School of Life and Pharmaceutical Sciences (LPS), Panjin Institute of Industrial Technology (PIIT), Liaoning Key Laboratory of Chemical Additive Synthesis and Separation, Dalian University of Technology, Panjin 124221, China.
State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, School of Chemical Engineering, Dalian University of Technology, Dalian 116023, China.
Molecules. 2022 Dec 23;28(1):107. doi: 10.3390/molecules28010107.
Macrophages secrete a variety of pro-inflammatory cytokines in response to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) but abnormal release of cytokines unfortunately promotes cytokine storms. Dimethyl fumarate (DMF), an FDA-approved drug for multiple sclerosis (MS) treatment, has been found as an effective therapeutic agent for resolution. In this study, the anti-inflammatory effect of DMF was found to correlate to selenoprotein thioredoxin reductase 1 (TXNRD1). DMF irreversibly modified the Sec residue and C-terminal catalytic cysteine residues of TXNRD1 in a time- and dose-dependent manner. In LPS-stimulated RAW 264.7 cells, cellular TXNRD activity was increased through up-regulation of the protein level and DMF inhibited TXNRD activity and the nitric oxide (NO) production of RAW 264.7 cells. Meanwhile, the inhibition of TXNRD1 by DMF would contribute to the redox regulation of inflammation and promote the nuclear factor erythroid 2-related factor 2 (NRF2) activation. Notably, inhibition of cellular TXNRD1 by auranofin or TRi-1 showed anti-inflammatory effect in RAW 264.7 cells. This finding demonstrated that targeting TXNRD1 is a potential mechanism of using immunometabolites for dousing inflammation in response to pathogens and highlights the potential of TXNRD1 inhibitors in immune regulation.
巨噬细胞在受到病原体相关分子模式（PAMPs）和损伤相关分子模式（DAMPs）的刺激后会分泌多种促炎细胞因子，但细胞因子的异常释放会促进细胞因子风暴的发生。富马酸二甲酯（DMF）是一种已被 FDA 批准用于治疗多发性硬化症（MS）的药物，被发现是一种有效的消退治疗药物。在本研究中，发现 DMF 的抗炎作用与硒蛋白硫氧还还原酶 1（TXNRD1）有关。DMF 可不可逆地修饰 TXNRD1 的 Sec 残基和 C 端催化半胱氨酸残基，具有时间和剂量依赖性。在 LPS 刺激的 RAW 264.7 细胞中，通过上调蛋白水平增加细胞 TXNRD 活性，DMF 抑制 TXNRD 活性和 RAW 264.7 细胞的一氧化氮（NO）产生。同时，DMF 对 TXNRD1 的抑制作用有助于炎症的氧化还原调节，并促进核因子红细胞 2 相关因子 2（NRF2）的激活。值得注意的是，通过金诺芬或 TRi-1 抑制细胞 TXNRD1 在 RAW 264.7 细胞中表现出抗炎作用。这一发现表明，靶向 TXNRD1 是利用免疫代谢物扑灭病原体引起的炎症的潜在机制，并强调了 TXNRD1 抑制剂在免疫调节中的潜力。
