In a study published in Cell, a team led by Prof. SUN Bing from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences (CAS), along with Prof. LIU Xing's team from the Shanghai Institute of Materia and Medica of CAS, revealed that environmental allergens can activate gasdermin D (GSDMD) in airway epithelial cells through a iron-dependent mechanism, thereby promoting IL-33 release and initiating allergic airway inflammation.

Allergic airway inflammation is a main pathological basis for the onset and progression of asthma. When environmental allergens such as pollen, house dust mites, and fungal proteases enter the airway, they act on lung epithelial cells and induce the release of alarmins, including IL-33. IL-33 then activates type 2 innate lymphoid cells (ILC2s), leading to eosinophil infiltration, mucus production, and airway tissue damage.

Previous studies have shown that GSDMD is involved in IL-33 release, but how allergens activate GSDMD remains unclear. In this study, the researchers found that allergen stimulation rapidly increased the labile iron pool in airway epithelial cells, and cleaved and activated GSDMD through a mechanism independent of conventional proteases.

Using mouse models induced by papain or house dust mite, the researchers observed a rapid rise in lung iron levels after allergen challenge, occurring in parallel with IL-33 release. Treatment with an iron chelator markedly inhibited GSDMD cleavage and IL-33 release, whereas iron supplementation enhanced these responses. This iron-driven effect was largely abolished in GSDMD-deficient mice, indicating that the pro-inflammatory activity of iron is highly dependent on GSDMD.

Besides, the researchers showed that cell-surface protease-activated receptor PAR1 serves as an important entry point for allergen sensing. Papain directly cleaves PAR1, which in turn initiates NCOA4-mediated ferritinophagy and releases additional free iron. Iron chaperone PCBP2 delivers iron to the vicinity of GSDMD. E309/Q312 residues of GSDMD are responsible for iron binding. When these sites are mutated, GSDMD can no longer be efficiently cleaved or mediate IL-33 release.

It was found that this cleavage process does not depend on canonical inflammasome-associated caspases. Instead, iron delivered by PCBP2 locally triggers a Fenton reaction, generating short-range hydroxyl radicals that drive oxidative cleavage of GSDMD.

In vivo experiments showed that pretreatment with the iron chelator DFP significantly alleviates papain-induced airway inflammation, reducing eosinophil infiltration, IL-5 and IL-13 levels, and mucus secretion. Conversely, iron supplementation aggravates inflammatory responses in wild-type mice, but fails to produce the same effect in GSDMD-deficient mice.

These findings establish the iron-GSDMD-IL-33 axis as an important driver of allergen-induced type 2 immune responses, and suggest that PAR1, iron mobilization, PCBP2, and local iron-mediated reactions may represent potential intervention points for asthma and other allergic diseases.

This study proposes a new mechanism for the initiation of allergic airway inflammation. It expands the understanding of GSDMD activation and immunological functions of iron metabolism, and provides new insight into the prevention and treatment of asthma and related allergic diseases.