Early Growth Response 1-Associated Epithelial Autophagy-Related Changes in Allergic Airway Inflammation

Airway epithelial cells contribute critically to the initiation of allergic airway inflammation via the release of alarmins such as interleukin-33 (IL-33). Nevertheless, the intracellular regulatory networks governing epithelial alarmin release remain inadequately defined. Although autophagy has been implicated in epithelial stress adaptation and the transcription factor early growth response 1 (EGR1) is promptly induced upon allergen challenge, it remains uncertain whether EGR1 contributes to IL-33 release as a representative indicator of epithelial activation through autophagy-associated processes. In this study, human bronchial epithelial BEAS-2B cells were exposed to house dust mite (HDM) extract. EGR1 expression was manipulated using gain- and loss-of-function strategies. Autophagy-associated alterations were evaluated by monitoring LC3B, p62, and PI3K-III (Vps34) levels, together with immunofluorescence microscopy. IL-33 release into culture supernatants was quantified by ELISA as a functional readout of epithelial activation. Pharmacological interference with autophagy was employed to examine functional engagement. An HDM-driven murine model was utilized to assess in vivo correlates. Publicly accessible transcriptomic datasets were interrogated in an exploratory manner to characterize epithelial stress signatures linked to this axis. HDM treatment upregulated EGR1 in airway epithelial cells, concomitant with autophagy-associated alterations and enhanced IL-33 release. Forced EGR1 expression coincided with elevated LC3B-II levels, diminished p62 accumulation, and increased PI3K-III abundance, whereas EGR1 silencing produced reciprocal effects. Pharmacological suppression of autophagy attenuated IL-33 release and inhibition of Class III PI3K blunted the EGR1 overexpression-driven increase in IL-33 release. In HDM-challenged mice, colocalization of EGR1 and LC3B was observed in lung tissue sections. Exploratory transcriptomic profiling further suggested that allergen provocation may elicit a coordinated epithelial stress response characterized by inflammatory and metabolic pathway enrichment. The results show that EGR1 is associated with epithelial autophagy-related alterations under allergic stimulation, and these changes are accompanied by augmented release of the alarmin IL-33. These observations support a conceptual framework wherein EGR1-linked autophagy-associated processes may contribute to epithelial stress responses during early inflammatory events in allergic airway disease. Elucidation of the precise molecular underpinnings and causal relationships awaits further investigation.