Redox regulation of intestinal epithelial permeability

Intestinal barrier permeabilization and the associated increased passage of deleterious luminal substances can cause local and systemic inflammation. This is a major contributor to the adverse consequences of obesity-associated pathologies. This paper investigated the role of oxidative stress and redox signaling in inflammation (TNFα)-induced permeabilization of intestinal epithelial cell monolayers. TNFα induced Caco-2 cell monolayer permeabilization within 3h. Reactive oxygen species (ROS) production increased starting 10 min after TNFα addition. TNFα caused an increase in NADPH oxidase activity after 10 min, and an increased expression of NOX1/NOX4 after 3h incubation. Mitochondria superoxide production (Mitosox) and membrane potential (TMRM) were increased and decreased, respectively, after 3 and 6h of exposure to TNFα. TNFα-triggered NF-κB and ERK1/2 activation, the two major signaling pathways underlying intestinal barrier permeabilization. Attenuation of ROS production with NADPH oxidase inhibitors led to a downregulation of these cascades and to the prevention of TNFα-induced increase of monolayer permeability. Thus, regulation of redox homeostasis in the intestinal epithelium plays a central role in the regulation of intestinal permeability. ROS production and redox-sensitive signals represent potential targets in the treatment of barrier inflammation-associated pathologies.