Increased expression of miR146a dysregulates TLR2-induced HBD2 in airway epithelial cells from patients with COPD.

Background: Airway epithelial cells from patients with COPD show suboptimal innate immune responses to nontypeable (NTHi) and Toll-like receptor (TLR)2 ligands despite expressing TLR2 similar to normal airway epithelial cells, but the underlying mechanisms are poorly understood.

Methods: Normal or COPD mucociliary-differentiated airway epithelial cells were treated with TLR2 agonists or infected with NTHi and expression of β-defensin (HBD)2 was examined. Interleukin-1 receptor-associated kinase (IRAK)-1 and microRNA (miR)146a were genetically inhibited in normal and COPD airway epithelial cell cultures, respectively, and HBD2 responses to TLR2 ligands were determined. IRAK-1 expression in lung sections was determined by immunofluorescence microscopy.

Results: Compared to normal, COPD airway epithelial cell cultures showed impaired expression of HBD2 in response to TLR2 agonists or NTHi infection. Apical secretions from TLR2 agonist-treated normal, but not COPD, airway epithelial cells efficiently killed NTHi. Knockdown of HBD2 significantly reduced NTHi killing by apical secretions of normal airway epithelial cells. Compared to normal, COPD cells showed significantly reduced expression of IRAK-1 and this was associated with increased expression of miR146a. Inhibition of miR146a increased the expression of IRAK-1, improved the expression of HBD2 in response to TLR2 agonists in COPD cells and enhanced the killing of bacteria by apical secretions obtained from TLR2 agonist-treated COPD cells. Bronchial epithelium of COPD patients showed reduced expression of IRAK-1.

Conclusions: These results suggest that reduced levels of IRAK-1 due to increased expression of miR146a may contribute to impaired expression of TLR2-induced HBD2 in COPD airway epithelial cells.