bims-traimu Biomed News
on Trained immunity
Issue of 2025–09–28
fifteen papers selected by
Yantong Wan, Southern Medical University
  1. Targeting Innate Immune Memory for Stroke Prevention and Prognosis.
  2. Trained immunity modulators: A new frontier in immunoregulation and disease intervention.
  3. The epigenomic landscape of bronchial epithelial cells reveals the establishment of trained immunity.
  4. Involvement of (trained) immunity in cardioprotection.
  5. IgA-dependent cell phagocytosis of HIV-infected cells elicits cross-presentation to CD8+T cells and immune memory in effector monocytes.
  6. Endotoxin's Impact on Organism: From Immune Activation to Tolerance and Beyond.
  7. Synthetic anticoagulant octaparin targets mitochondrial cardiolipin-GSDMD axis to rescue redox homeostasis in sepsis.
  8. RIPK1 S161 phosphorylation promotes further autophosphorylation and cecal necroptosis in TNF-treated mice.
  9. Resolved versus uncontrolled inflammation: a mathematical model to decipher the role of innate immunity.
  10. Adenosine 2A receptor-dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming.
  11. STK11 coordinates IL-4 signaling with metabolic reprogramming to control M2 macrophage polarization and antitumor immunity.
  12. The immunology of sepsis: translating new insights into clinical practice.
  13. Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis.
  14. Single-cell RNA-sequencing of BCG naïve and recurrent non-muscle invasive bladder cancer reveals a CD6/ALCAM-mediated immune-suppressive pathway.
  15. Itaconate promotes the differentiation of murine stress erythroid progenitors by increasing Nrf2 activity.
  1. Stroke. 2025 Oct;56(10): 3095-3098
    Targeting Innate Immune Memory for Stroke Prevention and Prognosis.
    Aurora Semerano, Juan F Arenillas, Louise D McCullough, María Ángeles Moro.
      
    Keywords:  atherosclerosis; cardiovascular diseases; immune tolerance; ischemic stroke; myeloid cells; prognosis; trained immunity
    DOI:  https://doi.org/10.1161/STROKEAHA.125.049900
  2. J Adv Res. 2025 Sep 18. pii: S2090-1232(25)00734-9. [Epub ahead of print]
    Trained immunity modulators: A new frontier in immunoregulation and disease intervention.
    Jiao Chen, Chenxi Wang, Shilin Chen, Hui Cai, Mengke Wang, Jingjie Chang, Xueting Cai, Jie Yang, Peng Cao.
       BACKGROUND: Immunotherapy has emerged as one of the most revolutionary approaches in disease treatments. However, most current and emerging immunotherapeutic strategies primarily target the adaptive immune system. Recent studies have elucidated that innate immune myeloid cells can develop sustained phenotypic modifications upon exposure to specific immunomodulators, mediated through coordinated metabolic alterations and epigenetic reprogramming. These changes lead to either hyperresponsive or hyporesponsive innate immune cells when exposed to secondary stimuli, a phenomenon termed "trained immunity". Over the past decade, trained immunity has garnered increasing attention for its potential to enhance host defense. While numerous studies have investigated trained immunity modulators, comprehensive reviews-especially those focusing on recently identified modulators-are still lacking.
    AIM OF REVIEW: This review aims to elucidate the molecular mechanisms underlying trained immunity and its dual roles in various pathological conditions. We provide a comprehensive summary of the classifications and mechanisms of trained immunity inducers and suppressors identified in the past decade, emphasizing their therapeutic potential in immune-related diseases. Additionally, we discuss the limitations of these trained immunity modulators and offer insights into future directions for developing novel therapies targeting trained immunity. Key scientific concepts of review: This review first provide an overview of the molecular mechanisms underlying trained immunity, highlighting both its beneficial and detrimental effects on various diseases. Then it focuses on summarizing the classification and mechanisms of trained immunity modulators, including vaccines, polysaccharides, nanobiologics, endogenous mediators and other non-canonical modulators. Finally, the limitations of current trained immunity modulators and insights into future directions for developing novel therapies targeting trained immunity are proposed.
