Inhibition of calcium-calmodulin-dependent phosphodiesterase (PDE1) suppresses inflammatory responses.
Inhibition of calcium-calmodulin-dependent phosphodiesterase (PDE1) suppresses inflammatory responses.
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DOI：
10.1016/j.mcn.2019.103449
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Hendrick JP
中科院分区：
文献类型：
--
作者：
O'Brien JJ;O'Callaghan JP;Miller DB;Chalgeri S;Wennogle LP;Davis RE;Snyder GL;Hendrick JP
PDE 1家族的钙-钙调蛋白依赖性磷酸二酯酶（PDE）的一种新型、强效和高度特异性抑制剂ITI-214被用于研究PDE 1在炎症反应中的作用。ITI-214剂量依赖性抑制脂多糖（LPS）诱导的永生化小鼠小胶质细胞系BV 2细胞中促炎细胞因子的基因表达。使用RNA谱分析（RNA-Seq）来分析在不存在和存在LPS的情况下ITI-214对BV 2细胞转录组的影响。ITI-214被发现调节参与炎症和细胞迁移对LPS暴露的反应的基因类别。用ITI-214治疗观察到的基因表达变化不同于由具有抗炎活性的其他PDE的抑制剂（例如，PDE 4抑制剂），表明PDE 1的独特作用机制。在功能上，ITI-214通过P2 Y12受体依赖性途径抑制ADP诱导的BV 2细胞迁移，可能是由于受体活化下游cAMP和VASP磷酸化程度增加。重要的是，这种作用在体外P2大鼠小胶质细胞中重现，表明这些途径在天然小胶质细胞中是活跃的。这些研究首次证明抑制PDE 1通过影响小胶质细胞信号通路发挥抗炎作用。PDE 1抑制剂预防或抑制BV 2细胞和小胶质细胞过度炎症反应的能力为探索其在治疗与炎症和小胶质细胞增殖增加相关的神经退行性疾病如帕金森病和阿尔茨海默病中的治疗效用提供了基础。
A novel, potent, and highly specific inhibitor of calcium-calmodulin-dependent phosphodiesterases (PDE) of the PDE1 family, ITI-214, was used to investigate the role of PDE1 in inflammatory responses. ITI-214 dose-dependently suppressed lipopolysaccharide (LPS)-induced gene expression of pro-inflammatory cytokines in an immortalized murine microglial cell line, BV2 cells. RNA profiling (RNA-Seq) was used to analyze the impact of ITI-214 on the BV2 cell transcriptome in the absence and the presence of LPS. ITI-214 was found to regulate classes of genes that are involved in inflammation and cell migration responses to LPS exposure. The gene expression changes seen with ITI-214 treatment were distinct from those elicited by inhibitors of other PDEs with anti-inflammatory activity (e.g., a PDE4 inhibitor), indicating a distinct mechanism of action for PDE1. Functionally, ITI-214 inhibited ADP-induced migration of BV2 cells through a P2Y12-receptor-dependent pathway, possibly due to increases in the extent of cAMP and VASP phosphorylation downstream of receptor activation. Importantly, this effect was recapitulated in P2 rat microglial cells in vitro, indicating that these pathways are active in native microglial cells. These studies are the first to demonstrate that inhibition of PDE1 exerts anti-inflammatory effects through effects on microglia signaling pathways. The ability of PDE1 inhibitors to prevent or dampen excessive inflammatory responses of BV2 cells and microglia provides a basis for exploring their therapeutic utility in the treatment of neurodegenerative diseases associated with increased inflammation and microglia proliferation such as Parkinson's disease and Alzheimer's disease.
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