Zhou Min, Zhang Yadi, Chen Xulin, Zhu Jianjun, Du Min, Zhou Liang, Zhang Ling, Wang Wei, Sun Gengyun
Department of Respiratory Medicine, The First Affiliated Hospital of Anhui Medical University, JiXi Road 218, Hefei, 230022, Anhui, People's Republic of China.
Immunol Res. 2015 May;62(1):95-105. doi: 10.1007/s12026-015-8639-z.
PTEN is a multifunctional phosphatase that regulates immune responses through a PI3K/Akt signaling cascade. HMGB1 plays an important role in the initiation of innate immune responses to induce acute lung injury (ALI). This study was designed to investigate the role of PTEN/Foxo1 signaling in the regulation of in vivo and in vitro innate immune responses in ALI. Using a mouse model of ALI, wild-type (WT) and myeloid-specific PTEN knockout (PTEN(M-KO)) mice were instilled with a recombinant HMGB1 (rHMGB1) or PBS. In some experiments, Foxo1 siRNA or non-specific siRNA was injected into mice 6 h prior to rHMGB1 instillation into lung. We found that rHMGB1 treatment in WT mice increased the expression of PTEN, Foxo1, TLR4, and NF-κB in alveolar macrophages from WT mice. However, macrophage-specific PTEN ablation resulted in reduced Foxo1 and TLR4 while increasing β-catenin (Ser552) and Akt (Ser473) phosphorylation in these cells. Knockdown of Foxo1 with siRNA administration in WT mice ameliorated lung injury and inhibited myeloperoxidase activity followed by rHMGB1 treatment, which was accompanied by decreased mRNA expression coding for TNF-α, IL-1β, MIP2, and IP-10. Moreover, Foxo1 knockdown inhibited the expression of TLR4-dependent IRF3 and IFN-β both in vitro and in vivo. These results demonstrate that PTEN/Foxo1 signaling is critical for triggering HMGB1-mediated innate TLR4 activation during ALI. By identifying the molecular signaling pathways within innate immune system, our studies provide the potential therapeutic targets for ALI.
PTEN是一种多功能磷酸酶，通过PI3K/Akt信号级联反应调节免疫反应。HMGB1在引发先天性免疫反应以诱导急性肺损伤（ALI）中起重要作用。本研究旨在探讨PTEN/Foxo1信号在ALI体内和体外先天性免疫反应调节中的作用。使用ALI小鼠模型，向野生型（WT）和髓系特异性PTEN基因敲除（PTEN（M-KO））小鼠滴注重组HMGB1（rHMGB1）或PBS。在一些实验中，在向小鼠肺内滴注rHMGB1前6小时，将Foxo1 siRNA或非特异性siRNA注入小鼠体内。我们发现，WT小鼠经rHMGB1处理后，WT小鼠肺泡巨噬细胞中PTEN、Foxo1、TLR4和NF-κB的表达增加。然而，巨噬细胞特异性PTEN缺失导致这些细胞中Foxo1和TLR4减少，同时β-连环蛋白（Ser552）和Akt（Ser473）磷酸化增加。在WT小鼠中给予siRNA敲低Foxo1可改善rHMGB1处理后的肺损伤并抑制髓过氧化物酶活性，同时伴有编码TNF-α、IL-1β、MIP2和IP-10的mRNA表达降低。此外，Foxo1敲低在体外和体内均抑制了TLR4依赖性IRF3和IFN-β的表达。这些结果表明，PTEN/Foxo1信号对于在ALI期间触发HMGB1介导的先天性TLR4激活至关重要。通过识别先天性免疫系统内的分子信号通路，我们的研究为ALI提供了潜在的治疗靶点。
