bims-traimu Biomed News
on Trained immunity
Issue of 2026–05–17
fourteen papers selected by
Yantong Wan, Southern Medical University
  1. Trained Immunity in Neutrophils and Mononuclear Phagocytes: Mechanisms and Pathophysiological Functions.
  2. Trained Immunity Induced by Vaccines: A Shifting Paradigm for Infant and Adult Immunity.
  3. Systems pharmacology approaches to modeling immune training and tolerance.
  4. Trained immunity in monocytes and macrophages in atherosclerotic cardiovascular disease.
  5. Intermittent Cobalt (II, III) Oxide Exposure Exacerbates Inflammatory Injury through Tumor Necrosis Factor-Alpha-Dependent Bone Marrow-Mediated Trained Immunity.
  6. Forging resilient warriors within: exercise's epic role in training innate immunity and taming inflammation's storm.
  7. Metabolic-epigenetic rewiring in rheumatoid arthritis: from pathogenic memory to precision restoration.
  8. The alkylation of AIM2 by itaconate mediates macrophage PANoptosis during sepsis.
  9. Cell-mediated immune responses of beta-glucan on the pathogenesis of chronic tuberculosis infection.
  10. ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis.
  11. Transcription-based identification of uncharacterized genes in the human immune response.
  12. The devil you know: a longer history of pathogen coevolution predicts higher behavioural tolerance of infection among host populations.
  13. Artificial exosomes synergistically reshape sepsis immune homeostasis by modulating neutrophil fate and blocking PD-1/PD-L1.
  14. Dynamics of severity-associated immune remodeling by granulocytes and macrophages in acute lung injury.
  1. Cells. 2026 Apr 23. pii: 752. [Epub ahead of print]15(9):
    Trained Immunity in Neutrophils and Mononuclear Phagocytes: Mechanisms and Pathophysiological Functions.
    Wanying Li, Jialei Wei, Liyuan Li, Wei Sun.
      Trained immunity refers to the enduring functional reprogramming of innate immune cells after particular stimuli, driven by epigenetic and metabolic alterations that augment non-specific responses upon subsequent exposure. Neutrophils and monocytes/macrophages, as essential innate effectors, are crucial for the induction and control of trained immunity, which is the primary emphasis of this review. Neutrophils, the predominant circulating leukocytes, were historically considered incapable of memory owing to their brief lifespan. Emerging evidence indicates that trained immunity functions at the bone marrow progenitor level, influencing granulopoiesis to produce neutrophils with lasting functional modifications. This research offers new insights into neutrophil functions in infection, cancer, and inflammation. Monocytes and macrophages, characterized by phenotypic plasticity and tissue residence, function as conventional models of trained immunity. They experience direct peripheral reprogramming or emerge as primed descendants of trained bone marrow precursors, performing pro-inflammatory or reparative roles in malignancies, infections, and ischemia lesions. This study comprehensively outlines the regulatory mechanisms of trained immunity in these cells, clarifies their functions in various clinical situations, and examines therapeutic applications. Comprehending these pathways is crucial for elucidating the cellular foundation of innate immunological memory, uncovering its multiple functions in disease, and guiding innovative therapeutics aimed at granulopoiesis and monocyte-macrophage polarization.
    Keywords:  hypoxia; infectious diseases; ischemia; monocytes/macrophages; neutrophils; trained immunity; tumor immunology
    DOI:  https://doi.org/10.3390/cells15090752
  2. Int J Mol Sci. 2026 May 05. pii: 4133. [Epub ahead of print]27(9):
    Trained Immunity Induced by Vaccines: A Shifting Paradigm for Infant and Adult Immunity.
    Shana Singh-Anderson, Gio Aguilar, Lina Zhang, Kuang-Chih Hsiao, Gergely Toldi.
      In addition to inducing pathogen-specific adaptive immune responses, vaccines can train the innate immune system, thereby providing broader host protection. This concept of trained immunity (TRIM) is well-established in benchtop laboratory science. This review aims to evaluate the current evidence of vaccine-induced TRIM and translate these findings into a clinical context. Various laboratory methods are used to assess TRIM; however, inconsistent results have been reported across non-BCG vaccine studies. Existing analyses lack exploration of the mechanistic basis of vaccine-induced TRIM, particularly epigenetic reprogramming and metabolic rewiring. Patterns emerge between vaccines: live-attenuated vaccines generally induce TRIM, as evidenced by increased inflammatory cytokine production upon restimulation, whereas non-live vaccines tend to demonstrate reduced trained immunity. Such findings are not consistently observed for mRNA vaccines, which show heterogeneous patterns. The limited variety of studies on non-BCG vaccines impacts the reliability of findings. A more comprehensive understanding of the mechanisms and outputs of TRIM induced by specific vaccines could better inform rational vaccine design. Furthermore, various modifiers can alter vaccine-induced TRIM responses, including sequence and route of administration, sex, and age. Consideration of these modifiers has important clinical implications in optimising vaccine administration for enhanced immune protection.
