DCLK1 mediates airway epithelial barrier disruption through NF-κB activation in severe asthma

BACKGROUND: Severe asthma is characterized by epithelial barrier dysfunction, airway remodeling, and chronic inflammation. Doublecortin-like kinase 1 (DCLK1), a kinase initially identified as a cancer stem cell marker, has been linked to NF-κB-mediated inflammatory responses. However, its role in TGF-β-induced epithelial barrier disruption in severe asthma remains unclear. METHODS: The expression of DCLK1 and junctional proteins was examined in bronchial epithelial tissue biopsies and air-liquid interface (ALI) cultures derived from patients with severe asthma and healthy controls. The role of DCLK1 was investigated in vitro using TGF-β-treated BEAS-2B cells and in vivo using ovalbumin (OVA)- and house dust mite (HDM)-induced murine asthma models. Global DCLK1 knockout mice were employed to assess epithelial integrity, airway remodeling, and inflammatory responses in murine asthma. RESULTS: DCLK1 expression was increased in bronchial epithelial cells from patients with severe asthma. DCLK1 siRNA reversed TGF-β-induced epithelial dysfunction by restoring E-cadherin expression and reducing fibronectin and N-cadherin levels in BEAS-2B cells. Moreover, DCLK1 silencing improved epithelial barrier function, as evidenced by increased transepithelial electrical resistance (TEER) and E-cadherin expression. Mechanistically, DCLK1 mediates TGF-β-induced EMT via activation of the NF-κB signaling pathway. DCLK1 knockout mice exhibited improved lung function and reduced airway inflammatory cell infiltration compared with wild-type mice under both OVA and HDM exposure. CONCLUSIONS: DCLK1 promotes airway epithelial barrier dysfunction in severe asthma through NF-κB activation. Targeting DCLK1 may represent a novel therapeutic strategy to restore epithelial integrity in severe asthma.