Activation of α7nAChR preserves intestinal barrier integrity by enhancing the HO-1 / STAT3 signaling to inhibit NF-κB activation in mice

Activation of alpha-7 nicotinic acetylcholine receptor (α7nAChR) can inhibit a systemic inflammatory response and preserve intestinal barrier integrity. This study aimed at elucidating the molecular mechanisms by which α7nAChR activation could inhibit intestinal barrier injury and cholestatic liver fibrosis in mice following bile duct ligation (BDL). The intestine-specific heme oxygenase-1 (HO-1) knockout VillinCreHmox1-/- and control Hmox1flox/flox C57BL/6 mice were subjected to the BDL procedure. The therapeutic effects of GST-21, a specific ligand for α7nAChR, on systemic and intestinal inflammation, intestinal barrier integrity, liver fibrosis and injury, HO-1 expression, STAT3, AKT and NF-κBp65 activation were examined in these mice and intestinal epithelial cells after being co-cultured with macrophages. Compared with the vehicle-injected BDL group, treatment with GST-21 to activate α7nAChR decreased intestinal and liver injury and fibrosis in BDL mice, accompanied by reducing serum cytokine levels. In addition, activation of α7nAChR preserved the levels of tight junction protein expression and intestinal epithelial barrier integrity in BDL mice and epithelial cells following co-cultured with macrophages. The therapeutic effects of α7nAChR activation were mediated by enhancing HO-1 expression and STAT3 phosphorylation, and reducing the NF-κBp65 activation in intestinal tissues and epithelial cells co-cultured with macrophages. Finally, activation of α7nAChR induced HO-1 expression and STAT3 phosphorylation in an interdependent manner, independent of the PI3K/AKT signaling. Activation of α7nAChR enhanced HO-1 expression and STAT3 signaling to inhibit NF-κB activation, preserving the intestinal barrier integrity, and reducing inflammation and liver fibrosis in cholestatic mice. Therefore, targeting α7nAChR may be a promising interventional strategy for primary biliary cholangitis.