A Wnt/β-catenin negative feedback loop represses TLR-triggered inflammatory responses in alveolar epithelial cells

Increasing evidence has demonstrated that the epithelial cells in the lung play crucial roles in regulating certain inflammatory responses by modulating Wnt signaling during microbial infection. However, the anti-microbial functions of Wnt signaling in alveolar epithelial cells remain elusive. In this report, we show that Wnt/β-catenin signaling is repressed in A549 alveolar epithelial cells during a Toll-like receptor ligand stimulation with Mycobacterium bovis Bacillus Calmette-Guerin (BCG) or lipopolysaccharide (LPS). In addition to activating TLR signaling, a stimulation of BCG or LPS led to the up-regulation of a Wnt receptor Frizzled-1, cytosolic GSK3β and Axin, and the down-regulation of nuclear β-catenin, lymphoid enhancer factor 1 and transcription factor 4. While an enhancement of β-catenin activity suppressed the TLR signal response, and substantially led to alleviate the TLR ligand-induced pro-inflammatory responses. Importantly, gain and loss of function studies by overexpressing or silencing of TLR signaling adaptor, myeloid differentiation primary response gene 88 (MyD88) further demonstrated an inverse relationship between TLR signaling and canonical Wnt signaling in A549 cells. These data imply that Wnt/β-catenin signaling acts as a negative feedback loop to suppress inflammation in alveolar epithelial cells, and averts cell injury from excessive inflammatory reactions. This study thus reveals a novel immunoregulatory mechanism in alveolar epithelial cells in response to bacterial infection.