    Keywords:  innate immunity; trained immune tolerance; trained immunity; vaccines
    DOI:  https://doi.org/10.3390/ijms27094133
  3. Curr Opin Pharmacol. 2026 Apr 21. pii: S1471-4892(26)00026-3. [Epub ahead of print]89 102630
    Systems pharmacology approaches to modeling immune training and tolerance.
    Kevser Kübra Kırboğa, Mithun Rudrapal.
      Trained immunity is defined as the epigenetic and metabolic reprogramming of innate immune cells, conferring enhanced or diminished responsiveness to secondary challenges following initial stimulation. Immune tolerance represents the state of immunological unresponsiveness to self-antigens or innocuous foreign antigens. Systems pharmacology approaches have emerged as essential tools for understanding and modulating these complex immunological processes. In this mini-review, we evaluate quantitative systems pharmacology (QSP) approaches which are predominantly based on ordinary differential equation (ODE) frameworks and artificial intelligence (AI)/machine learning (ML) applications in the context of trained immunity and immune tolerance. QSP models enable in silico clinical trials, thereby accelerating drug development and supporting cost-effective therapeutic decision-making. Recent advances have identified histone lactylation, particularly H3K18la, as a central epigenetic mark linking metabolic rewiring to long-term innate immune memory, revealing novel pharmacological targets including LDHA, EP300, and ACAT2. ML algorithms integrated with explainable AI frameworks have facilitated biomarker discovery and therapeutic target identification. Digital twin technology holds considerable promise for developing personalized immunomodulatory strategies. This review highlights the translational potential of systems pharmacology tools in pharmacological targeting of trained immunity and tolerance, emphasizing the convergence of computational modeling with precision medicine approaches.
    DOI:  https://doi.org/10.1016/j.coph.2026.102630
  4. Cardiovasc Res. 2026 May 14. pii: cvag109. [Epub ahead of print]
    Trained immunity in monocytes and macrophages in atherosclerotic cardiovascular disease.
    Xiaoyi Zhang, Mo Wang, Yunshan Wang, Li Li, Shuai Wang, Yang Xiang.
      Monocytes and macrophages are critically involved in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Accumulating evidence indicates that monocytes and macrophages can develop innate immune memory and exhibit sustained pro-inflammatory properties in response to stimuli such as hyperlipidemia and hyperglycemia. Persistent activation of innate immune cells is referred to as trained immunity (TI), a process mediated by metabolic and epigenetic reprogramming. This concept provides insight into why cardiovascular events remain challenging to reduce significantly, even when key risk factors for atherosclerosis (AS) are effectively controlled. Previous studies have shown that both pathogen-associated molecular patterns (PAMPs) or endogenous damage-associated molecular patterns (DAMPs) can activate TI in monocytes/macrophages through various receptors, such as Dectin-1, cluster of differentiation 36 (CD36), and glucose transporter 1 (GLUT1), thereby inducing metabolic reprogramming and epigenetic modifications (e.g., histone lactylation and methylation). Moreover, recent research has increasingly focused on developing preventive and therapeutic strategies for ASCVD by modulating TI. In this review, we systematically elucidate the regulatory mechanisms underlying the induction of TI in monocytes and macrophages, and analyze the impact of TI on the persistence of chronic inflammatory states, which may ultimately contribute to the development of ASCVD. We summarize key signaling pathways associated with TI, as well as the metabolic and epigenetic reprogramming processes involved, covering the activation mechanisms of ASCVD-related risk factors, alterations in metabolic regulation, and representative epigenetic modification markers. Finally, we discuss current immunotherapeutic strategies for ASCVD based on the mechanisms of TI and highlight their progress in research.
