Downregulation of HMGB1 is required for the protective role of Nrf2 in EMT‐mediated PF

Abstract

Epithelial–mesenchymal transition (EMT) is considered to be the key event in the formation of pulmonary fibrosis (PF). High‐mobility group box 1 (HMGB1) is a novel mediator of EMT. Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a critical transcription factor for protecting against PF. However, it is unknown the relationship between Nrf2 and HMGB1 in EMT‐mediated PF. Bleomycin (BLM)‐induced PF in Nrf2‐knockout (Nrf2−/−) and wild‐type (WT) mice and transforming growth factor β1 (TGF‐β1)‐induced EMT in rat type II alveolar epithelial cell line (RLE‐6TN) and human alveolar epithelial cell line (A549) were established to observe the relationship among Nrf2, HMGB1, and EMT by western blot and immunohistochemistry. BLM‐induced EMT was more severe and the expression of HMGB1 was more increased in Nrf2 −/− mice compared with WT mice. In vitro, Nrf2 activation attenuated TGF‐β1‐induced EMT and ROS production accompanied by the downregulation of HMGB1. In contrast, silencing Nrf2 enhanced TGF‐β1‐induced EMT and ROS production along with increased the protein expression and the release of HMGB1. Moreover, HMGB1 activation aggravated TGF‐β1‐induced EMT and HMGB1 deficiency alleviated TGF‐β1‐induced EMT. Furthermore, HMGB1 silence attenuated the protective effect of Nrf2 on EMT. These findings suggest downregulation of HMGB1, which is required for the protective role of Nrf2 in EMT‐mediated PF and provide an important therapeutic target for PF.

Nrf2 regulates cell motility through RhoA–ROCK1 signalling in non-small-cell lung cancer cells

“…Well-known EMT makers such as Snail, Slug, and E-cadherin, were examined in Nrf2-overexpressing or -knockdown NSCLC cells. Results showed that the www.nature.com/scientificreports/ expression of these molecules was not consistent, which might explain why previously published reports have shown controversial and cell-type specific results [21][22][23][24] . Other molecules associated with cytoskeletal remodelling such as RhoA and ROCK1 were also examined and we observed that overexpression of Nrf2 up-regulated, and suppression of Nrf2 down-regulated the RhoA-ROCK1 pathway.…”

Superoxide Dismutase Administration: A Review of Proposed Human Uses

“…Two cross-talking pathways are involved: Nrf2/HO-1 and the Toll-like receptor (TLR)/NF-κB axis [241]. Indeed, HMGB1 can suppress the Nrf2 pathway [236,242], as well as activating TLR-4, and thus activates NF-κB signaling [243,244]. Considering its crucial role in SOD induction, the Nrf2 pathway is an attractive target for different chronic diseases in which oxidative stress is involved [245,246].…”

The implication of the crosstalk of Nrf2 with NOXs, and HMGB1 in ethanol-induced gastric ulcer: Potential protective effect is afforded by Raspberry Ketone

“…A similar result was reported by Qu et al who also reported increased HMGB1 expression in Nrf2 silencing. Moreover, they reported that HMGB1 inhibition is essential for Nrf2 protective activity [53].…”