Chronic respiratory diseases—bronchial asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, and chronic rhinosinusitis—impose large global health and socioeconomic burdens. Historically, airway pathophysiology emphasized adaptive immunity, but contemporary evidence positions the airway epithelium as an active regulator of mucosal immunity that both senses the environment and shapes innate and adaptive responses. The airway epithelial–immune axis integrates three interrelated functions: maintenance of barrier integrity, immune sensing, and amplification of inflammatory responses. Disruption of this axis contributes to disease onset, progression, and heterogeneity across life stages.
The conducting airway epithelium is a pseudostratified tissue comprising classical cell types—basal cells, club cells, ciliated cells, and mucus-secreting goblet cells—each with distinct roles. Basal cells serve as resident progenitors with self-renewal and multipotent differentiation capacity required for epithelial repair. Club cells contribute to xenobiotic detoxification, immunoregulatory secretions, and facultative progenitor functions. Ciliated cells mediate mucociliary clearance through coordinated ciliary beating, while goblet cells produce gel-forming mucins that trap inhaled particles and microbes.
High-resolution single-cell transcriptomic studies have uncovered rare or novel epithelial populations, including pulmonary ionocytes (high CFTR expression, FOXI1+), tuft cells, solitary neuroendocrine cells, and specialized structures termed hillocks (KRT13, SCEL, SPRR1A/B). These rare populations appear important for specialized environmental sensing, ion transport, neuroimmune interactions, or injury resistance, although their lineage relationships and precise functional roles remain to be fully defined.
Barrier integrity is governed by a multilayered defense system: mucociliary clearance, intercellular junctional complexes, and secreted antimicrobial factors. The apical junctional complex (AJC) includes tight junctions (TJs) and adherens junctions (AJs) localized at the apicolateral membrane, linking transmembrane proteins to the actin cytoskeleton via scaffolding proteins such as ZO-1/2/3 and cingulin. Desmosomes provide lateral mechanical adhesion by connecting cadherins to intermediate filaments and contribute to tissue resilience.
Tight junction transmembrane components include claudins, occludin, and junctional adhesion molecules. Specific claudin isoforms have distinct functional impacts: claudin-18 associates closely with epithelial barrier integrity and is reduced in individuals with asthma; claudin-4 correlates with paracellular sodium permeability and inflammatory severity. Disruption of these complexes increases epithelial permeability, facilitating translocation of environmental agents into subepithelial compartments and promoting immune activation.
Clinical studies corroborate defective barrier function in asthma: bronchial epithelial cells from patients show impaired barrier formation, increased fragility, and altered repair. Experimental evidence implicates regulators such as NLRP3 in barrier homeostasis; NLRP3 deficiency reduces expression of barrier-associated molecules (Cldn18, Tjp1, E-cadherin), increases allergen uptake by dendritic cells, and exacerbates airway hyperresponsiveness in allergic models.
Airway epithelial cells continuously survey the luminal environment through pattern recognition receptors (PRRs) and sensory ion channels. PRRs include Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs). For example, Dectin-1 recognizes β-glucan structures from fungi and may contribute to responses against complex environmental allergens; TLR4 responds to HDM-associated microbial components such as LPS; intracellular NOD1/NOD2 detect bacterial peptidoglycan fragments.
Complementary to PRRs, epithelial sensory channels—particularly TRPV1 and TRPV4—detect proteolytic activities of aeroallergens, while extracellular ATP released during stress activates purinergic receptors (P2X7, P2Y2), raising intracellular calcium and amplifying downstream signaling. Activation of these sensing systems leads to transcription and secretion of antimicrobial peptides, reactive oxygen species, and chemokines that recruit and educate innate and adaptive immune cells, often biasing toward Type 2 inflammation.
The airway mucosa is exposed to very large volumes of inhaled air and diverse environmental insults. Environmental allergens (house dust mite, fungi, pollens) frequently contain proteases that directly cleave junctional proteins and activate signaling cascades (EGFR, Wnt/β-catenin), promoting structural damage. Particulate pollutants (PM2.5) and cigarette smoke induce oxidative stress, lipid peroxidation, epithelial cytotoxicity, and loss of mucociliary function.
Respiratory pathogens—particularly viruses such as respiratory syncytial virus (RSV), human rhinovirus (HRV), and human metapneumovirus (hMPV)—infect epithelial cells and can produce long-lasting epigenetic alterations in basal progenitors. These changes lower the threshold for future Type 2 inflammation and increase susceptibility to chronic disease, especially when early-life infections occur.
In response to barrier disruption and sensing events, epithelial cells rapidly release alarmins—notably TSLP, IL-33, and IL-25—that function as upstream cytokines linking the epithelium to both innate and adaptive immunity. These epithelial-derived mediators engage innate lymphoid cells (ILC2s) and promote Th2 cell polarization, establishing reciprocal epithelial-immune circuits and self-perpetuating inflammatory loops. Such epithelial dysfunction and alarmin-driven amplification are central to the pathogenesis of asthma and contribute to inflammation in COPD and upper airway disorders.
The pattern of epithelial alterations correlates with clinical phenotypes summarized in disease categories: asthma (impaired barrier, elevated alarmins, Type 2/eosinophilic inflammation with features such as airway hyperresponsiveness and mucus overproduction), COPD (senescence, goblet cell hyperplasia, TGF-β persistence, neutrophil/macrophage skewing), and upper airway diseases (TSLP-driven Type 2 amplification, polyp formation).
Given the epithelium’s central role, therapeutic strategies are shifting upstream toward the epithelial–immune axis. These include neutralizing biologics that target alarmins, inhibition of upstream receptors, and approaches aimed at barrier restoration. The review emphasizes that targeting epithelial drivers may offer disease-modifying potential beyond downstream immune suppression.
Concurrently, technological advances—single-cell RNA sequencing, spatial transcriptomics, organoid models, and multi-omics integration—are revealing cellular heterogeneity, spatial niches, and epithelial cell states. These tools are accelerating identification of actionable upstream nodes and biomarker discovery to enable precision therapies tailored to epithelial phenotypes.
Several important gaps remain. Disease-specific epithelial cell states and their causal roles in chronic inflammation are not fully defined. The relative value of repairing barrier integrity versus blocking alarmin-driven immune pathways needs clarification, and robust biomarkers are required to select patients most likely to benefit from epithelial-targeted therapies. Continued integration of high-resolution cellular atlases with functional models and clinical studies is necessary to translate mechanistic insights into long-term, disease-modifying interventions in respiratory medicine.