Laboratorio de Plasticidad Neural. Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain.
Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002, Madrid, Spain.
Mol Neurobiol. 2017 Nov;54(9):6737-6749. doi: 10.1007/s12035-016-0142-6. Epub 2016 Oct 15.
The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is a neuroprotective agent in various animal models of neuropathologies. We have previously shown the anti-inflammatory properties of TUDCA in an animal model of acute neuroinflammation. Here, we present a new anti-inflammatory mechanism of TUDCA through the regulation of transforming growth factor β (TGFβ) pathway. The bacterial lipopolysaccharide (LPS) was injected intravenously (iv) on TGFβ reporter mice (Smad-binding element (SBE)/Tk-Luc) to study in their brains the real-time activation profile of the TGFβ pathway in a non-invasive way. The activation of the TGFβ pathway in the brain of SBE/Tk-Luc mice increased 24 h after LPS injection, compared to control animals. This activation peak increased further in mice treated with both LPS and TUDCA than in mice treated with LPS only. The enhanced TGFβ activation in mice treated with LPS and TUDCA correlated with both an increase in TGFβ3 transcript in mouse brain and an increase in TGFβ3 immunoreactivity in microglia/macrophages, endothelial cells, and neurons. Inhibition of the TGFβ receptor with SB431542 drug reverted the effect of TUDCA on microglia/macrophages activation and on TGFβ3 immunoreactivity. Under inflammatory conditions, treatment with TUDCA enhanced further the activation of TGFβ pathway in mouse brain and increased the expression of TGFβ3. Therefore, the induction of TGFβ3 by TUDCA might act as a positive feedback, increasing the initial activation of the TGFβ pathway by the inflammatory stimulus. Our findings provide proof-of-concept that TGFβ contributes to the anti-inflammatory effect of TUDCA under neuroinflammatory conditions.
牛磺熊脱氧胆酸（TUDCA）是各种神经病理学动物模型中的神经保护剂。我们之前已经在急性神经炎症的动物模型中显示了 TUDCA 的抗炎特性。在这里，我们通过转化生长因子 β（TGFβ）途径的调节提出了 TUDCA 的一种新的抗炎机制。通过静脉内（iv）注射细菌脂多糖（LPS）于 TGFβ报告小鼠（Smad 结合元件（SBE）/Tk-Luc），以非侵入性方式研究其大脑中 TGFβ 途径的实时激活谱。与对照动物相比，LPS 注射后 24 小时，SBE/Tk-Luc 小鼠大脑中 TGFβ 途径的激活增加。与仅用 LPS 处理的小鼠相比，用 LPS 和 TUDCA 处理的小鼠中的这种激活峰进一步增加。用 LPS 和 TUDCA 处理的小鼠中 TGFβ 激活的增强与 TGFβ3 转录物在小鼠大脑中的增加以及 TGFβ3 免疫反应性在小胶质细胞/巨噬细胞、内皮细胞和神经元中的增加相关。用 SB431542 药物抑制 TGFβ 受体使 TUDCA 对小胶质细胞/巨噬细胞激活和 TGFβ3 免疫反应性的作用逆转。在炎症条件下，TUDCA 的处理进一步增强了 TGFβ 途径在小鼠大脑中的激活，并增加了 TGFβ3 的表达。因此，TUDCA 诱导的 TGFβ3 可能作为正反馈，增加炎症刺激下 TGFβ 途径的初始激活。我们的研究结果提供了概念验证，即 TGFβ 在神经炎症条件下有助于 TUDCA 的抗炎作用。
