Allergic airway inflammation is a key 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 first 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.
Although previous studies have shown that GSDMD is involved in IL-33 release, 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.
In a study published in Cell, the research 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, collaborated with the team led by Prof. LIU Xing Liu from the Shanghai Institute of Materia and Medica, Chinese Academy of Sciences, reveals that environmental allergens can activate gasdermin D (GSDMD) in airway epithelial cells through a previously unrecognized iron-dependent mechanism, thereby promoting IL-33 release and initiating allergic airway inflammation. These findings provide new insight into the prevention and treatment of asthma and related allergic diseases.
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.
Further mechanistic studies showed that the 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. Meanwhile, the iron chaperone PCBP2 delivers iron to the vicinity of GSDMD. The E309/Q312 residues of GSDMD are responsible for iron binding; when these sites were mutated, GSDMD could no longer be efficiently cleaved or mediate IL-33 release. The researchers further 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 alleviated papain-induced airway inflammation, reducing eosinophil infiltration, IL-5 and IL-13 levels, and mucus secretion. Conversely, iron supplementation aggravated inflammatory responses in wild-type mice, but failed to produce the same effect in GSDMD-deficient mice. These results 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.
Together, the study proposes a new mechanism for the initiation of allergic airway inflammation. Environmental allergens are sensed by lung epithelial cells through PAR1, triggering ferritinophagy and the release of free iron. PCBP2 then delivers iron to GSDMD, where a local Fenton reaction promotes protease-independent GSDMD cleavage and generates an active fragment capable of mediating IL-33 release. This process ultimately activates ILC2s and amplifies type 2 inflammation. The discovery expands current understanding of GSDMD activation and the immunological functions of iron metabolism, while pointing to new therapeutic possibilities for allergic inflammatory diseases such as asthma.
Reference: https://www.cell.com/cell/abstract/S0092-8674(26)00653-7
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