---
title: "Airway epithelial–immune axis: mechanisms, alarmins, and therapeutic directions"
id: "frontiers-in-immunology-9-the-airway-epithelial-immune-axis-mechanisms-and-therapeutic-implications"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-9-the-airway-epithelial-immune-axis-mechanisms-and-therapeutic-implications"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1891760"
published_at: "2026-07-24T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Airway epithelial–immune axis: mechanisms, alarmins, and therapeutic directions
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-9-the-airway-epithelial-immune-axis-mechanisms-and-therapeutic-implications
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1891760)
- **Published At:** 2026-07-24T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The airway epithelium is an active regulator of mucosal immunity, not merely a passive barrier; it detects environmental stimuli and shapes innate and adaptive responses. - Disruption of epithelial tight junctions and adherens junctions increases permeability and facilitates allergen and pathogen translocation, contributing to chronic airway inflammation. - Epithelial cells rapidly release epithelial-derived cytokines or **alarmins**—notably **TSLP**, **IL-33**, and **IL-25**—which engage innate lymphoid cells (ILC2s) and Th2 adaptive networks to create self-perpetuating inflammatory loops. - Structural epithelial cell types include basal, club, ciliated, and goblet cells, with rare populations (ionocytes, tuft cells, solitary neuroendocrine cells, hillocks) revealed by single-cell transcriptomics and implicated in specialized sensing and repair. - Tight junction proteins (claudins, occludin, JAMs) and scaffold proteins (ZO-1/2/3, cingulin) maintain barrier integrity; specific isoforms (e.g., **claudin-18**) are reduced in asthma and correlate with disease susceptibility. - Pattern recognition receptors (TLRs, NLRs, CLRs) and sensory channels (TRPV1/4, P2X7/P2Y2) enable epithelial immune sensing; Dectin-1 and TLR4 mediate responses to fungal components and HDM-associated microbial ligands. - Environmental proteases, particulate pollutants (e.g., PM2.5), cigarette smoke, and respiratory viruses (RSV, HRV, hMPV) damage epithelial junctions, induce oxidative stress, and can imprint long-lasting epithelial changes that lower thresholds for future Type 2 inflammation. - NLRP3 has roles beyond inflammasome activation, contributing to barrier homeostasis; NLRP3 deficiency reduces expression of barrier molecules (Cldn18, Tjp1, E-cadherin) and worsens allergen uptake and airway hyperresponsiveness in experimental models. - Disease-specific epithelial alterations are linked to clinical phenotypes: asthma (impaired barrier, elevated TSLP/IL-33/IL-25, Type 2 inflammation), COPD (senescence, goblet hyperplasia, TGF-β, neutrophil/macrophage skewing), and upper airway disorders (TSLP-driven Type 2 amplification). - Therapeutic focus is shifting toward targeting the epithelial–immune axis via alarmin-neutralizing biologics, upstream receptor inhibition, and barrier restoration. Emerging tools—single-cell RNA sequencing, spatial transcriptomics, organoids, and multi-omics—are decoding heterogeneity and spatial niches to enable precision, disease-modifying approaches. - Key unresolved issues include defining disease-specific epithelial cell states, determining the relative benefits of barrier repair versus immune blockade, and identifying biomarkers to select patients for epithelial-targeted therapies.
