Rebecca Palmer, Olivier Lamiable, Kerry L. Hilligan
In this Highlights article, allergic asthma and rhinitis are reframed as diseases of epithelial-immune dysregulation. Advances from 2025 establish epithelial-immune circuitry as a central organizing principle of allergic airway inflammation—spanning allergen sensing, memory T-cell function and perpetuation of inflammatory niches—and provide a foundation for next-generation, tissue-directed therapies. Allergic airway inflammation is increasingly recognized as a dynamic, locally coordinated process shaped by reciprocal interactions between epithelial cells and immune populations.1-3 Over the past decade, airway epithelial cells have emerged as active immunological participants that sense environmental stimuli, instruct immune cell differentiation and function, and remodel local niches to sustain chronic inflammation. In parallel, immune cells reciprocally influence epithelial identity, differentiation and barrier function, driving persistent disease states such as asthma and chronic rhinosinusitis. A series of studies published in 2025 has significantly refined this paradigm by mapping epithelial-immune circuits with unprecedented detail and spatial resolution. Together, these works move the field beyond viewing epithelial cells as mere “alarm bells.” Instead, epithelial cells emerge as central drivers of disease across multiple stages, acting not only as cytokine producers but also as antigen-presenting cells and architects of tissue-resident immune niches. Here, we highlight five key studies that reshape our understanding of allergic airway inflammation, from the earliest stages of allergen sensing to the regulation of tissue-resident memory T cells.4-8 Epithelial damage is widely regarded as a proximal trigger of type 2 immunity, explaining how diverse stimuli (e.g., helminths, venoms) converge on a shared inflammatory program.9 A key consequence is the release of IL-33, an alarmin constitutively stored in epithelial cells and rapidly released upon loss of membrane integrity.10 IL-33 activates type 2 innate lymphoid cells (ILC2s), basophils and CD4+ T helper (Th)-2 cells, initiating and amplifying type 2 inflammation.11 However, how seemingly inert and structurally diverse aeroallergens engage this pathway has been less clear. Shi et al. demonstrate that some aeroallergens directly damage epithelial cells though pore-forming activity.4 Extracts of the mold allergen Alternaria alternata were found to contain pore-forming complexes that disrupt epithelial membranes, leading to direct release of pre-formed IL-33. Importantly, structurally unrelated pore-forming proteins from heterologous sources recapitulate this effect when delivered intranasally to mice.4 These findings establish epithelial membrane perforation as a mechanistic driver of allergic inflammation, acting at least in part through the release of IL-33 and other damage-associated molecular patterns. Notably, pore formation is not a universal property of allergens. Many clinically important aeroallergens, including house dust mite, instead possess protease activity that disrupts epithelial barrier integrity and proteolytically processes extracellular IL-33 into highly bioactive mature forms.12 Thus, whether through direct membrane perforation, protease-mediated barrier disruption, or related cellular stress pathways, epithelial injury emerges as a convergent upstream mechanism through which diverse allergens initiate inflammation. Following aeroallergen exposure, immune cells rapidly accumulate within the respiratory mucosa, where they interact with epithelial populations to reinforce inflammatory pathways. Spatial transcriptomics enables high-resolution mapping of these microenvironments, revealing that inflammation in allergic airways is not uniform but organized within discrete anatomical niches. By profiling intact clinical biopsies from the upper and lower airways, two recent studies resolve tissue architecture and epithelial-immune interactions that shape allergic pathology in humans,5, 6 features that animal models often fail to capture. In the upper airway, Liao et al. map the inflammatory landscape of chronic rhinosinusitis (CRS),5 an immunologically heterogenous disease of the nasal passages.1 CRS with nasal polyps (CRSwNP) represents a type 2 high allergic endotype characterized by eosinophilic infiltration, which allowed the authors to directly compare inflammatory niches in polyp tissue with adjacent mucosa. Within polyps, spatial analysis revealed correlations between eosinophil accumulation and macrophage expression of the chemokines CCL13 and CCL18, particularly within epithelial regions, suggesting that macrophages recruit eosinophils into the nasal epithelium. Type 2-associated epithelial populations are also enriched: tuft cells expanded and, based on ligand–receptor interaction analyses, are predicted to engage Th2 cells, while basal epithelial cells exhibited an IL-4/IL-13-associated remodeling program, predicted to be regulated by KLF4.5 Notably, these spatially organized inflammatory circuits were largely confined to polyp tissue and were less pronounced in adjacent mucosa, underscoring the localized nature of type 2 inflammatory niches in CRSwNP. A similar pattern was observed by Joulia et al. in the lower airway.6 They identified discrete inflammatory hubs within the bronchial epithelium that are present in both healthy and asthmatic individuals but become dysregulated in asthma, characterized by increased cell density and enhanced mucus production despite ongoing treatment. As in the upper airway, structural cells within these niches act as central regulators, serving as dominant sources of chemokines and alarmins that organize and sustain inflammatory responses within defined regions of the airway. This study also highlights the emergence of