TonEBP Suppresses the HO-1 Gene by Blocking Recruitment of Nrf2 to Its Promoter

Abstract

TonEBP is a key transcriptional activator in macrophages with an M1 phenotype. High expression of TonEBP is associated with many inflammatory diseases. Heme oxygenase-1 (HO-1), a stress-inducible protein, is induced by various oxidative and inflammatory signals, and its expression is regarded as an adaptive cellular response to inflammation and oxidative injury. Here, we show that TonEBP suppresses expression of HO-1 by blocking Nrf2 binding to the HO-1 promoter, thereby inducing polarization of macrophages to the M1 phenotype. Inhibition of HO-1 expression or activity significantly reduced the inhibitory responses on M1 phenotype and stimulatory effects on M2 phenotype by TonEBP knockdown. Additional experiments showed that HO-1 plays a role in the paracrine anti-inflammatory effects of TonEBP knockdown in macrophages. Identification of HO-1 as a downstream effector of TonEBP provides new possibilities for improved therapeutic approaches to inflammatory diseases.

<p>Exosomes Derived from MicroRNA-146a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Alleviate Intracerebral Hemorrhage by Inhibiting Neuronal Apoptosis and Microglial M1 Polarization</p>

“…41 In another study, NFAT5 suppresses the macrophage M2 phenotype. 47 Thus, it can be assumed that BMSCs-miR -146a-5p-Exos administration elevates microglial M2 polarization by suppressing the expression of IRAK1 and NFAT5. The related M2 polarization will be studied in the future investigations.…”

Transcriptional Regulator TonEBP Mediates Oxidative Damages in Ischemic Kidney Injury

“…Initially discovered as a DNA binding transcriptional enhancer in response to hypertonicity [9], TonEBP (tonicity-responsive enhancer binding protein) is a pleiotropic transcriptional regulator—both as a transcriptional cofactor [10,11] and a transcriptional suppressor [12,13,14,15]. In addition, TonEBP is a stress protein that is induced by a variety of stresses including hyperglycemia [16], excess calorie intake or hyperlipidemia [15], inflammation [10,17,18], and hypoxia [19].…”

TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy

“…Pro-inflammatory M1 macrophages, CD4 + T lymphocytes, and CD8 + cytotoxic T-cells are considered to be the major cell types that promote the development of type 1 DM [ 81 , 82 ], while M2 macrophages, which function in wound healing and tissue remodeling, promote β-cell proliferation by inducing crosstalk among different cell types [ 83 ]. Notably, a depletion of TonEBP in macrophages suppresses the polarization of M1 macrophages [ 30 , 84 ] and activates the polarization of M2 macrophages [ 29 , 85 ]. More importantly, the downregulation of TonEBP attenuates pathological CD4 + T cell differentiation and autoimmunity [ 19 , 86 ].…”

“…The induction and activation of TonEBP in response to autoimmune and metabolic stresses are implicated in immunometabolic diseases such as rheumatoid arthritis [ 18 , 19 ], atherosclerosis [ 20 ], hepatocellular carcinoma [ 21 ], obesity [ 22 ], and DM [ 22 , 23 ]. By contrast, TonEBP-mediated responses to hypertonicity [ 16 , 24 , 25 , 26 , 27 ], bacterial infection [ 28 , 29 , 30 ], and genotoxic stress [ 31 ] have protective or homeostatic functions. Although the function of TonEBP in the responses to a range of cellular stresses is well-established, its role in the determination of cell fate under ER stress remains to be elucidated.…”