    Keywords:  ASCVD; epigenetic reprogramming; histone lactylation; monocytes/macrophages; trained immunity
    DOI:  https://doi.org/10.1093/cvr/cvag109
  5. ACS Nano. 2026 May 14.
    Intermittent Cobalt (II, III) Oxide Exposure Exacerbates Inflammatory Injury through Tumor Necrosis Factor-Alpha-Dependent Bone Marrow-Mediated Trained Immunity.
    Hongyan Yu, Yidi Chen, Zhe Kou, Jingxu Zhang, Chen Wang, Yijiao Li, Duxing Li, Yubin Zhang, Yuxin Zheng, Xiaoting Jin.
      Environmental nanoparticle exposure in real-world scenarios is often intermittent rather than continuous, yet its associated risks and mechanisms remain poorly understood. This study investigates whether such intermittent exposure induces maladaptive trained immunity within the bone marrow (BM) to drive inflammatory injury. We establish a physiologically relevant "prime-rest-rechallenge" mouse model of intermittent inhalation to cobalt (II, III) oxide (Co3O4) nanoparticles, a representative environmental stressor. Using this model, we provide in vivo evidence that intermittent Co3O4 exposure establishes a lasting, maladaptive immune memory in the BM─termed BM-mediated trained immunity. Primary Co3O4 exposure induces hematopoietic reprogramming toward a myeloid-biased phenotype, a state that is restored following a rest period. Upon secondary challenge, this reprogrammed state drives an augmented myelopoietic response, characterized by a 1.5-fold expansion of myeloid progenitors and a sustained output of mature myeloid cells. Integrated bioinformatics analysis and functional validation identify tumor necrosis factor-alpha (TNF-α), the highest-degree node (degree = 17) in the interaction network, as the central mediator orchestrating this BM-mediated trained immunity. In vivo TNF-α neutralization abrogates this trained myelopoietic phenotype. Furthermore, this Co3O4-induced, TNF-α-dependent trained immunity exacerbates inflammatory injury in distant organs, including the heart and brain. Our work establishes intermittent exposure as a critical yet overlooked risk paradigm, reveals trained immunity as a mechanistic link between nanoparticles and inflammatory disorders, and positions TNF-α as a potential therapeutic target to mitigate pollution-related risks.
    Keywords:  BM-mediated trained immunity; III) oxide; TNF-α; cobalt (II; inflammatory injury; myeloid-biased hematopoiesis
    DOI:  https://doi.org/10.1021/acsnano.6c03750
  6. Front Immunol. 2026 ;17 1777470
    Forging resilient warriors within: exercise's epic role in training innate immunity and taming inflammation's storm.
    Yahui Li, Dongdong Wang.
      The concept of "trained immunity," which refers to a type of long-term immunological memory within innate cells, has significantly challenged the traditional division between the non-specific innate and antigen-specific adaptive immune systems. Simultaneously, it is now understood that the resolution of inflammation is not just a passive return to homeostasis but rather an active, strictly regulated biological process. This comprehensive review synthesizes these evolving concepts by hypothesizing that exercise, through its pleiotropic effects on cellular metabolism, may strongly stimulate both the active resolution of inflammation and the formation of innate immunological memory via epigenetic control (emerging evidence from non-exercise models like Bacillus Calmette-Guérin (BCG) vaccination and β-glucan exposure suggests parallels, but direct causation in exercise remains associative). The review describes the biological foundations of this relationship, including the metabolic changes that define trained immunity and the epigenetic reprogramming of myeloid progenitors. It explores the central role of myokines, particularly Interleukin-6 (IL-6), which act as critical mediators, steering the immune response toward a pro-resolving phenotype, while acknowledging contributions from other factors such as IL-15, catecholamines, and neural signals. Furthermore, the review outlines how exercise promotes the synthesis of specialized pro-resolving mediators (SPMs) and enhances efferocytosis, a key cellular mechanism for restoring tissue homeostasis. By providing a unifying framework, this analysis offers a mechanistic explanation for the profound health benefits of exercise, from enhanced immunosurveillance to the prevention of chronic inflammatory diseases. The review concludes by highlighting significant knowledge gaps and advocating for the use of multi-omics and in vivo models to fully elucidate this complex nexus and translate these discoveries into novel therapeutic strategies.
    Keywords:  epigenetic reprogramming; exercise immunology; inflammation resolution; sustainable development; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1777470
  7. Front Immunol. 2026 ;17 1836618
    Metabolic-epigenetic rewiring in rheumatoid arthritis: from pathogenic memory to precision restoration.
