Protective effect of dimethyl itaconate against fibroblast–myofibroblast differentiation during pulmonary fibrosis by inhibiting TXNIP

Abstract

Fibroblast-myofibroblast differentiation (FMD) is a critical cellular phenotype during the occurrence and deterioration of pulmonary fibrosis (PF). FMD can increase with an elevated level of reactive oxygen species (ROS) on fibroblasts under oxidative stress. Thioredoxin-interacting protein (TXNIP) is an α-arrestin family protein that regulates the level of intracellular ROS. Nuclear factor erythroid 2-related factor 2 (Nrf2) can protect against FMD in PF. However, the relationship between Nrf2 and TXNIP in FMD remains elusive. Therefore, we established TGF-β1-induced FMD in vitro and bleomycin (BLM)-induced mouse PF model in vivo to explore whether the activation of Nrf2 can inhibit TXNIP-mediated FMD in PF.Dimethyl itaconate (DMI) was selected to activate Nrf2. Our results showed that TXNIP was elevated and FMD was aggravated in mice lung tissues after BLM administration compared with the saline group. Inversely, Nrf2 decreased TXNIP expression and alleviated FMD in PF. In vitro, TXNIP overexpression enhanced FMD and increased the level of ROS. In contrast, TXNIP deficiency by small interfering RNA (siRNA) attenuated TGF-β1-induced FMD and reduced ROS. An increase in ROS by H 2 O 2 can upregulate TXNIP expression. Moreover, Nrf2 also inhibited TGF-β1-induced FMD and the increase of ROS, with reducing expression of TXNIP, and the inhibitory effect was better than TXNIP siRNA. These results suggest that activation of Nrf2 by DMI can protect against PF via inhibiting TXNIP expression.Our study may provide new therapeutic targets and treatment approaches for PF.

COX-2/sEH dual inhibitor PTUPB attenuates epithelial-mesenchymal transformation of alveolar epithelial cells via Nrf2-mediated inhibition of TGF-β1/Smad signaling

“…Nrf2 balances not only oxidative stress but also has negative effects on TGF-β1-mediated profibrotic signal transduction [14,15]. Previous studies have shown that Nrf2 plays an important role in preventing lung inflammation and fibrosis [16,17]. These results indicate that strategies targeting Nrf2 have antipulmonary fibrosis potential.…”

The Role of Nrf2 in Pulmonary Fibrosis: Molecular Mechanisms and Treatment Approaches

“…TGF-β1 has been identified as a major pro-fibrogenic cytokine in IPF patients and can be produced by a variety of cells, such as alveolar macrophages, alveolar epithelial cells, and myofibroblasts [ 139 , 140 ]. Recently, a growing number of studies have suggested that fibroblast–myofibroblast differentiation (FMD) is a critical cellular phenotype during the occurrence and deterioration of PF [ 141 , 142 , 143 ]. FMD can increase with an elevated level of ROS in fibroblasts under oxidative stress.…”

“…Compared with Nrf2 knockdown, Nrf2 activation increased antioxidant capacity and myofibroblast dedifferentiation in IPF fibroblasts [ 147 ]. The activation of Nrf2 by dimethyl itaconate 13 can protect against TGF-β1-induced FMD via the ROS/TXNIP signaling pathway and inhibit TXNIP-mediated FMD in PF [ 141 ]. Tanshinone IIA inhibited myofibroblast activation, rebalanced Nrf2-NOX4, and limited glutaminolysis in myofibroblast proliferation by activating the Nrf2/GSH signaling pathway [ 63 ].…”

“…It has been demonstrated that itaconate directly modifies 151, 257, 288, 273, and 297 on the protein Keap1 via alkylation of cysteine residues enabling Nrf2 to increase the expression of downstream antioxidant and anti-inflammatory genes [ 161 ]. Dimethyl itaconate (DMI), a cell-permeable itaconate derivative synthesized in vitro, was reported to protect against PF via activating Nrf2 and inhibiting thioredoxin-interacting protein (TXNIP) expression, thereby restraining TXNIP-mediated FMD [ 141 ]. Collectively, itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and control the severity of PF [ 161 , 162 , 163 ].…”

COX-2/sEH Dual Inhibitor PTUPB Attenuates Epithelial-Mesenchymal Transformation of Alveolar Epithelial Cells via Nrf2-Mediated Inhibition of TGF-β1/Smad Signaling

“…Nrf2 balances not only oxidative stress but also has negative effects on TGF- β 1-mediated profibrotic signal transduction [ 14 , 15 ]. Previous studies have shown that Nrf2 plays an important role in preventing lung inflammation and fibrosis [ 16 , 17 ]. These results indicate that strategies targeting Nrf2 have antipulmonary fibrosis potential.…”