    Keywords:  Inducer; Polysaccharide; Suppressor; Trained immunity; Vaccine
    DOI:  https://doi.org/10.1016/j.jare.2025.09.029
  3. Genes Immun. 2025 Sep 24.
    The epigenomic landscape of bronchial epithelial cells reveals the establishment of trained immunity.
    Jeanne Bigot, Rachel Legendre, Juliette Hamroune, Sébastien Jacques, Mathieu Le Gars, Nicolas Millet, Loïc Guillot, Harriet Corvol, Christophe Hennequin, Juliette Guitard, Jean-Yves Coppée, Viviane Balloy, Claudia Chica.
      Innate immune memory, also called trained immunity, refers to the ability of innate immune cells to gain memory characteristics after transient stimulation, resulting in a nonspecific modified inflammatory response upon secondary remote challenge. Bronchial epithelial cells (BECs) participate in innate immune defence and are the first cells of the lower respiratory tract to encounter inhaled pathogens. We recently showed that BECs are capable of innate immune memory after preexposure to Pseudomonas aeruginosa flagellin through epigenetic mechanisms. In the present study, we investigated such mechanisms through the modification of chromatin architecture induced by flagellin preexposure that results in subsequent changes of gene expression. By conducting an unsupervised approach to jointly analyse chromatin accessibility and gene expression, we mapped the remodelling of the epigenomic and transcriptomic profiles during the establishment of BECs memory. We identified a Memory regulatory profile induced by flagellin exposure. It includes clusters of upregulated genes related to inflammation that are linked to a sustainable gain in chromatin accessibility and with an increased activity of specific transcription factors (TFs) whose binding may drive this process. In summary, we demonstrated that flagellin exposure induced changes in chromatin condensation in BECs, which sustains the reprogramming of transcriptional patterns.
    DOI:  https://doi.org/10.1038/s41435-025-00357-z
  4. Cardiovasc Res. 2025 Sep 24. pii: cvaf170. [Epub ahead of print]
    Involvement of (trained) immunity in cardioprotection.
    Gerd Heusch, Petra Kleinbongard.
      
    DOI:  https://doi.org/10.1093/cvr/cvaf170
  5. Mucosal Immunol. 2025 Sep 18. pii: S1933-0219(25)00094-7. [Epub ahead of print]
    IgA-dependent cell phagocytosis of HIV-infected cells elicits cross-presentation to CD8+T cells and immune memory in effector monocytes.
    Andrea Cottignies-Calamarte, Annouk Dauvilliers, Lucie Adoux, Benjamin Saint-Pierre, Franck Letourneur, Sylvain Cardinaud, Daniela Tudor, Morgane Bomsel.
      Mucosal IgA antibodies are the first defence against mucosal infections. Besides targeting specific antigens by their Fab-region, IgA also mediates antiviral functions via their Fc-domain, allowing infected cells destruction by antibody-dependent cellular phagocytosis (ADCP). Passive immunisation with anti-HIV-1 IgG protected Non-Human Primates in a CD8+ T cell-dependent manner, a process likely involving ADCP. Here, we unravel the consequences of ADCP of HIV-1-infected cells mediated by anti-HIV envelope IgA compared to IgG. We found that IgA-mediated ADCP, not IgG, drives viral antigen cross-presentation to HIV-1-specific cytotoxic CD8+ T cells. IgA effector function reprogrammed ADCP effector monocytes into activated macrophages exhibiting a mixed pro- and anti-inflammatory profile combined with increased pro-inflammatory chemokines. IgA-mediated ADCP sensitizes monocytes to respond to a novel bacterial challenge by secreting IL-6 and TNFα, indicative of acquired trained immunity. Altogether, these data establish a bridge between humoral and cellular immunity that could be exploited in HIV preventive strategies.
    Keywords:  Antibody-dependent cell phagocytosis; Cross-presentation; HIV-1; IgA; Trained immunity
    DOI:  https://doi.org/10.1016/j.mucimm.2025.09.004
  6. J Clin Med. 2025 Sep 14. pii: 6478. [Epub ahead of print]14(18):
    Endotoxin's Impact on Organism: From Immune Activation to Tolerance and Beyond.
