Institute of Neuroanatomy, RWTH Aachen University, Aachen, Germany.
Department of Neurology, University Hospital of Münster, Münster, Germany.
J Steroid Biochem Mol Biol. 2018 Oct;183:18-26. doi: 10.1016/j.jsbmb.2018.05.003. Epub 2018 May 15.
Clinical and animal model studies have demonstrated the neuroprotective and anti-inflammatory effects of 17beta-estradiol (E2) and progesterone (P) in different disease models of the central nervous system (CNS) including ischemic stroke. Inflammasomes are involved in the interleukin-1 beta (IL1beta) maturation, in particular, NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and the active caspase-1 (Casp1) form. Recently, we showed that administration of E2 or P selectively regulated these components after experimental ischemic stroke in rats. Therefore, we investigated the impact of E2 and P on the NLRP3/ASC/Casp1 axis in the murine microglia-like cell line BV-2 cells and primary astrocytes after short-term in vitro hypoxia. The inflammatory cytokine IL1beta but not IL18 was increased after short-term hypoxia in astroglia and BV-2 cells. The same applied to NLPR3 and ASC. Casp1 activity was also elevated in astroglia and BV-2 cells after hypoxia. The administration of E2 or P selectively dampened IL1beta, ASC and NLRP3 expression mainly in BV-2 cells. Both steroid hormones failed to reduce Casp1 activity after hypoxia. We conclude that E2- and P-mediated anti-inflammatory mechanisms occur upstream of Casp1 through the regulation of NLRP3 and its adaptor ASC.
临床和动物模型研究表明，17β-雌二醇（E2）和孕酮（P）在包括缺血性中风在内的中枢神经系统（CNS）的不同疾病模型中具有神经保护和抗炎作用。炎性小体参与白细胞介素-1β（IL1β）的成熟，特别是 NLRP3、衔接蛋白凋亡相关斑点样蛋白含有 CARD（ASC）和活性半胱氨酸蛋白酶-1（Casp1）。最近，我们表明，在大鼠实验性缺血性中风后，E2 或 P 的给药选择性调节这些成分。因此，我们研究了 E2 和 P 对短暂体外缺氧后小鼠小胶质细胞样细胞系 BV-2 细胞和原代星形胶质细胞中 NLRP3/ASC/Casp1 轴的影响。在星形胶质细胞和 BV-2 细胞中，短期缺氧后炎性细胞因子 IL1β而不是 IL18 增加。NLRP3 和 ASC 也是如此。缺氧后 Casp1 活性在星形胶质细胞和 BV-2 细胞中也升高。E2 或 P 的给药选择性地下调了主要在 BV-2 细胞中 IL1β、ASC 和 NLRP3 的表达。两种类固醇激素在缺氧后均不能降低 Casp1 活性。我们得出结论，E2 和 P 介导的抗炎机制通过调节 NLRP3 和其衔接蛋白 ASC 发生在 Casp1 之前。
