Dual Anti-inflammatory Actions of a Novel Retinoid X Receptor Agonist Derived from a Natural Compound in Microglial Cells.

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Koji Tomita, Ken-Ichi Nakashima, Eiji Yamaguchi, Akichika Itoh, Makoto Inoue
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Abstract

Microglia-mediated neuroinflammation plays a critical role in the onset and progression of Alzheimer's disease. In a previous study, we synthesized 6-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid (6OHA) based on the structure of magnaldehyde B, a natural compound that our group identified as a retinoid X receptor (RXR) agonist. However, its potential effects on inflammation in microglial cells remain unexplored. In this study, we specifically focused on the early-phase inflammatory responses to lipopolysaccharide (LPS) and evaluated the inhibitory effects of 6OHA on BV-2 microglial cells following 2 h of LPS exposure. Similar to the existing RXR agonist bexarotene (Bex), 6OHA treatment (0.1 and 1 μM) resulted in a dose-dependent decrease in the mRNA levels of proinflammatory mediators, including interleukin-1β (Il1b), Il6, and inducible nitric oxide synthase. However, these effects on proinflammatory mediators were effectively abolished by the RXR antagonist UVI3003. Additionally, 6OHA promoted M2 microglia polarization after 24 h of treatment, as evidenced by the increased mRNA levels of the M2 marker genes arginase-1 (Arg1), C-C motif chemokine ligand 6 (Ccl6), Ccl17, and Ccl22. Notably, 6OHA induced a distinct set of M2 microglial markers compared with IL-4, a known M2 microglial inducer. Furthermore, the transcription of Arg1, a key M2 marker gene, is regulated by retinoic acid receptor/RXR heterodimers and the IL-4 signaling pathway. Collectively, 6OHA suppressed the early inflammatory responses to LPS and promoted M2 microglial polarization through a mechanism distinct from that of IL-4. Therefore, RXR agonists, including 6OHA and Bex, may exhibit dual anti-inflammatory effects and serve as novel modulators of neuroinflammation.

天然化合物衍生的新型类视黄醇X受体激动剂在小胶质细胞中的双重抗炎作用。
小胶质细胞介导的神经炎症在阿尔茨海默病的发病和进展中起着关键作用。在之前的一项研究中,我们基于magnaldehyde B的结构合成了6-羟基-3'-丙基-[1,1'-联苯]-3-propanoic acid (6OHA),该天然化合物被我们的团队鉴定为类视黄醛X受体(RXR)激动剂。然而,其对小胶质细胞炎症的潜在影响仍未被探索。在这项研究中,我们特别关注了脂多糖(LPS)的早期炎症反应,并评估了6OHA在LPS暴露2小时后对BV-2小胶质细胞的抑制作用。与现有的RXR激动剂bexarotene (Bex)类似,6OHA处理(0.1 μM和1 μM)导致促炎介质mRNA水平呈剂量依赖性降低,包括白细胞介素-1β (Il1b), Il6和诱导型一氧化氮合酶。然而,这些对促炎介质的作用被RXR拮抗剂UVI3003有效地消除。此外,6OHA在24 h后促进M2小胶质细胞极化,M2标记基因精氨酸酶-1 (Arg1)、C-C基序趋化因子配体6 (Ccl6)、Ccl17和Ccl22 mRNA水平升高。值得注意的是,与已知的M2小胶质诱导剂IL-4相比,6OHA诱导了一组不同的M2小胶质标记物。此外,M2关键标记基因Arg1的转录受视黄酸受体/RXR异源二聚体和IL-4信号通路的调控。总的来说,6OHA通过不同于IL-4的机制抑制了对LPS的早期炎症反应,促进了M2小胶质细胞的极化。因此,包括6OHA和Bex在内的RXR激动剂可能具有双重抗炎作用,并可作为神经炎症的新型调节剂。
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来源期刊
CiteScore
3.50
自引率
5.00%
发文量
247
审稿时长
2 months
期刊介绍: Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.) began publication in 1978 as the Journal of Pharmacobio-Dynamics. It covers various biological topics in the pharmaceutical and health sciences. A fourth Society journal, the Journal of Health Science, was merged with Biol. Pharm. Bull. in 2012. The main aim of the Society’s journals is to advance the pharmaceutical sciences with research reports, information exchange, and high-quality discussion. The average review time for articles submitted to the journals is around one month for first decision. The complete texts of all of the Society’s journals can be freely accessed through J-STAGE. The Society’s editorial committee hopes that the content of its journals will be useful to your research, and also invites you to submit your own work to the journals.
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