    Kacper Roszak, Konkonika Roy, Justyna Sobocińska, Paulina Spisz, Tomasz Jędrzejewski, Sylwia Wrotek.
      Endotoxin, a key component of Gram-negative bacterial membranes, remains a central focus in understanding host-pathogen interactions and immune modulation. In this review, we examine the multifaceted roles of endotoxin, with particular emphasis on how its structural variants modulate host immune recognition and inflammatory signalling. We explore the complex mechanisms by which endotoxin activates innate immune pathways and how these responses evolve under repeated or chronic exposure conditions. Special attention is given to the phenomenon of endotoxin tolerance, an adaptive reprogramming of immune cells that can profoundly alter inflammatory outcomes. While this tolerance serves as a protective mechanism against hyperinflammation, mounting evidence suggests that it may have a "dark side", potentially impairing immune surveillance and promoting disease states such as cancer. We also discuss emerging clinical and therapeutic strategies that harness or counteract endotoxin-driven responses, from vaccine adjuvants to anti-sepsis interventions. By integrating recent findings from immunology, microbiology, and translational medicine, this review sheds light on the dual nature of endotoxin and its far-reaching implications for human health.
    Keywords:  LPS; TLR4 signalling; endotoxemia; endotoxin; endotoxin tolerance; inflammasome; inflammation; sepsis; septic shock; tumor microenvironment
    DOI:  https://doi.org/10.3390/jcm14186478
  7. Redox Biol. 2025 Sep 22. pii: S2213-2317(25)00390-8. [Epub ahead of print]87 103877
    Synthetic anticoagulant octaparin targets mitochondrial cardiolipin-GSDMD axis to rescue redox homeostasis in sepsis.
    Shule Zhang, Cong Feng, Ning Yu, Rui Fang, Yingxin Zhang, Simeng Chen, Lijuan Cao, Jianfa Zhang.
      Sepsis, characterized by dysregulated immune responses and mitochondrial dysfunction, currently has few effective therapies that directly target these cellular mechanisms, and conventional heparin and related analogues provide inadequate immunomodulatory benefits. Here, we investigated the synthetic heparin analogue octaparin, which exhibits enhanced anticoagulant safety, for its potential to mitigate sepsis by targeting mitochondrial and redox pathways. Using murine models of lipopolysaccharide (LPS)-induced endotoxemia and Salmonella typhimurium-induced sepsis, along with in vitro studies performed using murine bone marrow-derived macrophages (BMDMs) and the human acute monocytic leukemia THP-1 cell line, we demonstrate that octaparin significantly improves survival and attenuates multi-organ (lung, liver, kidney) damage. Octaparin outperformed heparin, enoxaparin, and fondaparinux in suppressing systemic inflammation including TNF-α, IL-6, IL-1β and bacterial burden. Transcriptomic analysis revealed octaparin reprograms macrophage immunometabolism, suppressing pro-inflammatory pathways while enhancing phagocytosis. Crucially, octaparin inhibited both canonical and non-canonical inflammasome activation, reduced generation of the pyroptotic executor GSDMD-N-terminal fragment (GSDMD-NT), and specifically diminished mitochondrial localization of GSDMD-NT by downregulating key cardiolipin synthesis and transport genes. Furthermore, octaparin uniquely reversed LPS-induced mitochondrial dysfunction. This restoration was accompanied by improvements in mitochondrial quality and the reestablishment of redox homeostasis. Collectively, octaparin confers multifaceted protection in sepsis, positioning it as a promising redox-targeted therapeutic for sepsis.
    Keywords:  Cardiolipin; Mitochondria; Octaparin; Pyroptosis; Redox homeostasis; Sepsis
    DOI:  https://doi.org/10.1016/j.redox.2025.103877
  8. J Exp Med. 2025 Dec 01. pii: e20250277. [Epub ahead of print]222(12):
    RIPK1 S161 phosphorylation promotes further autophosphorylation and cecal necroptosis in TNF-treated mice.
    Tao Han, Chenchen Ruan, Huiyong Lin, Yuxia Zhang, Lang Li, Ye-Hsuan Sun, Chuan-Qi Zhong, Xin Chen, Kai Huang, Yating Cao, Zusen Fan, Hongbing Zhang, Jiahuai Han, Yingying Zhang.
