GLCCI1-Deficiency Facilitates Persistent Eosinophilic Lung Inflammation in Asthma via Upregulation of CCL5.

The presence of eosinophils in the lung is a decisive pathophysiological feature of asthma. Some severe asthma patients have persistent eosinophil infiltration in the lung despite receiving high-dose glucocorticoid treatment. Previous studies indicate an association between glucocorticoid-induced transcript 1 (GLCCI1) expression and the clinical efficacy of glucocorticoids. Whether there is a correlation between eosinophilic inflammation and GLCCI1 deficiency remains to be discussed. Wild-type (WT) and GLCCI1-deficient (GLCCI1-/-) mice were sensitized with ovalbumin (OVA) to induce asthma, followed by eosinophilic inflammation assessment. CCL5 and eotaxins expression was measured in asthmatic mice and BEAS-2B bronchial epithelial cells. Mechanisms were explored using RNA-Seq, western blot, and transwell migration assays. Clinical correlations between GLCCI1 expression and CCL5 levels, eosinophil counts, or inflammatory molecules were analyzed in asthma patients' PBMCs and induced sputum. Compared to WT mice, GLCCI1-/- mice exhibited enhanced lung eosinophilic inflammation after OVA challenge. Both murine asthma models and BEAS-2B cell experiments revealed that GLCCI1 deficiency upregulated CCL5 expression under asthmatic conditions, potentially via the AKT pathway. Supernatant from GLCCI1-silenced BEAS-2B cells enhanced eosinophil chemotaxis, while CCL5 inhibition attenuated this effect. Clinically, GLCCI1 expression inversely correlated with blood eosinophil counts, CCL5 levels in PBMCs/sputum, and eosinophil-related molecules in asthma patients. Our findings show that GLCCI1 deficiency promotes sustained eosinophil accumulation through the upregulation of CCL5, which may be modulated by the AKT pathway.