor, effectively suppressed the cytokine storm, mitigated organ damage, and increased survival rates in mice. The findings present new insights to treat fatal jellyfish stings.

Keywords:  NF‐κB p65; cytokine storm; envenomation; inflammation; jellyfish

DOI:  https://doi.org/10.1002/advs.202501104
Signal Transduct Target Ther. 2025 Jul 18. 10(1): 225

Phosphorylated Toll-like receptor 3 nuclear translocation in cancer cell promotes metastasis and chemoresistance.

Zixin Wang, Yan Gu, Yanfang Liu, Ziqiao Wang, Xinyuan Chen, Haoze Wang, Wei Zhang, Gang Jin, Xuetao Cao.

Aberrant expression and subcellular location of innate sensors in cancer cells, such as Toll-like receptors (TLRs), correlates with pro-tumoral inflammation and cancer progression, but the mechanism is still largely unknown. Deciphering the proinflammatory mediators in tumor microenvironment will contribute to the development of cancer therapeutics. By using immunohistochemistry in pancreatic ductal adenocarcinoma (PDAC) and multiple other cancer samples, here we found that cancer cell TLR3, a well-known cytoplasmic dsRNA sensor, translocated to the nucleus especially upon chemotherapy stress. Nuclear TLR3 increased the invasive and proliferative properties, and inhibited chemotherapy-induced apoptosis of cancer cells in vitro. Meanwhile, mice bearing cancer cells with nuclear TLR3 exhibited increased liver metastasis and shortened survival. Mechanistically, phosphokinase JAK1 was responsible for TLR3 phosphorylation at S155 to induce its nuclear translocation in cooperation with a nuclear transport factor importin α5. Chemotherapeutic stress induced the aberrant aggregation of dsRNA in the nucleus, which potentially contributed to nuclear TLR3 activation. Then nuclear TLR3 recruited protein arginine methyltransferase 5 (PRMT5) and bound to c-Myc to promote symmetrical dimethylation and multimerization of c-Myc, resulting in the activation of c-Myc downstream target genes and pro-tumoral signaling pathways. Accordingly, high levels of cancer cell nuclear TLR3 in clinical samples predicted patients' worse prognosis with shorter disease-free survival, overall survival and poor response to neoadjuvant chemotherapy. Therefore, the identification of nuclear TLR3 provides new insight into non-classical functions of innate immune sensors in cancer, and JAK1/TLR3/PRMT5/c-Myc axis may sever as a potential prognostic indicator and therapeutic target to overcome chemoresistance.

DOI: https://doi.org/10.1038/s41392-025-02307-7
Cell Rep. 2025 Jul 15. pii: S2211-1247(25)00773-9. [Epub ahead of print]44(8): 116002

Endolysosomal damage surveillance enables rapid inflammasome sensing of pathogens.

Sonia Shivcharan, Doulathunnisa Ahamed Younis, Skylar S Wright, Chengliang Wang, Bharat Behl, Patience Shumba, Kristina N Delgado, Arshmeet K Chawla, Neal M Alto, Noorjahan Panjwani, Sivapriya Kailasan Vanaja, Jianbin Ruan, Zhichao Fan, Vijay A Rathinam.

  Host cell cytosol is monitored by inflammasomes. Cytosolic invasion of pathogens involves breaching endolysosomal membranes, which is sensed by galectins triggering endolysosomal damage response. Whether and how endomembrane damage surveillance impacts inflammasome sensing of pathogens is unknown. Here, we show that endosomal damage sensing by galectin-8 licenses rapid noncanonical inflammasome sensing of intracellular bacteria; caspase-4 sensing of cytosol-invading bacteria, the consequent gasdermin D (GSDMD)-mediated pyroptosis, and interleukin (IL)-18 activation are greatly reduced in galectin-8-deficient human epithelial cells. Interestingly, galectin-8 promotes caspase-4 activation independently of the autophagic receptor NDP52 and bacterial restriction. Instead, we demonstrate that galectin-8 exists in a complex with caspase-4 in naive cells and recruits caspase-4 to bacteria upon endolysosomal rupture, enabling lipopolysaccharide (LPS) sensing. Collectively, this study reveals galectin-8 as a hub integrating endomembrane damage sensing and inflammasome sensing. Thus, tethering the pathogen sensor caspase-4 to the endomembrane damage sensor galectin-8 poises the host to rapidly detect bacteria that breach the endolysosomal network.

Keywords:  CP: Immunology; caspase-4; cell death; endolysosomes; galectins; gasdermin D; inflammasome; pathogen sensing; pyroptosis

DOI:  https://doi.org/10.1016/j.celrep.2025.116002