      Excess TNF causes systemic inflammatory response syndrome and mortality. RIPK1 coordinates TNF signaling through kinase-dependent and -independent mechanisms. S161 autophosphorylation is a primary function of RIPK1 kinase activity in vitro, and here we show that it is sufficient to mediate RIPK1 kinase-dependent function in vivo. S161 phospho-mimic mutation (S161E) effectively overcomes chemical or genetic inhibition of RIPK1 kinase activity in TNF-treated cells and mice. Mechanistically, S161 autophosphorylation is necessary for further autophosphorylation in RIPK1, including at S166. Ripk1S161E/S161E mice are hypersensitive to TNF, enabling us to observe low-dose TNF-induced necroptosis in cecal intestinal epithelial cells (IECs) and endothelial cells (ECs) and uncover a reciprocal enhancement between IEC and EC necroptosis and a selective increase of IL-6 in the circulation by necroptosis. IL-6 promotes cecal edema and synergizes with IEC and EC necroptosis, causing cecal damage and mouse death. Our data elucidate a mechanism of RIPK1 kinase-dependent function in TNF signaling and its role in cecal pathology and mouse mortality.
    DOI:  https://doi.org/10.1084/jem.20250277
  9. J Leukoc Biol. 2025 Sep 26. pii: qiaf132. [Epub ahead of print]
    Resolved versus uncontrolled inflammation: a mathematical model to decipher the role of innate immunity.
    Karina García-Martínez, Nuris Ledón, Agustín Lage.
      Understanding the impact of Neutrophils and Macrophages in the dynamic outcome of resolution vs uncontrolled response is still an open debate. Here, we develop a mathematical model that describe the dynamic of the innate immune response after an acute damage. Our model includes all the described processes that mediate this response, including the regulatory mechanisms carried out by type-2 Macrophages (M2). Additionally, we estimate the resolution indices to quantify the efficiency of resolution mechanisms by controlling the initial expansion of Neutrophils and/or the subsequent contraction kinetics of the cell response. We predict that the partial reduction of Neutrophil influx and the increase of type-1 Macrophage (M1)-mediated efferocytosis rate are the best strategies to control the Neutrophil initial expansion. On the other hand, the partial reduction of M1 cells influx or the increase of Neutrophil apoptosis rate are predicted as good strategies to accelerate the Neutrophils decay during the contraction phase of the response.
    Keywords:  Macrophage; Neutrophil; acute inflammation; mathematical model; resolution indices
    DOI:  https://doi.org/10.1093/jleuko/qiaf132
  10. Sci Signal. 2025 Sep 23. 18(905): eadr3177
    Adenosine 2A receptor-dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming.
    Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A J O'Neill, Georgina Xanthou.
      Metabolic reprogramming controls protective and pathogenic T helper 17 (TH17) cell responses. When naïve T cells are differentiated into TH17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic TH17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A2A receptor (A2AR) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic TH17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic TH17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys9 (H3K9ac) of genes involved in aerobic glycolysis and TH17 pathogenic programs. In contrast, in nonpathogenic activin A-treated TH17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic TH17 programs. Together, our findings uncover A2AR-AMPK signaling as a central metabolic checkpoint that suppresses TH17 cell pathogenicity.
    DOI:  https://doi.org/10.1126/scisignal.adr3177
  11. Sci Adv. 2025 Sep 26. 11(39): eadx5495
    STK11 coordinates IL-4 signaling with metabolic reprogramming to control M2 macrophage polarization and antitumor immunity.
    Jing Yang, Naresh Singh, Chengxian Xu, Dehui Kong, Samantha Sharma, Sheng Liu, Joseph Lechner, Ankhbayar Lkhagva, Haiyan Tan, Zhiping Wu, Martin J Richer, Yong Zang, Xiumei Huang, Reuben Kapur, Jun Wan, Anthony A High, Xinna Zhang, Xusheng Wang, Xiongbin Lu, Kai Yang.