    Shu Li, Lei Wan, Kun Wang, Xiaojun Zhang.
      Rheumatoid arthritis (RA) is a systemic autoimmune disorder wherein sustained, drug-free remission remains an elusive clinical goal. Frequent disease flares upon treatment withdrawal indicate that conventional immunosuppression fails to eradicate a deeply ingrained "pathogenic memory." In this Review, we provide a comprehensive framework illustrating how the hostile, nutrient-deprived synovial microenvironment acts as a metabolically restrictive microenvironment. Driven by "metabolic parasitism" and mitochondrial collapse, the massive accumulation of intermediate metabolites-most notably lactate, acetyl-CoA, and succinyl-CoA-transcends their traditional roles as bioenergetic waste to function as potent epigenetic regulators. We decode the emerging "PTM multiverse," highlighting how aberrant lactylation, acetylation, and RNA modifications (ac4C) persistently rewire chromatin architecture and critical non-histone sensors (e.g., cGAS). Amplified by hyperactive acetyltransferases and the hypoxia-induced collapse of Sirtuin deacetylases, these modifications engrave resilient "epigenetic scars" that lock innate immune and stromal cells into highly destructive phenotypes via trained immunity. We further integrate this localized articular inflammation into a holistic meta-organ model, tracing disease origins to mucosal gene-environment interactions and detailing systemic regulation via the gut-microbiota-joint axis and chronobiological rhythms. Ultimately, we explore how deciphering these integrated networks translates into next-generation prognostic biomarkers (e.g., AMPAs and GlycA) and heralds a critical therapeutic paradigm shift-from transient immune blockade to precise metabolic-epigenetic restoration.
    Keywords:  epigenetic reprogramming; immunometabolism; lactylation; rheumatoid arthritis; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1836618
  8. Cell Mol Immunol. 2026 May 12.
    The alkylation of AIM2 by itaconate mediates macrophage PANoptosis during sepsis.
    Jiamin Ma, Ying Chen, Pei Wang, Yan Zhang, Yi Li, Qing Tu, Xinru Zhao, Xuanqi Yao, Fang Li, Yuan Yuan, Chenwei Wu, Lin Wang, Yuwei Chen, Chenchen Liu, Rui Kang, Daolin Tang, Liangfang Yao, Feng Chen, Jinbao Li.
      Although the immunometabolite itaconate has long been considered an anti-inflammatory, we found that its profound accumulation paradoxically drives macrophage cell death and pro-inflammatory responses. However, the exact molecular mechanisms underlying itaconate-induced macrophage toxicity remain unclear. Here, we demonstrate that pathophysiologically relevant high concentrations of itaconate covalently alkylate the absent in melanoma 2 (AIM2) protein at the cysteine 113 (C113) residue. Itaconate-mediated C113 alkylation structurally stabilizes the AIM2 protein and triggers a conformational change, enabling it to drive ASC oligomerization, PANoptosome assembly, and subsequent macrophage PANoptosis. Utilizing in vitro lentiviral reconstitution in primary macrophages alongside plasmid-mediated expression in cell lines, we rigorously confirmed that the AIM2 C113A mutation completely abolishes itaconate-induced AIM2 stabilization and PANoptosis. In vivo models further corroborated the pathogenic contribution of this axis to systemic sepsis. Taken together, our findings reveal a novel pro-inflammatory mechanism of itaconate via the post-translational modification of AIM2. The itaconate-AIM2 alkylation axis provides crucial mechanistic insights into macrophage depletion and systemic inflammation, highlighting a potential therapeutic target for severe sepsis.
    Keywords:  AIM2; Itaconate; Macrophages; PANoptosis; Sepsis
    DOI:  https://doi.org/10.1038/s41423-026-01414-x
  9. Front Immunol. 2026 ;17 1784128
    Cell-mediated immune responses of beta-glucan on the pathogenesis of chronic tuberculosis infection.
    Shreya Chakraborty, Devi Rajeswari V.
      Tuberculosis (TB) has become the most common reason for contagious disease-related fatalities globally. Due to the estimated 8.6 million fresh tuberculosis infections and 1.6 million fatalities, this disease is a leading contributor to mortality globally. Tuberculosis refers to a condition in which individuals are infected with M. tuberculosis but do not exhibit clinical symptoms and are generally not capable of transmitting the disease. β-glucan, a biologically active polysaccharide known for its immunomodulatory properties, has recently gained attention for its role in regulating metabolic and immune responses. Through mechanisms such as trained immunity, macrophage activation, and cytokine modulation, β-glucan may enhance host defense against M. tuberculosis and influence susceptibility to tuberculosis disease progression. Hence, this study focuses on the underlying relationship of beta-glucan involved in Tuberculosis infection, along with their physiopathology, and, clinical implications including the immunological responses.
