Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, China.
Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.
Dev Comp Immunol. 2020 Jul;108:103690. doi: 10.1016/j.dci.2020.103690. Epub 2020 Mar 25.
Notch signaling, an evolutionarily conserved signal pathway has emerged as a key signal pathway to regulate host immune response but the contribution of Notch signaling to immune response in pigs remains unknown. Infection of porcine alveolar macrophages (PAM) with porcine reproductive and respiratory syndrome virus (PRRSV) triggers expression of Jagged1 mRNA, suggesting that Notch signaling might play a role in the immune response to PRRSV infection. To further explore it, we examined the expression profile of Notch molecules in PAM following a highly pathogenic PRRSV (HP-PRRSV) strain infection. We demonstrated that HP-PRRSV infection resulted in the induction of Notch ligands (Jagged1, Dll3, Dll4), the transcription factor RBP-J, and the target gene Hes1, consistent with activation of Notch signaling. Next, using DAPT treatment and the knockdown of RBP-J illustrated that inhibition of activation of Notch signaling attenuated induction of the inflammatory cytokines (TNF-α and IL-1β) instead of viral replication in PAM during HP-PRRSV infection. Furthermore, the knockdown of Jagged1, the most induced ligand not only inhibited activation of Notch signaling, but also reduced the expression of inflammatory cytokines without any influence in viral replication. Moreover, our data revealed that several signaling including NF-κB, MAPK and Notch signaling contributed to the induction of Jagged1 in PAM during HP-PRRSV infection. In summary, these findings reveal that Notch as an important signaling pathway could contribute to the regulation of inflammatory response induced by HP-PRRSV infection.
Notch 信号通路是一种进化上保守的信号通路，已成为调节宿主免疫反应的关键信号通路，但 Notch 信号通路对猪免疫反应的贡献尚不清楚。猪肺泡巨噬细胞（PAM）感染猪繁殖与呼吸综合征病毒（PRRSV）会触发 Jagged1 mRNA 的表达，表明 Notch 信号通路可能在 PRRSV 感染的免疫反应中发挥作用。为了进一步探索这一点，我们研究了高致病性 PRRSV（HP-PRRSV）株感染后 PAM 中 Notch 分子的表达谱。我们证明 HP-PRRSV 感染导致 Notch 配体（Jagged1、Dll3、Dll4）、转录因子 RBP-J 和靶基因 Hes1 的诱导，这与 Notch 信号通路的激活一致。接下来，使用 DAPT 处理和 RBP-J 的敲低表明，在 HP-PRRSV 感染期间，抑制 Notch 信号通路的激活可减弱促炎细胞因子（TNF-α和 IL-1β）的诱导，而不是病毒复制。此外，最诱导的配体 Jagged1 的敲低不仅抑制了 Notch 信号通路的激活，而且减少了促炎细胞因子的表达，而对病毒复制没有任何影响。此外，我们的数据表明，几种信号通路，包括 NF-κB、MAPK 和 Notch 信号通路，有助于 HP-PRRSV 感染期间 PAM 中 Jagged1 的诱导。总之，这些发现表明 Notch 作为一种重要的信号通路，可能有助于调节 HP-PRRSV 感染引起的炎症反应。
