Allergic asthma is a complex disease in which immunological processes, structural alterations of the airways, and functional impairments are closely intertwined. A recent study highlights a previously underappreciated link between these levels: the role of the inflammasome sensor NLRP3 in maintaining the integrity of the airway epithelial barrier.
The publication, published in Frontiers in Immunology, is the result of close, cross-site collaboration within the German research landscape. Researchers from the DZL sites BREATH and CPC-M worked together with the associated DZL site Berlin as well as the newly established German Center for Child and Adolescent Health. The project was funded by the CHAMP consortium (CHildhood Allergy and tolerance: Biomarkers and Predictors) with support from the German Federal Ministry of Research, Technology and Space (BMFTR).
Using an experimental mouse model of allergic asthma, the researchers investigated the consequences of genetic NLRP3 deficiency. NLRP3-deficient animals developed significantly increased airway hyperresponsiveness and enhanced mucus production. These functional changes were accompanied by a clear structural weakening of the epithelial barrier. Key components of cell–cell junctions in the bronchial epithelium, including tight junction and adhesion proteins, were significantly reduced. As a result, epithelial permeability increased, facilitating immune system exposure to inhaled allergens and further amplifying the asthmatic inflammatory response.
Importantly, these effects were not limited to the animal model. In human bronchial epithelial cells, pharmacological inhibition of NLRP3 also led to a reduction of essential barrier proteins. The study thus directly bridges experimental basic research and human-relevant mechanisms.
“Our findings show that NLRP3 is not only a classical immune sensor, but also plays a fundamental role in maintaining the epithelial barrier of the airways,” emphasizes first author Dr. Stephanie DeStefano from the DZL site BREATH. “Particularly in the context of allergic asthma, this opens a new perspective on disease mechanisms that have so far been viewed primarily from an immunological standpoint.”
The added value of the study lies in this functional re-evaluation of NLRP3. While previous research has mainly focused on its role in activating inflammatory cascades, this publication highlights its contribution to structural stability of the airway epithelium. The data suggest that NLRP3 acts as a molecular guardian that preserves barrier function and thereby protects against excessive airway reactivity. Importantly, NLRP3 is not presented as a therapeutic target per se, but rather as a central factor in the finely balanced interplay between barrier maintenance and immune response.
This shift in perspective has important implications for translational research. “The study expands our understanding of NLRP3 beyond its role in immune responses,” notes senior author Gesine Hansen, Director of the Clinic for Pediatric Pulmonology, Neonatology and Allergology at Hannover Medical School (MHH). “It highlights how closely barrier function and immunological regulation are interconnected in the airways — an aspect that is highly relevant for future therapeutic strategies.” Particularly with regard to early disease mechanisms and age-related differences in allergic airway diseases, the findings open new avenues for asthma research.
Originalpublikation: DeStefano S et al. NLRP3 regulates epithelial barrier integrity and protects from airway hyperresponsiveness in experimental allergic asthma. Front Immunol. 2025 Nov 27;16:1655205. doi: 10.3389/fimmu.2025.1655205. PMID: 41394833; PMCID: PMC12695735.
Source: BREATH