      Macrophages integrate microenvironmental cues to orchestrate complex transcriptional and metabolic programs that drive functional polarization. Here, we demonstrate that STK11 links interleukin-4 (IL-4) signaling with metabolic reprogramming to restrain alternatively activated (M2) macrophage polarization. Through integrative transcriptomic and metabolomic analyses, we identified STK11 as a key transcriptional and metabolic regulator during M2 polarization. STK11 deficiency enhanced the expression of M2-associated markers and promoted glutamine metabolism in IL-4-stimulated macrophages. Mechanistically, STK11 deficiency led to increased FOXO1 activation, thereby promoting M2 polarization. Pharmacological inhibition of FOXO1 or glutamine metabolism effectively reversed the enhanced M2 polarization. In an orthotopic model of pancreatic ductal adenocarcinoma, myeloid-specific deletion of STK11 resulted in increased accumulation of M2-like tumor-associated macrophages, impaired antitumor immunity, and accelerated tumor progression. These findings uncover a previously unrecognized role for STK11 in modulating M2 macrophage polarization, offering mechanistic insights that may inform the development of immunometabolic therapies for pancreatic cancer.
    DOI:  https://doi.org/10.1126/sciadv.adx5495
  12. Nat Rev Nephrol. 2025 Sep 24.
    The immunology of sepsis: translating new insights into clinical practice.
    Matthijs Kox, Michael Bauer, Lieuwe D J Bos, Hjalmar Bouma, Thierry Calandra, Carolyn S Calfee, Benjamin G Chousterman, Lennie P G Derde, Evangelos J Giamarellos-Bourboulis, Hernando Gómez, Mihai G Netea, Marlies Ostermann, Tom van der Poll, Brendon P Scicluna, Christopher Seymour, Manu Shankar-Hari, Nathan Shapiro, Mervyn Singer, Fabienne Venet, Alexander P J Vlaar, Lonneke A van Vught, Sebastian Weis, W Joost Wiersinga, Peter Pickkers.
      Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Treatments that influence this dysregulated host response are sparse. The immunopathophysiology of sepsis entails overzealous inflammation causing acute organ dysfunction, as well as a profound and/or persistent anti-inflammatory response that increases susceptibility to secondary infection. The immune response in sepsis is under the influence of various endogenous and exogenous factors, including genetic makeup, age, sex, comorbidities, metabolism, prior microbial exposure and medications. The consequent heterogeneity of the syndrome hampers immunomodulatory treatment strategies that rely on a 'one-size-fits-all' approach. A precision medicine approach is therefore warranted. Balanced application of prognostic- and predictive-enrichment strategies is instrumental to achieve precision medicine. Phenotyping of patients using clinical, physiological, microbiological and/or molecular ('omics') data enables the identification of more homogeneous patient subgroups. Several studies suggest that such approaches can be used to tailor adjunctive immunomodulatory therapies in patients with sepsis. As well as repurposing existing drugs to treat sepsis, new drugs aimed at restoring immune homeostasis are under investigation. New clinical trial methodologies, including flexible platform trials, Bayesian statistics and embedding trials in health care systems are increasingly being used to keep pace with rapid developments in the field of sepsis immunobiology and ultimately to improve clinical outcomes.
    DOI:  https://doi.org/10.1038/s41581-025-01004-6
  13. Nat Metab. 2025 Sep;7(9): 1924-1938
    Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis.
    Saloua Benhmammouch, Coraline Borowczyk, Clara Pierrot-Blanchet, Thibault Barouillet, Florent Murcy, Sébastien Dussaud, Marina Blanc, Camille Blériot, Tiit Örd, Lama Habbouche, Nathalie Vaillant, Yohan Gerber, Clément Cochain, Emmanuel L Gautier, Florent Ginhoux, Edward B Thorp, Erik A L Biessen, Judith C Sluimer, Susanna Bodoy, Manuel Palacin, Béatrice Bailly-Maitre, Minna U Kaikkonen, Laurent Yvan-Charvet.
