Nicotine and its metabolite cotinine target MD2 and inhibit TLR4 signaling.
Nicotine and its metabolite cotinine target MD2 and inhibit TLR4 signaling.
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尼古丁及其代谢物可替宁靶向 MD2 并抑制 TLR4 信号传导。
DOI：
10.1016/j.xinn.2021.100111
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发表时间：
2021-05-28
期刊：
影响因子：
--
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Li H;Peng Y;Lin C;Zhang X;Zhang T;Wang Y;Li Y;Wu S;Wang H;Hutchinson MR;Watkins LR;Wang X
尼古丁是烟草的主要生物碱，通常被制造成香烟，属于高度成瘾的一类药物。尼古丁可以减轻小胶质细胞激活引起的神经炎症。然而，尼古丁抗炎作用的分子靶点尚未完全了解。考虑到精神活性物质吗啡、可卡因和甲基苯丙胺作为异生素相关分子模式，可以被先天免疫受体 Toll 样受体 4 (TLR4) 特异性感知，这里我们试图阐明先天免疫系统是否可以通过髓样分化蛋白 2 (MD2) 识别尼古丁和/或其代谢物可替宁，髓样分化蛋白 2 (MD2) 是 TLR4 的一种辅助蛋白，负责配体识别。 MD2 固有荧光滴定、表面等离子体共振和姜黄素（MD2 探针）竞争性置换结合测定表明，尼古丁和可替宁均以相似的亲和力靶向 MD2 的脂多糖（LPS；TLR4 激动剂）结合袋。细胞热位移测定表明，尼古丁结合增加，而可替宁结合减少，MD2 稳定性。这些生物物理结合结果得到了计算机模拟的进一步支持。与靶向 MD2 一致，尼古丁和可替宁均可抑制 LPS 诱导的一氧化氮和肿瘤坏死因子 α (TNF-α) 的产生，并阻断小胶质细胞的激活。泛烟碱乙酰胆碱受体 (nAChR) 抑制剂和 nAChR 的 RNAi 均不能消除尼古丁和可替宁诱导的神经炎症的抑制作用。这些数据表明，在 BV-2 细胞中测试的浓度下，尼古丁和可替宁对 TLR4 的抑制作用独立于经典神经元 nAChR，并验证 MD2 是尼古丁和可替宁抑制先天免疫的直接靶标。尼古丁和可替宁与小胶质细胞中的 MD2 结合 尼古丁和可替宁抑制促炎因子的表达 小胶质细胞中尼古丁和可替宁的活性不依赖于 nAChR
Nicotine is the principal alkaloid of tobacco often manufactured into cigarettes and belongs to a highly addictive class of drugs. Nicotine attenuates the neuroinflammation induced by microglial activation. However, the molecular target(s) underlying anti-inflammatory action of nicotine has not been fully understood. Considering the psychoactive substances morphine, cocaine, and methamphetamine act as xenobiotic-associated molecular patterns and can be specifically sensed by the innate immune receptor Toll-like receptor 4 (TLR4), here we sought to delineate whether nicotine and/or its metabolite cotinine may be recognized by the innate immune system via myeloid differentiation protein 2 (MD2), an accessory protein of TLR4 that is responsible for ligand recognition. MD2-intrinsic fluorescence titrations, surface plasmon resonance, and competitive displacement binding assays with curcumin (MD2 probe) demonstrated that both nicotine and cotinine targeted the lipopolysaccharide (LPS; TLR4 agonist) binding pocket of MD2 with similar affinities. The cellular thermal shift assay indicated that nicotine binding increased, while cotinine binding decreased, MD2 stability. These biophysical binding results were further supported by in silico simulations. In keeping with targeting MD2, both nicotine and cotinine inhibited LPS-induced production of nitric oxide and tumor necrosis factor alpha (TNF-α) and blocked microglial activation. Neither a pan nicotinic acetylcholine receptor (nAChR) inhibitor nor RNAi for nAChRs abolished the suppressive effect of nicotine- and cotinine-induced neuroinflammation. These data indicate that TLR4 inhibition by nicotine and cotinine at the concentrations tested in BV-2 cells is independent of classic neuronal nAChRs and validate that MD2 is a direct target of nicotine and cotinine in the inhibition of innate immunity. Nicotine and cotinine bind to MD2 in microglia cell Nicotine and cotinine inhibit the expression of pro-inflammatory factors The activity of nicotine and cotinine in microglia is independent of nAChRs
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