a distinct epithelial serous cell population in asthma that closely interacts with mast cells, macrophages and endothelial cells. Given their role in host defense,13 serous cells potentially contribute to the organization and persistence of inflammatory niches within asthmatic airways. These spatial approaches can also reveal how therapies disrupt inflammation. Joulia et al. show that imatinib (KIT inhibitor14) remodels the inflammatory hubs, reducing alarmin and cytokine expression while increasing intercellular distance, consistent with reduced cellular interactions.6 Similarly, Liao et al. demonstrate that dupilumab (anti-IL-4Rα15) treatment reduces pathological remodeling in basal epithelial cells in CRSwNP.5 Thus, spatial transcriptomics not only maps inflammatory circuits but also provides a platform to interrogate how they are reshaped by targeted therapies in patients. The alveolar niche of the distal lung is maintained by alveolar type 2 (AT2) epithelial cells, which support tissue homeostasis through surfactant production and secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF).16 While GM-CSF is well established as a critical factor for alveolar macrophage development and maintenance,17 Gschwend et al. extend its role to the regulation of conventional dendritic cell (cDC) development within the type 2 immune axis.7 Specifically, the authors use mouse models to identify AT2-derived GM-CSF as a nonredundant signal for the development of CD301b+ cDC2s, a subset previously implicated in Th2 priming.18 They demonstrate that epithelial-specific deletion of GM-CSF in AT2 cells results in a marked loss of CD301b+ cDC2s. Mechanistically, GM-CSF signaling promotes the maturation of cDC2s toward the CD301b+ phenotype while simultaneously inducing a pro-survival program. Importantly, AT2-specific loss of GM-CSF attenuates house dust mite-induced eosinophilic airway inflammation, whereas restoration of GM-CSF expression selectively in AT2 cells restores both the CD301b+ cDC2 compartment and type 2 pathology.7 Together, these findings redefine AT2 cells as key epithelial regulators that instruct DC differentiation within the alveolar niche, thereby controlling the initiation and magnitude of allergic responses in the lung. Allergic airway research has predominantly focused on type 2-mediated eosinophilic inflammation. In contrast, Ravi et al. investigate neutrophilic asthma,8 a treatment-resistant endotype.19 Using a recurrent inhaled allergen mouse model, the authors define an epithelial–lymphocyte–neutrophil axis orchestrated by airway secretory cells and CD4+ resident memory T (TRM) cells. In this context, IL-17 produced by an unconventional RORγtlow CD4+ TRM population stimulates Muc5ac+ secretory epithelial cells which then become the dominant source of the neutrophil chemoattractant CXCL5, driving acute neutrophil recruitment and airway inflammation. Importantly, epithelial antigen presentation functions as a rheostat that constrains disease severity. Genetic ablation of epithelial MHCII skews TRM cells away from IFNγ production, thereby unleashing IL-17A-driven neutrophilia.8 This identifies epithelial antigen presentation as a previously unappreciated mechanism for tuning TRM cell function and limiting inflammatory amplification. Ravi et al. extend epithelial-immune crosstalk beyond cytokine signaling, positioning epithelial cells as active regulators of memory T-cell fate and allergic responses in the airway. Together, these studies support a shift in how we view allergic airway inflammation. Rather than being driven solely by immune cells, asthma and CRSwNP emerge as disorders of epithelial-immune dysregulation. By establishing epithelial cells as instructors of DC differentiation, regulators of TRM function and drivers of chronic tissue remodeling, these studies suggest that disease arises when epithelial cells adopt stable, immune-interactive phenotypes that reinforce pathogenic circuits. In this framework, chronic inflammation is sustained not only by aberrant immune activity but by epithelial states that continuously fuel immune responses. This model has important implications for disease heterogeneity. Differences between eosinophilic and neutrophilic asthma, or between CRS subtypes, may reflect divergent epithelial lineage programs and niche configurations rather than fundamentally distinct initiating immune triggers. Epithelial perturbations (genetic, environmental, or infectious) may durably reprogram local immune niches, predisposing individuals to allergic inflammation and specific inflammatory endotypes.3 For example, factors that increase epithelial vulnerability, including viral infection, environmental pollutants or metabolic stressors (e.g., high-fat, low-fiber Western diet), may be important modulators of susceptibility to allergic disease and its severity.20 Future work must define how epithelial-immune circuits are initiated, how stable they remain over time and across anatomical sites, and how they differ between upper and lower airway compartments. Collectively, the advances of 2025 firmly establish epithelial-immune circuitry as a central organizing principle in allergic airway inflammation and provide a conceptual foundation for next-generation, tissue-directed therapies in asthma and rhinitis. R.P. is supported by a Doctoral Scholarship from the University of Otago, New Zealand. K.L.H. is supported by a Sir Charles Hercus Health Research Fellowship from the Health Research Council of New Zealand. The graphical abstract was created in Biorender. Rebecca Palmer: Writing – original draft. Olivier Lamiable: Writing – original draft; writing – review and editing. Kerry L. Hilligan: Conceptualization; visualization; funding acquisition; writing – original draft; writing – review and editing; supervision. The authors declare no conflict of interest.