Disulfiram blocks inflammatory TLR4 signaling by targeting MD-2.
Disulfiram blocks inflammatory TLR4 signaling by targeting MD-2.
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DOI：
10.1073/pnas.2306399120
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发表时间：
2023-08
影响因子：
11.1
通讯作者：
Liu, Xing
中科院分区：
文献类型：
--
作者：
Bai, Yang;Min, Rui;Chen, Pengcheng;Mei, Shenglin;Deng, Fan;Zheng, Zengzhang;Jiang, Cong;Miao, Rui;Wu, Zeyu;Zhang, Peng;Pan, Youdong;Lieberman, Judy;Liu, Xing
Toll样受体4（TLR 4）对病原体/损伤相关的分子模式作出响应，启动宿主先天免疫炎症反应以控制感染、组织修复和再生，而TLR 4的异常激活引起组织损伤和各种炎性疾病。因此，TLR 4信号传导是治疗TLR 4驱动的炎症性疾病的有吸引力的药物靶标。在这里，我们发现FDA批准的药物双硫仑通过修饰MD-2的半胱氨酸残基（TLR 4的关键辅因子）抑制人类和小鼠细胞中的TLR 4信号传导，并发现DSF显著改善帕金森病（PD）侵袭性小鼠模型中TLR 4介导的病理学。这项研究提出了一种治疗TLR 4介导的炎症性疾病的方法。Toll样受体4（TLR 4）对脂多糖（LPS）（革兰氏阴性菌最有效的病原体相关分子模式）的敏感性激活NF-κB和Irf 3，从而诱导炎症细胞因子和干扰素，引发强烈的炎症反应，这对宿主防御至关重要，但也可能导致严重的炎症病理，包括脓毒症。尽管TLR 4抑制是一种有吸引力的抑制过度兴奋的炎症信号传导的治疗方法，但先前鉴定的TLR 4拮抗剂尚未显示出任何临床益处。在这里，我们确定双硫仑（DSF），一种FDA批准的酒精中毒药物，作为TLR 4介导的炎症信号的特异性抑制剂。TLR 4细胞表面表达、LPS传感、二聚化和信号传导依赖于TLR 4与MD-2的结合。DSF和其他半胱氨酸反应性药物，以前被证明可以阻断LPS触发的炎性细胞死亡（焦亡），通过共价修饰MD-2的Cys 133来抑制TLR 4信号传导，MD-2是介导TLR 4传感和信号传导的关键保守残基。DSF在体外阻断LPS触发的巨噬细胞产生的炎性细胞因子、趋化因子和干扰素。在侵袭性N-甲基-4-苯基-1，2，3，6-四氢吡啶帕金森病（PD）小鼠模型中，DSF显著抑制神经炎症和多巴胺能神经元损失，并恢复运动功能。我们的研究结果确定了DSF在抑制TLR 4介导的炎症中的作用，并表明DSF和其他靶向MD-2的药物可能有助于治疗PD和其他炎症对发病机制起重要作用的疾病。
In response to pathogen/damage-associated molecular patterns, Toll-like receptor 4 (TLR4) initiates a host innate immune inflammatory response to control infection, tissue repair, and regeneration, while aberrant activation of TLR4 causes tissue damage and various inflammatory diseases. Therefore, TLR4 signaling is an attractive drug target for the treatment of TLR4-driven inflammatory disorders. Here, we showed that the FDA-approved drug disulfiram inhibits TLR4 signaling in both human and mouse cells by modifying a cysteine residue of MD-2, a critical cofactor of TLR4, and found that DSF markedly ameliorates TLR4-mediated pathology in an aggressive mouse model of Parkinson’s disease (PD). This study suggests an approach to treating TLR4-mediated inflammatory diseases. Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
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