NF‐κB inactivation attenuates the M1 macrophage polarization in experimental necrotizing enterocolitis by glutaredoxin‐1 deficiency

Abstract

The pathogenesis of necrotizing enterocolitis (NEC) is severe inflammatory injury in preterm infants, which resulted from macrophage polarization. Nuclear factor‐κB (NF‐κB) is implicated to be involved in macrophage polarization. We here evaluated the essential role of NF‐κB in macrophage polarization in NEC in human samples from neonates with NEC and the mouse experimental NEC model. Enhanced intestinal macrophage (IM) infiltration was presented in human neonates with NEC, the majority of which were M1 macrophages. Meanwhile, NF‐κB was activated in the IMs in human NEC samples. NF‐κB inhibition by BAY promoted the M1 to M2 macrophage polarization. Furthermore, glutaredoxin‐1 (Grx1) deficiency promoted M2 polarization via NF‐κB inactivation from the lipopolysaccharide‐induced proinflammatory macrophages. The IMs isolated from Grx1−/− mice presented with decreases in total numbers and less macrophage differentiation. Grx1−/− derived IM were effective in the increased survival in experimental NEC through inflammation blocking. Our study provides evidence that NF‐κB inactivation by Grx1 depletion contributed to the alleviation of NEC via inhibiting M1 macrophage polarization. The modulation to alternative macrophages in the intestines may provide a promising benefits for NEC treatment.

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

“…shown to be lower in NEC mice in prior research, and Grx1 depletion alleviated the severity of experimental NEC [34,23]. We provided additional evidence that NEC stress decreases Grx1 levels in intestinal tissues and that Grx1 ablation relieves the severity of intestinal morphology and increases survival in experimental NEC.…”

New insights into intestinal macrophages in necrotizing enterocolitis: the multi-functional role and promising therapeutic application

“…Myeloid-specific deficiency of IRF5, which is associated with reduced M1 macrophage polarization and systematic inflammation, dramatically prevents experimental NEC ( 70 ). Glutaredoxin-1 deficiency promotes the inactivation of NF-κB, which attenuates the recruitment of monocytes and M1 macrophage polarization and protects against NEC-like intestinal injury ( 103 ). Hydrogen promotes the polarization of Mφs from M1 to M2 by inhibiting the expression of NF-κB p65 in the nucleus, thus reducing the severity of NEC ( 104 ).…”