    Keywords:  T-lymphocytes; beta-glucan; biomarkers; immune system; pathogenesis; tuberculosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1784128
  10. Cell Rep. 2026 May 15. pii: S2211-1247(26)00438-9. [Epub ahead of print]45(5): 117360
    ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis.
    Yi-Chieh Perng, Jessica M C Warsaw, Sachendra S Bais, Bradley E Hiller, Marissa C Locke, David J Morales-Heil, Chaoqun Li, Alissa R Young, Kristen J Monte, Robert E Schmidt, Douglas R Green, Yi-Nan Gong, Deborah J Lenschow.
      Necroptosis, a form of programmed, inflammatory necrosis, plays an important role in viral-host defense and inflammation. The receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway mediates necroptosis. Yet, the mechanisms that control necroptosis to limit immunopathology are poorly understood. Here, we report that interferon-stimulated gene 15 (ISG15) negatively regulates RIPK3-mediated cell death, including necroptosis, and limits immunopathology during chikungunya virus (CHIKV) infection. ISG15-deficient mice infected with CHIKV display increased levels of necroptosis, resulting in elevated proinflammatory cytokine and chemokine production, leading to increased lethality. This dysregulated host response is fully prevented when MLKL or RIPK3 is ablated in Isg15-/- mice. Mechanistically, ISG15 non-covalently associates with the RIPK3 necrosome in an RIP homotypic interaction motif (RHIM)-dependent manner, regulating necroptosis downstream of CHIKV infection, tumor necrosis factor (TNF), lipopolysaccharide (LPS), and poly(I:C) stimulation. These results demonstrate a role for ISG15 in limiting immunopathology during infection by modulating necroptosis-dependent inflammation and pathogenesis.
    Keywords:  CHIKV; CP: immunology; CP: microbiology; ISG15; MLKL; RIPK3; chikungunya virus; homeostasis; immunopathology; necroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117360
  11. Eur J Hum Genet. 2026 May 12.
    Transcription-based identification of uncharacterized genes in the human immune response.
    Emil E Vorsteveld, Simone Kersten, Charlotte Kaffa, Annet Simons, Peter A C 't Hoen, Mihai G Netea, Alexander Hoischen.
      Host-pathogen interactions are shaped by the nature of the pathogen and by host-related factors. Human host responses can be characterized in microbe-stimulated immune cells using transcriptomics. We set out to characterize gene expression changes as a result of microbial in vitro stimulation in medium-cultured human primary immune cells, using four pathogen ligands representing bacteria (LPS and S. aureus), viruses (Poly(I:C)) and fungi (C. albicans) for 4 and 24 h, resulting in a total of 52 samples for analysis. We analyze the transcriptional changes on gene and pathway levels, highlighting common and distinct effects of pathogen stimulation. We highlight genes without a known function that were differentially expressed as a common effect of pathogen stimulation. Amongst those, we find uncharacterized genes such as KIAA0040 and CYRIA to be co-expressed with genes involved in innate immunity and downstream signaling from the PRRs, respectively. Further linking our differential expression data to IEI, we identify 901 variants in uncharacterized genes in a cohort of patients with rare immune disorders, prioritizing 5 candidate variants in 4 genes that could underlie these diseases. Our results therefore indicate a potential role of these genes in the human immune response and provide further candidate variants for rare immune-mediated diseases.
    DOI:  https://doi.org/10.1038/s41431-026-02117-7
  12. Biol Lett. 2026 May 13. pii: 20250668. [Epub ahead of print]22(5):
    The devil you know: a longer history of pathogen coevolution predicts higher behavioural tolerance of infection among host populations.
    James S Adelman, Amberleigh E Henschen, Francis E Tillman, Rami A Dalloul, Marissa M Langager, Allison A Rowley, Dana M Hawley.
