In a groundbreaking study poised to reshape our understanding of respiratory immunity, researchers have unveiled the intricate epigenomic landscape of bronchial epithelial cells, revealing how these frontline defenders of the airway establish a form of innate immune memory known as trained immunity. Published in the prestigious journal Genes & Immunity, this work elucidates the molecular underpinnings that allow bronchial epithelial cells to “remember” past encounters with pathogens or environmental insults and mount enhanced responses upon re-exposure, a concept previously well-characterized mainly in innate immune cells like macrophages and natural killer cells.
The bronchial epithelium—which forms the critical physical and immunological barrier lining the airways—is traditionally known for its role as the first line of defense against inhaled particulates, pathogens, and pollutants. This research, led by Bigot and colleagues, breaks new ground by demonstrating that these epithelial cells themselves are not just passive barriers but active participants in trained immunity. The findings imply that epithelial memory mechanisms could have significant implications for respiratory health, disease resilience, and therapeutic strategies targeting chronic lung inflammation and infection.
At the core of this discovery is the epigenomic remodeling of bronchial epithelial cells following exposure to microbial stimuli. The researchers employed high-resolution chromatin profiling techniques, including ATAC-seq and ChIP-seq, to map changes in chromatin accessibility and histone modifications that facilitate an altered transcriptional landscape. This epigenetic reprogramming primes the cells for an augmented immune response upon secondary challenge, vastly improving their capacity to produce antimicrobial peptides, cytokines, and chemokines essential for efficient pathogen clearance.
Intriguingly, the study delves deeply into histone modifications, notably increases in H3K27ac and H3K4me1 marks at enhancer regions of immune-related genes, signifying long-lasting epigenetic “marks” that enhance gene transcription. These modifications do not represent permanent genetic changes but rather reversible and dynamic chromatin states that integrate environmental cues to tailor cellular function. The data suggest that bronchial epithelial cells maintain a poised chromatin organization, which is activated upon re-exposure to pathogens or other inflammatory stimuli, thereby orchestrating a heightened and swift response.
Notably, Bigot and colleagues identify specific signaling pathways integral to the establishment of this trained immunity. Toll-like receptor (TLR) signaling appears central, activating downstream pathways that culminate in the recruitment of chromatin remodelers and histone-modifying enzymes. This concerted action enforces epigenetic memory, underscoring how innate immune surveillance and epigenetic machinery coalesce in these epithelial cells to mount a more robust defense.
This paradigm-shifting concept challenges the dogma that trained immunity is restricted to classical innate immune cells. The bronchial epithelium’s acquisition of a memory-like state suggests a multi-layered immune system in the airways, where epithelial and immune cells act synergistically to confer durable protection. Such findings refine the understanding of how environmental exposures, from infections to pollution, imprint long-lived immunomodulatory effects in respiratory tissues.
From a clinical perspective, these insights into bronchial epithelial trained immunity could open novel avenues for therapeutic intervention. If the establishment and modulation of this epigenetic memory can be harnessed pharmacologically, it could lead to innovative treatments that boost mucosal resilience against recurrent respiratory infections or ameliorate hyperinflammatory conditions such as asthma and chronic obstructive pulmonary disease (COPD).
Moreover, the research touches on the possible role of trained immunity in vaccine efficacy, particularly mucosal vaccines targeting respiratory pathogens. Understanding the epigenomic basis of immune memory in epithelial cells might inform the design of vaccines that promote beneficial training effects at the mucosal surface, thus enhancing local immunity and protection.
The study is also significant in the context of emerging respiratory viruses, including novel coronaviruses, where innate immune responsiveness at the mucosal interface is a crucial determinant of disease severity and outcome. Epigenetic training of epithelial cells, as revealed here, may contribute to differential susceptibilities observed among individuals and offer a molecular explanation for varying clinical courses.
Technically, the researchers employed an integrative multi-omics approach, combining epigenomic, transcriptomic, and functional assays to comprehensively characterize the trained immunity phenotype. This robust methodological framework allowed them to delineate not only chromatin changes but also the resultant gene expression dynamics and functional consequences, establishing a direct link between epigenetic remodeling and enhanced immune function.
Importantly, the findings also highlight temporal dynamics of epithelial training. The epigenomic alterations persisted over weeks, signifying a durable state of preparedness rather than transient inflammation. Such persistence lays the foundation for chronic modulation of airway immune landscapes and invites further investigation into the mechanisms governing the longevity and reversibility of trained immunity in epithelial cells.
The study also poses compelling questions regarding the interplay between trained immunity and airway diseases involving epithelial dysfunction. The potential contribution of maladaptive or excessive training to chronic inflammatory disorders merits future exploration, as does the impact of environmental pollutants that could aberrantly induce or repress these epigenetic programs.
In addition, the authors reveal that metabolic reprogramming, a hallmark of trained immunity in myeloid cells, may also underpin epithelial training. Altered glycolytic and mitochondrial pathways were observed, emphasizing the link between cellular metabolism and epigenetic regulation. These findings align with emerging paradigms that view metabolism as a driver of immune cell fate and function, and now, apparently, of epithelial immunity as well.
This pioneering research opens exciting frontiers in mucosal immunology, merging epigenetics, environmental science, and respiratory medicine. It affirms the concept that immune memory is not the exclusive domain of adaptive lymphocytes but a shared feature among diverse cell types poised at the interface of host and environment. The bronchial epithelium, akin to a cellular memory bank, adapts to past exposures to fine-tune defense strategies, thus revolutionizing how we conceptualize respiratory immunity.
Future investigations are likely to explore how this trained immunity influences interactions with resident microbiota and systemic immunity, as well as identifying molecular targets to modulate training for therapeutic benefit. Additionally, age, genetic factors, and lifestyle influences on epithelial training profiles could unravel personalized approaches to respiratory health management.
In sum, Bigot and colleagues’ landmark study propels the field forward by shining a light on the epigenomic mechanisms by which bronchial epithelial cells acquire a trained immunity phenotype. By mapping the chromatin landscape and decoding the molecular reprogramming of these cells, the research offers a novel blueprint for understanding and manipulating innate immune memory within the respiratory tract—holding promise for transforming disease prevention and treatment in the years ahead.
Subject of Research: Epigenomic characterization of trained immunity in bronchial epithelial cells
Article Title: The epigenomic landscape of bronchial epithelial cells reveals the establishment of trained immunity
Article References:
Bigot, J., Legendre, R., Hamroune, J. et al. The epigenomic landscape of bronchial epithelial cells reveals the establishment of trained immunity.
Genes Immun (2025). https://doi.org/10.1038/s41435-025-00357-z
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