Glutaredoxin-1 modulates the NF-κB signaling pathway to activate inducible nitric oxide synthase in experimental necrotizing enterocolitis

Abstract

Abstract Glutaredoxin-1 (Grx1) is a cytosolic thioltransferase that catalyzes reduction of GSH-protein adducts and plays an important role in pathophysiological of Necrotizing enterocolitis (NEC). The Nuclear factor kappa B (NF-κB) pathway is inhibited by S-glutathionylation of inhibitory kappa B kinase beta (IKKβ), which can be restored by Grx1. Inducible nitric oxide synthase (iNOS) regulated by NF-κB is crucial in the progression of NEC. We aim to explore the role of Grx1 in experimental NEC. Wild-type (WT) and Grx1-knockout (Grx1-/-) mice were treated with a NEC-inducing regimen. The production of iNOS, NO, and inflammation injuries were assessed. NF-κB and involved signaling pathways were also explored. The severity of NEC was attenuated in Grx1-/- mice. Grx1 ablation promoted IKKβ glutathionylation, NF-κB inactivation, and decreased iNOS and NO production in NEC mice. Grx1 ablation protected NEC through iNOS and NO inhibition, which may be related to S-glutathionylation of IKKβ to inhibit NF-κB signaling. Grx1-related signaling pathways maybe provide a new therapeutic target in NEC.