      Animals can achieve tolerance of infection, defined as minimizing per-pathogen reductions in host fitness, through physiology and behaviour. However, whether physiological tolerance and behavioural tolerance covary within or among host populations is poorly understood. Because these mechanisms of tolerance can influence the transmission of pathogens in complex and even opposing ways, revealing such patterns has important implications for the spread and evolution of infectious diseases. Here we compare behavioural tolerance among a subset of house finch (Haemorhous mexicanus) populations at the extremes of a historical invasion gradient of the bacterial pathogen, Mycoplasma gallisepticum (MG): two with a 20-25 year history of pathogen endemism and two with no such history. We assessed behavioural tolerance as the relationship between locomotion and pathogen load and found that, similar to prior work on physiological tolerance, behavioural tolerance was more pronounced in populations with a longer history of MG endemism. In addition, we saw substantial inter-individual variation in locomotion both before and during infection. Our results suggest that while physiological and behavioural tolerance appear to covary across populations in this system, individuals can express a range of both, yielding diverse consequences for pathogen transmission.
    Keywords:  Mycoplasma; disease ecology; finch; infection; resistance; tolerance
    DOI:  https://doi.org/10.1098/rsbl.2025.0668
  13. Cell Rep Med. 2026 May 14. pii: S2666-3791(26)00236-3. [Epub ahead of print] 102819
    Artificial exosomes synergistically reshape sepsis immune homeostasis by modulating neutrophil fate and blocking PD-1/PD-L1.
    Pengcheng Zhang, Yahui Gao, Yaxin Wang, Xin Li, Yi Jiang, Yigang Xu, Keliang Xie, Yixuan Ma, Sheng Wang, Hui Zheng, Wen Li, Xu Jin.
      A critical challenge in sepsis treatment lies in its complex immune microenvironment, characterized by concurrent hyperinflammation and immunosuppression. This imbalance is jointly driven by dysregulated neutrophil programmed death and abnormal activation of the PD-1/PD-L1 immune checkpoint. Therefore, precisely modulating neutrophil fate and blocking this immune checkpoint are highly promising therapeutic strategies. We engineered an artificial exosome nano-decoy (AT@NV-PD1) that homes to senescent-like neutrophils. It comprises a pH-responsive bovine serum albumin core carrying AT7519, a cyclin-dependent kinase inhibitor, cloaked with macrophage membrane presenting PD-1. After intravenous delivery, PD-1 selectively binds PD-L1 on target neutrophils. In the mildly acidic microenvironment, AT7519 release triggers timely neutrophil apoptosis, curbing excessive inflammation. Concurrently, the nano-decoy neutralizes bacterial toxins and inflammatory cytokines. By engaging PD-L1, AT@NV-PD1 also alleviates T cell exhaustion, reduces immunosuppression, and promotes immune homeostasis. In conclusion, AT@NV-PD1 represents a sepsis therapy by precisely regulating neutrophil fate and rebuilding immune balance.
    Keywords:  T-cell exhaustion; apoptosis; immune homeostasis; neutrophils; sepsis
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102819
  14. iScience. 2026 May 15. 29(5): 115816
    Dynamics of severity-associated immune remodeling by granulocytes and macrophages in acute lung injury.
    Wanqin Zeng, Caijin Wang, Chengjian Cao, Chunlai Nie, Yingjun Fan, Yi Zhang, Zhongshan He.
      Acute lung injury (ALI) is driven by dysregulated alveolar immune responses. While granulocytes and macrophages are critical effectors, their coordinated molecular reprogramming and severity-associated crosstalk shape immune remodeling during disease progression. Here, we performed single-cell RNA sequencing (scRNA-seq) of bronchoalveolar lavage fluid from patients with intermediate- and late-severity ALI to map immune microenvironment remodeling. We observed pronounced granulocyte expansion coupled with macrophage depletion. Granulocytes exhibit distinct transcriptional states along a continuum from acute migratory states toward pro-inflammatory, metabolically reprogrammed subsets, dominated by TNF and MAPK signaling. Simultaneously, macrophages shift toward inflammatory M1-like phenotypes, characterized by distinct metabolic reprogramming and reduced oxidative phosphorylation. Furthermore, we infer a granulocyte-centric inflammatory network mediated through TNF, IFN, and RESISTIN pathways, suggesting a feedforward inflammatory loop. Collectively, this study elucidates the transcriptional and metabolic reprogramming associated with escalating ALI severity, providing a framework for severity-adapted therapeutic interventions to restore pulmonary homeostasis.
    Keywords:  biological sciences
    DOI:  https://doi.org/10.1016/j.isci.2026.115816
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