      Atherosclerosis is a life-threatening condition characterized by chronic inflammation of the arterial wall. Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates the progression of pathogenesis. Here we show that reduced macrophage glutaminase activity is related to glutaminase (GLS)-1 and not GLS2 expression. While glutamine synthetase serves as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relies more heavily on glutamine influx. Enhanced glutamine flux is largely mediated by the SLC7A7 exchanger in macrophages: Slc7a7-silenced macrophages have reduced glutamine influx and GLS1-dependent glutaminolysis, impeding downstream signalling involved in macrophage restorative functions. In vivo, macrophage-specific deletion of Slc7a7 accelerates atherosclerosis in mice with more complex necrotic core composition. Finally, cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodelling and restorative functions. Thus, we uncover a role of SLC7A7-dependent glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability.
    DOI:  https://doi.org/10.1038/s42255-025-01354-2
  14. NPJ Precis Oncol. 2025 Sep 26. 9(1): 318
    Single-cell RNA-sequencing of BCG naïve and recurrent non-muscle invasive bladder cancer reveals a CD6/ALCAM-mediated immune-suppressive pathway.
    Ivan Juric, Emily E Fink, Hong Qiu, Pierre-Emmanuel Desprez, Arvind Ravi, Mark Holton, Vladimir Makarov, Nima Almassi, Booki Min, Gad Getz, Timothy A Chan, Tyler Alban, Angela H Ting, Byron H Lee.
      Bacillus Calmette-Guérin (BCG) is the mainstay of treatment for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC), yet recurrence rates remain high. To improve the efficacy of BCG, a better understanding of the immune landscape underlying BCG resistance is critical. Here, we performed single-cell RNA-sequencing (scRNA-seq) and whole-exome sequencing on tumors from NMIBC patients before and after BCG treatment. Our analysis revealed a marked increase in CD6/ALCAM interactions between T cells and urothelial cells in BCG recurrent tumors. CD6-high T cells were enriched in recurrent tumors and exhibited downregulation of activation-related genes, indicative of functional impairment. These observations were supported by analysis of an independent BCG-treated NMIBC cohort, in which CD6/ALCAM signaling was correlated with shorter recurrence-free survival (p = 0.00059). Our findings reveal a previously unrecognized association between CD6/ALCAM signaling and BCG resistance in NMIBC patients and highlight this pathway as a potential therapeutic target to enhance response to BCG.
    DOI:  https://doi.org/10.1038/s41698-025-01093-3
  15. Blood Red Cells Iron. 2025 Jun;pii: 100001. [Epub ahead of print]1(1):
    Itaconate promotes the differentiation of murine stress erythroid progenitors by increasing Nrf2 activity.
    Baiye Ruan, Yuanting Chen, Sara Trimidal, Meghna Chakraborty, Aashka Shah, Hangdi Gong, Imhoi Koo, Jingwei Cai, John Mcguigan, Molly A Hall, Andrew D Patterson, K Sandeep Prabhu, Robert F Paulson.
      Steady-state erythropoiesis produces new erythrocytes at a constant rate to replace senescent erythrocytes removed in the spleen and liver. Inflammation caused by infection or tissue damage skews bone marrow hematopoiesis, increasing myelopoiesis at the expense of steady-state erythropoiesis. To compensate for the loss of production, stress erythropoiesis is induced. Stress erythropoiesis is highly conserved between mice and humans. It uses a strategy different to the constant production of steady-state erythropoiesis. Inflammatory signals promote the proliferation of immature stress erythroid progenitors (SEPs), which then commit to differentiation. This transition relies on signals made by niche macrophages in response to erythropoietin. Nitric oxide-dependent signaling drives the proliferation of SEPs, and nitric oxide production must be decreased so that progenitor cells can differentiate. Here, we show that as progenitor cells transition to differentiation, increased production of the anti-inflammatory metabolite itaconate activates nuclear factor erythroid 2-related factor 2, which decreases nitric oxide synthase 2 expression, leading to decreased nitric oxide production. Mutation of immunoresponsive gene 1, the enzyme that catalyzes the production of itaconate, causes a delayed recovery from inflammatory anemia induced by heat-killed Brucella abortus. These data show that the differentiation of SEPs relies on a switch to an anti-inflammatory metabolism and increased expression of proresolving cytokines.
    DOI:  https://doi.org/10.1016/j.brci.2025.100001
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