Aims
Adhesion molecules play vital roles in the induction of airway hyperresponsiveness (AHR) or airway inflammation. The down-regulation of catenin alpha-like 1 (CTNNAL1) in the bronchial epithelial cells of asthma patients and mice models has been noted in our previous study. In this work, we further explore the underlying mechanism of CTNNAL1 in asthma. Main
Methods
We constructed a house dust mite (HDM)-induced asthma animal model on control mice and applied CTNNAL1-siRNA transfection to create CTNNAL1-deficient mice. Key findings: We documented much more severe airway inflammation and increased leukocyte infiltration in the lungs of the CTNNAL1-deficient mice comparing to control mice, along with elevated expression of inflammatory cytokines. Dexamethasone (DEX) treatment led to less reduced inflammation in CTNNAL1-deficient mice compared with control mice. Immunoprecipitation confirmed the interaction between heat shock protein90 (hsp90) and CTNNAL1. The expression of hsp90 was upregulated after CTNNAL1 silencing. Meanwhile, the use of hsp90 inhibitor geldanamycin significantly decreased the expression of NR3C1, ICAM-1 and the ratio of p-p65/p65 in CTNNAL1-silenced 16HBE14o- cells. Both geldanamycin and DEX could function to suppress the expression of ICAM-1 and the phosphorylation level of p65. Nevertheless, the anti-inflammatory effect of DEX proved less potent than geldanamycin in the CTNNAL1-silenced group. The combined therapy of geldanamycin and DEX significantly decreased the inflammatory responses in CTNNAL1-deficient HBE cells than DEX monotherapy. Significance: Our study corroborates that CTNNAL1 deficiency induced aggravated airway inflammation and rendered insensitivity to glucocorticoids via triggering hsp90 signaling pathway.
Significance
Our study corroborates that CTNNAL1 deficiency induced aggravated airway inflammation and rendered insensitivity to glucocorticoids via triggering hsp90 signaling pathway.