IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy.
IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy.
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DOI：
10.3389/fphar.2021.695712
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发表时间：
2021
影响因子：
5.6
通讯作者：
Kumar A
中科院分区：
文献类型：
--
作者：
Ali M;Gupta M;Wani A;Sharma A;Abdullaha M;Kour D;Choudhary S;Bharate SB;Singh G;Kumar A
NLRP3炎症体的异常激活与多种炎症性疾病有关。自噬是调节NLRP3炎症体活性的主要机制之一。在这项研究中，我们试图通过合成化合物IIIM-941来靶向NLRP3炎症体活性。我们发现，IIIM-941通过AMPK途径诱导骨髓巨噬细胞(BMDM)和J774A.1细胞自噬，从而抑制了ATP诱导的NLRP3炎症体。有趣的是，观察到IIIM941对脂多糖诱导的促炎细胞因子肿瘤坏死因子-α和IL-6没有显示任何抑制活性。当我们试图用药物抑制剂巴菲霉素A1或使用针对AMPK的siRNA来阻断自噬时，IIIM-941的抗NLRP3活性被显著逆转。此外，我们发现IIIM-941下调NLRP3的表达，阻止ASC的寡聚，从而发挥其抗J774A.1细胞NLRP3炎症体的作用。我们在三种不同的小鼠模型上验证了IIIM-941对NLRP3的抑制活性。在三磷酸腺苷诱导的腹膜炎症模型中，IIIM-941的抗炎作用非常显著。在气囊炎症模型中，IIIM941对亚硝胺诱导的IL-1β有类似的抑制作用，但不影响肿瘤坏死因子-α和IL-6的水平。最后，在10和20 mg/kg(Bw)MSU诱导的小鼠足肿胀炎症模型上，也证实了IIIM-941的口服作用。像IIIM-941这样的化合物可以进一步探索，以开发治疗阿尔茨海默病和帕金森病等疾病的方法，在这些疾病中，自噬受阻和NLRP3激活在病理发展中发挥着关键作用。
Aberrant activation of NLRP3 inflammasome has been implicated in several inflammatory diseases. Autophagy is one of the primary mechanisms that regulate NLRP3 inflammasome activity. In this study, we attempted to target NLRP3 inflammasome activity by a synthetic compound IIIM-941. We found that IIIM-941 inhibits ATP induced NLRP3 inflammasome by induction of autophagy through AMPK pathway in bone marrow derived macrophages (BMDMs) and J774A.1 cells. It was interesting to observe that IIIM-941 did not show any inhibitory activity against LPS induced pro-inflammatory cytokines TNF-α and IL-6. The anti-NLRP3 activity of IIIM-941 was significantly reversed when we attempted to block autophagy by using either pharmacological inhibitor bafilomycin A1or by using siRNA against AMPK. Further, we found that IIIM-941 downregulated the expression of NLRP3 and prevented the oligomerization of ASC to exert its anti-NLRP3 inflammasome effect in J774A.1 cells. We validated inhibitory activity of IIIM-941 against NLRP3 in three different mice models. The anti-inflammatory effect of IIIM-941 was highly significant in ATP induced peritoneal inflammation model. IIIM-941 was similarly effective in suppressing MSU induced IL-1β in the air pouch model of inflammation without affecting the levels of TNF-α and IL-6. Finally, oral efficacy of IIIM-941 was also proved in MSU indued foot paw edema model of inflammation in mice at 10 and 20 mg/kg (b.w.). The compounds like IIIM-941 can be explored further for the development of therapies against diseases such as Alzheimer’s disease and Parkinson’s disease, where hampered autophagy and NLRP3 activation play a crucial role in the pathological development.
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影响因子：
7.3
作者：
Lukens JR;Gross JM;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
7.3
作者：
Mewshaw, RE;Edsall, RJ;Harris, HA
通讯作者：
Harris, HA
影响因子：
13.3
作者：
Cho, Mi-Hyang;Cho, Kwangmin;Yoon, Seung-Yong
通讯作者：
Yoon, Seung-Yong
影响因子：
--
作者：
Ko JH;Yoon SO;Lee HJ;Oh JY
通讯作者：
Oh JY
影响因子：
13.3
作者：
Lodder, Jasper;Denaes, Timothe;Teixeira-Clerc, Fatima
通讯作者：
Teixeira-Clerc, Fatima