## Clinical Analysis & Structured Key Points
Frontiers | The airway epithelial–immune axis: mechanisms and therapeutic implications REVIEW article Front. Immunol. , 24 July 2026 Sec. Mucosal Immunity Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1891760 Published in Frontiers in Immunology Mucosal Immunity 7 impact factor 11.3 citescore Editor & Reviewers Edited by H W Hong Wei Chu Reviewed by S D Stephanie DeStefano S L Shixiu Liang W V Wim Van Den Broeck Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Table 1 Role of epithelium-driven inflammation in respiratory diseases. View in article REVIEW article Front. Immunol. , 24 July 2026 Sec. Mucosal Immunity Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1891760 The airway epithelial–immune axis: mechanisms and therapeutic implications Z Z Zhengyi Zhu 1 Q L Qiang Li 1 * B H Binjian Hua 2 * 1. Department of Hematology, Central Hospital of Haining, Jiaxing, Zhejiang, China 2. Department of Respiratory Medicine, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, Zhejiang, China Article metrics View details Abstract The airway epithelium is increasingly recognized not merely as a physical barrier, but as a central, active regulator of mucosal immunity. This review comprehensively summarizes the structural and functional basis of the airway epithelial-immune axis and its critical role in chronic respiratory diseases. Exposure to environmental allergens, pollutants, and respiratory pathogens disrupts epithelial tight junctions and triggers the rapid release of key alarmins, including TSLP, IL-33, and IL-25. These epithelial-derived cytokines participate in reciprocal epithelial-immune circuits, driving extensive crosstalk with both innate (ILC2s) and adaptive (Th2 cells) immune networks to establish self-perpetuating inflammatory loops. Such epithelial dysfunction can act as an important driver and amplifier in the pathogenesis of asthma, chronic obstructive pulmonary disease (COPD), and upper airway inflammatory disorders. Consequently, targeting this axis has emerged as a promising therapeutic strategy, shifting the focus toward alarmin-neutralizing biologics, upstream receptor inhibition, and barrier restoration. Furthermore, we highlight how emerging technologies—such as single-cell RNA sequencing, spatial transcriptomics, organoid models, and multi-omics integration—are decoding cellular heterogeneity and spatial niches, ultimately paving the way for precision medicine and long-term disease-modifying therapies in respiratory medicine. 1 Introduction Chronic respiratory diseases, including bronchial asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, and chronic rhinosinusitis, represent a substantial and growing global health burden ( 1 , 2 ). According to estimates from the World Health Organization, asthma alone affects more than 300 million individuals worldwide, whereas COPD remains a leading cause of morbidity and mortality across diverse populations ( 3 ). The considerable socioeconomic burden, the high frequency of acute exacerbations, and the progressive and often irreversible decline in lung function collectively highlight the urgent need for a more comprehensive understanding of disease mechanisms and the development of more effective therapeutic strategies. For decades, airway disease pathophysiology was viewed mainly through the lens of adaptive immunity. However, contemporary perspectives emphasize that epithelial barrier dysfunction and innate immune activation interact reciprocally with adaptive immune responses in chronic airway inflammation ( 4 , 5 ). In earlier models, the airway epithelium was primarily regarded as a passive structural component, functioning mainly as a physical barrier responsible for regulating water and ion transport, while facilitating mucociliary clearance of inhaled particles ( 6 ). In this bidirectional framework, epithelial cells can initiate and amplify inflammation, while Th2 cells, B cells, IgE-mediated mast-cell activation, and immune memory can in turn maintain or worsen epithelial dysfunction. In recent years, however, this traditional perspective has been fundamentally revised. Increasing evidence has demonstrated that the airway epithelium is not merely a structural barrier, but rather a highly dynamic and functionally versatile tissue involved in inflammation, immune regulation, host defense, and tissue remodeling ( 7 – 10 ). It is now widely accepted that the airway epithelium serves as an active regulator of innate immunity and acts as a critical interface between the external environment and the internal host milieu. Epithelial-derived mediators have been increasingly recognized as central contributors to the initiation and propagation of airway inflammation, particularly in asthma pathogenesis ( 3 ). As a result, the concept of an airway epithelial–immune axis has been established as a key framework for understanding the regulation of mucosal homeostasis and the development of airway diseases. This epithelial–immune axis can be understood through three interrelated functional components, including the maintenance of epithelial barrier integrity, the capacity for immune sensing, and the role of the epithelium as an amplifier of inflammatory