β-arrestin-2 enhances intestinal epithelial apoptosis in necrotizing enterocolitis

Abstract

Apoptosis among intestinal epithelial cells contributes to necrotizing enterocolitis (NEC), a severe intestinal disease that particularly affects premature infants. β-arrestin-2, an important regulator of G-protein-coupled receptors, is expressed in intestinal epithelial cells, where its activation promotes apoptosis. We found that β-arrestin-2 was overexpressed in both human and murine NEC samples. β-arrestin-2-deficient mice were protected from endoplasmic reticulum stress and NEC development. The endoplasmic reticulum-resident chaperone BiP was found to promote intestinal epithelial cell survival. Pretreatment of intestinal epithelial cells or mice with the BiP inhibitor HA15 increased cell apoptosis and promoted NEC development. β-arrestin-2 bound to BiP and promoted its polyubiquitination and degradation, thereby facilitating the release of the pro-apoptotic molecule BIK from BiP. Silencing β-arrestin-2 downregulated apoptosis by increasing BiP levels, which suppressed endoplasmic reticulum stress. This study suggests that β-arrestin-2 induces NEC development by inhibiting BiP, thereby triggering apoptosis in response to endoplasmic reticulum stress. Thus, novel therapeutic strategies to inhibit β-arrestin-2 may enhance the treatment of NEC.

Intestinal epithelial tight junctions and permeability can be rescued through the regulation of endoplasmic reticulum stress by amniotic fluid stem cells during necrotizing enterocolitis

“…Prolonged ER stress has been reported to be associated with cell apoptosis 33,34 . Hence, we next evaluated whether cell death is also involved in the AFSC‐induced beneficial effects on ER stress.…”

“…36 All three main branches of ER stress (IRE1α/XBP1, PERK/eIF2α, and ATF6 pathway) mediate the response through different mechanisms, 33 but all together maintain signaling within cells, which involves proteins production and proper folding before exporting the final products out of the cells. ER stress markers have been shown to be elevated in NEC, 33,34,55 and a recent study in the rat NEC model showed that BiP expression was upregulated and peaked at 48 hours after NEC induction, but dropped at 72 hours, coinciding with the most severe intestinal damage. 55 These findings support our results of ER stress makers being downregulated in our mouse NEC model at P9, the day at which intestinal damage is the highest.…”

“…Prolonged ER stress has been reported to be associated with cell apoptosis. 33,34 Hence, we next evaluated whether cell death is also involved in the AFSC-induced beneficial effects on ER stress. Surprisingly, cell necrosis and apoptosis were both reduced in organoids subjected to AFSC treatment ( Figure 3A-D), despite the high level of ER stress activity in these organoids.…”

“…CHOP regulates the expression of many anti‐apoptotic and pro‐apoptotic genes, including genes encoding the BCL2‐family proteins 32 . Sustained ER stress in intestinal epithelial cells induces cell apoptosis and represents one of the pathogenic mechanisms of NEC 33,34 . It has been shown that inhibiting CHOP expression and offsetting epithelial ER stress‐induced apoptosis prevents the intestine from NEC‐induced injury 35,36 …”

Differential Expression Profiles and Functional Prediction of circRNAs in Necrotizing Enterocolitis

“…GO analysis results indicated that host genes for differentially expressed circRNAs are correlated with regulating extrinsic apoptotic signaling pathways, ciliary transition fiber, and death receptor activity, all of which are implicated in NEC development. Apoptosis of intestinal epithelial cells is linked to NEC progression [ 18 ]. Extrinsic lipopolysaccharide-induced reactive oxygen species accumulation results in NF- κ B activation and subsequent release of proinflammation cytokines, including IL-6 and IL-1 β , which are involved in NEC pathogenesis [ 19 , 20 ].…”