responses ( 11 ). The primary function of the airway mucosa is to maintain internal homeostasis by separating the host from environmental exposures ( 12 – 14 ). When this barrier is disrupted by environmental toxins, allergens, or pathogens, epithelial cells rapidly activate pattern recognition receptors (PRRs), leading to the release of a wide range of mediators, including alarmins, antimicrobial peptides, and chemokines. These mediators collectively regulate the intensity, duration, and phenotype of subsequent innate and adaptive immune responses. In this context, epithelial dysfunction has been increasingly linked to airway remodeling processes and the heterogeneity of disease phenotypes observed across different stages of life ( 15 – 17 ). This review uses the airway epithelial-immune axis as a conceptual framework rather than a purely descriptive catalogue. We organize the literature around three linked questions: how epithelial structural defects arise, how injured epithelial cells translate environmental signals into immune programs, and which upstream nodes are most actionable therapeutically. Across these sections, we distinguish well-established mechanisms, such as tight-junction disruption and alarmin release, from unresolved issues, including disease-specific epithelial cell states, the relative value of barrier repair versus immune blockade, and the biomarkers needed to select patients for epithelial-targeted therapies. 2 Structural and functional basis of airway epithelium 2.1 Airway epithelial cell types and composition The airway epithelium exhibits a highly organized pseudostratified structure composed of multiple distinct yet functionally interconnected cell populations ( Table 1 ). In the conducting airways, the classical cellular composition includes basal cells, club cells, ciliated cells, and mucus-secreting goblet cells ( 39 , 40 ) ( Figure 1A ). Basal cells function as resident progenitor cells and are anchored to the basement membrane. They possess the capacity for self-renewal and multipotent differentiation, enabling them to regenerate the entire epithelial layer following injury or infection ( 39 ). Club cells, formerly termed Clara cells, are enriched within the distal conducting airways and contribute to epithelial homeostasis through xenobiotic detoxification, secretion of immunoregulatory proteins, and facultative progenitor activity during epithelial repair ( 41 , 42 ). Ciliated cells occupy much of the apical epithelial surface and mediate mucociliary clearance via synchronized ciliary beating, thereby enabling efficient removal of mucus, pathogens, and inhaled particulates ( 43 ). Goblet cells specialize in the production of gel-forming mucins that establish a protective mucus barrier capable of trapping environmental agents and microorganisms ( 44 ). Table 1 Disease category Key epithelial alterations Dominant immune mechanisms Clinical & pathological features References Asthma Impaired barrier integrity; disrupted tight junctions; increased baseline TSLP, IL-33, and IL-25. Primarily Type 2 (eosinophilic) via alarmins; severe subset driven by T1/IFN-γ (neutrophilic). Airway hyperresponsiveness (AHR); mucus overproduction; subepithelial fibrosis. ( 18 – 22 ) COPD Senescence; altered differentiation (goblet cell hyperplasia, reduced ciliated cells); persistent TGF-β production. Shift to Type 1-dominant; macrophage and neutrophil activation via altered IL-33/ST2 signaling. Small airway fibrosis; progressive lung function decline (reduced FEV1); tissue damage. ( 23 – 27 ) Upper Airway Diseases (Rhinitis, CRS) Barrier disruption; increased alarmin (TSLP) production linking upper and lower airways. Type 2 amplification; local eosinophilic inflammation; systemic immunomodulation. Tissue remodeling; nasal polyp formation; progression of inflammation to lower airways. ( 28 – 32 ) Viral Infections (RSV, hMPV) Structural disruption; long-lasting epigenetic alterations in basal progenitor cells. Release of IL-33, TSLP, and HMGB1; lower threshold for future Type 2 inflammation. Early-life sensitization; recurrent wheezing; increased susceptibility to chronic respiratory diseases. ( 33 – 38 ) Role of epithelium-driven inflammation in respiratory diseases. Figure 1 Structural and functional overview of the airway epithelium. (A) Cellular composition: the pseudostratified airway epithelium comprises classical populations (ciliated, goblet, club, and basal cells) and rare/novel cell types (ionocytes, tuft cells, neuroendocrine cells, and hillocks) that maintain tissue homeostasis. (B) Epithelial barrier: barrier integrity is maintained by apicolaterally positioned tight junctions and adherens junctions, which together form the AJC, while desmosomes provide additional lateral mechanical adhesion. The revised schematic depicts the actin cytoskeleton as an intracellular structure linked to junctional scaffolding proteins. Tight junctions consist of transmembrane proteins (claudins, occludin, JAMs) anchored to intracellular scaffolds (ZO-1/2/3, cingulin, MUPP1). (C) Immune sensing: Epithelial cells continuously monitor the environment. They detect allergens and pathogens via pattern recognition receptors (e.g., Dectin-1, TLR4, NOD1) and utilize sensory channels (e.g., TRPV1/4, P2X7/P2Y2) to integrate external stimuli. This triggers calcium influx and the secretion of antimicrobial effectors, cytokines, and chemokines to regulate downstream immune responses. Recent advances in single-cell transcriptomic technologies have revealed a previously underappreciated level of cellular heterogeneity within the airway epithelium. Rare epithelial cell populations, including solitary neuroendocrine cells and tuft cells, have been identified and are increasingly recognized for their specialized roles in environmental sensing and the regulation of neuroimmune interactions, although their lineage relationships and precise functional contributions remain to be fully elucidated ( 45 – 47 ). In addition to these populations, novel epithelial cell types have been identified through high-resolution transcriptomic analyses. Among these, pulmonary ionocytes represent a rare cell population characterized by expression of FOXI1. These cells exhibit high levels of CFTR expression, suggesting a central role in regulating airway ion transport and fluid homeostasis ( 48 ). Furthermore, distinct epithelial structures termed hillocks, marked by expression of KRT13, SCEL, and SPRR1A/B, have been described. These structures appear to function as a specialized epithelial compartment with enhanced resistance to injury and the capacity to repopulate the airway epithelium following severe damage ( 49 , 50 ) ( Figure 1A ). 2.2 Epithelial barrier function and its molecular basis The airway epithelial barrier is maintained by a multilayered defense system that tightly regulates the passage of solutes, pathogens, and environmental agents. The principal components of this system include mucociliary clearance, intercellular junctional complexes, and the secretion of antimicrobial factors ( 51 ).At the cellular level, barrier integrity is supported by the apical junctional complex (AJC), which is composed principally of tight junctions (TJs) and adherens junctions (AJs), together with additional adhesive structures that provide mechanical resilience. TJs and AJs occupy the apicolateral domain, regulate paracellular permeability, and connect junctional proteins to the actin cytoskeleton through adaptor proteins ( 52 ) ( Figure 1B ). Desmosomes are distinct from the AJC because they are positioned more laterally and link cadherin-family proteins to intermediate filaments rather than to actin. Nevertheless, they complement TJs and AJs by strengthening intercellular adhesion and altered desmosomal junctions have been implicated in inflammatory airway and sinonasal epithelial disease ( 53 ). Tight junctions are localized at the apicolateral membrane and play a central role in regulating paracellular permeability. Their molecular architecture consists of transmembrane proteins, including members of the claudin family, occludin, and junctional adhesion molecules, which interact across the intercellular space. Intracellularly, these proteins are anchored to cytoskeletal elements via scaffolding proteins such as zonula occludens (ZO-1, ZO-2, ZO-3), cingulin, and MUPP1 ( 54 , 55 ) ( Figure 1B ). Specific claudin isoforms contribute differentially to barrier function. Claudin-18 is closely associated with epithelial barrier integrity and has been shown to be reduced in individuals with asthma, indicating a potential role in disease susceptibility ( 21 ). Claudin-4 is involved in the regulation of paracellular sodium permeability and has been correlated with the severity of airway inflammation ( 56 ). Disruption of these junctional complexes compromises epithelial integrity, leading to increased permeability. This facilitates the translocation of environmental agents into subepithelial compartments, thereby promoting the activation of local immune responses. Clinical studies provide direct support for defective airway epithelial barrier function in asthma. Bronchial epithelial cells obtained from patients with asthma show impaired barrier formation, increased epithelial fragility, and altered repair responses compared with cells from healthy controls ( 57 ). These patient-derived observations complement mechanistic studies linking reduced junctional proteins, including claudin-18, to increased epithelial permeability and airway hyperresponsiveness ( 21 ). Recent experimental evidence also indicates that NLRP3 contributes to epithelial barrier homeostasis: NLRP3 deficiency reduced the expression of barrier-associated molecules, including Cldn18, Tjp1, and E-cadherin, increased allergen uptake by lung conventional dendritic cells, and enhanced airway hyperresponsiveness in allergic airway inflammation ( 22 ). 2.3 Immune sensing and regulatory functions The airway epithelium functions as an active interface that continuously monitors the luminal environment through a highly specialized array of sensory mechanisms. Upon exposure to environmental stimuli, epithelial cells detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), leading to the production of cytokines and chemokines that promote type 2 immune polarization and recruit dendritic cells ( 58 ). This surveillance process is primarily mediated by pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs) ( 3 ). For instance, the C-type lectin receptor Dectin-1 specifically recognizes β-glucan structures in the cell walls of inhaled fungi such as Aspergillus fumigatus . It also contributes to immune responses against complex environmental allergens like animal dander, pollen, cockroach allergens, and house dust mite (HDM) extracts, potentially by sensing contaminating fungal components or via indirect signaling pathways ( 59 , 60 ). In parallel, activation of TLR4 by HDM-associated microbial components (e.g., LPS)​ provides a rapid trigger for downstream inflammatory signaling pathways, while CLRs (such as Dectin-2) directly sense HDM-derived components. Additionally, intracellular NLRs such as NOD1/NOD2 detect bacterial peptidoglycan fragments, which may originate from microbial contaminants in the environment and contribute to Th2 polarization ( 61 , 62 ) ( Figure 1C ). The NLR family also includes NLRP3, which links epithelial immune sensing with barrier regulation; recent evidence suggests that NLRP3-dependent pathways may support airway epithelial barrier homeostasis rather than functioning solely as pro-inflammatory inflammasome signals ( 22 ). In addition to classical PRR-mediated sensing, airway epithelial cells utilize transient receptor potential (TRP) channels, particularly calcium-permeable channels such as TRPV1 and TRPV4, to detect proteolytic activity derived from common aeroallergens, including Alternaria alternata and HDMs ( 63 , 64 ). Allergen exposure also induces cellular stress responses that result in the release of extracellular ATP, which functions as a damage-associated molecular signal. Extracellular ATP subsequently activates purinergic receptors, including P2X 7 and P2Y 2 , leading to increased intracellular calcium levels and amplification of downstream signaling pathways ( 65 ) ( Figure 1C ). Activation of these sensory systems initiates a series of intracellular signaling cascades that promote the transcription and secretion of effector molecules, including reactive oxygen species (ROS) and antimicrobial peptides (AMPs). In addition, epithelial cells produce antimicrobial enzymes such as lactoperoxidase, which contributes to the generation of oxidized antimicrobial products ( 66 ). Through these mechanisms, the airway epithelium integrates diverse environmental signals and converts them into coordinated biochemical responses that regulate both innate and adaptive immunity. 3 Mechanisms of airway epithelial injury and barrier disruption 3.1 Environmental and pathogen-mediated epithelial injury The respiratory mucosa is continuously exposed to a large volume of inhaled air, estimated at approximately 10,000 to 20,000 liters per day ( 67 ). This extensive exposure places the epithelial layer in direct contact with a wide range of environmental challenges, including allergens, respiratory viruses, bacteria, and particulate pollutants. Environmental allergens, such as those derived from house dust mites, fungi, and pollens, often exhibit intrinsic proteolytic activity that directly compromises epithelial integrity ( 32 ). Proteases contained within these allergens disrupt both tight junctions and adherens junctions and can activate signaling pathways including epidermal growth factor receptor (EGFR) and Wnt/β-catenin pathways, thereby contributing to structural damage of the epithelial barrier ( 51 , 68 , 69 ). In addition, exposure to particulate matter, including fine particles such as PM2.5, as well as cigarette smoke, induces pronounced oxidative stress. This process leads to epithelial cytotoxicity, lipid peroxidation, and loss of epithelial coverage, ultimately impairing mucociliary clearance ( 70 ). Respiratory pathogens also play a critical role in epithelial injury, particularly in early life, where infections may influence long-term disease susceptibility. Viruses such as respiratory syncytial virus (RSV), human rhinovirus (HRV), and human metapneumovirus (hMPV) utilize epithelial cells as prim
## Related Clinical Research

- [Respiratory viruses trigger ferroptosis-like lipid peroxidation and mitochondrial remodeling in lu](https://medichelpline.com/clinical-feed/pubmed-42663456.md) (DOI: 10.1128/spectrum.01957-26)
- [Respiratory syncytial virus in COPD exacerbations: RECODE study protocol (full text blocked)](https://medichelpline.com/clinical-feed/bmj-open-11-respiratory-syncytial-virus-infection-in-copd-exacerbations-the-recode-study.md)
- [Tissue-resident immune cells and genetic risk in autoimmune and lung diseases](https://medichelpline.com/clinical-feed/nature-immunology-1-tissue-resident-immune-cells-drive-genetic-risk-in-autoimmune-and-lung-diseases.md)
- [Triglyceride-Glucose (TyG) Index and Mortality in Non-Diabetic Fibrotic Lung Disease on Antifibrot](https://medichelpline.com/clinical-feed/plos-one-1-association-between-triglyceride-glucose-index-and-all-cause-mortality-in-non.md)
- [Precision Nanomedicine for Pulmonary Diseases: Nanoparticle Design to Clinical Translation](https://medichelpline.com/clinical-feed/pubmed-42675037.md) (DOI: 10.1038/s41392-026-02982-0)

## Navigation
- [← Back to Infectious Disease Feed](https://medichelpline.com/clinical-feed/infectious-disease.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.