College of Veterinary Medicine, Southwest University, Chongqing, 400715, China.
Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China.
Vet Res. 2024 May 7;55(1):56. doi: 10.1186/s13567-024-01296-9.
The chemokine CXCL8, also known as the neutrophil chemotactic factor, plays a crucial role in mediating inflammatory responses and managing cellular immune reactions during viral infections. Porcine reproductive and respiratory syndrome virus (PRRSV) primarily infects pulmonary alveolar macrophages (PAMs), leading to acute pulmonary infections. In this study, we explored a novel long non-coding RNA (lncRNA), termed lnc-CAST, situated within the Cxcl8 gene locus. This lncRNA was found to be highly expressed in porcine macrophages. We observed that both lnc-CAST and CXCL8 were significantly upregulated in PAMs following PRRSV infection, and after treatments with lipopolysaccharide (LPS) or lipoteichoic acid (LTA). Furthermore, we noticed a concurrent upregulation of lnc-CAST and CXCL8 expression in lungs of PRRSV-infected pigs. We then determined that lnc-CAST positively influenced CXCL8 expression in PAMs. Overexpression of lnc-CAST led to an increase in CXCL8 production, which in turn enhanced the migration of epithelial cells and the recruitment of neutrophils. Conversely, inhibiting lnc-CAST expression resulted in reduced CXCL8 production in PAMs, leading to decreased migration levels of epithelial cells and neutrophils. From a mechanistic perspective, we found that lnc-CAST, localized in the nucleus, facilitated the enrichment of histone H3K27ac in CXCL8 promoter region, thereby stimulating CXCL8 transcription in a cis-regulatory manner. In conclusion, our study underscores the pivotal critical role of lnc-CAST in regulating CXCL8 production, offering valuable insights into chemokine regulation and lung damage during PRRSV infection.
趋化因子 CXCL8，也称为中性粒细胞趋化因子，在介导病毒感染期间的炎症反应和管理细胞免疫反应方面发挥着关键作用。猪繁殖与呼吸综合征病毒（PRRSV）主要感染肺泡巨噬细胞（PAMs），导致急性肺部感染。在这项研究中，我们探索了一种新型长非编码 RNA（lncRNA），称为 lnc-CAST，位于 Cxcl8 基因座内。这种 lncRNA 在猪巨噬细胞中高度表达。我们观察到 PRRSV 感染后 PAMs 中 lnc-CAST 和 CXCL8 均显著上调，并且在 LPS 或 LTA 处理后也是如此。此外，我们注意到 PRRSV 感染猪的肺部中 lnc-CAST 和 CXCL8 的表达同时上调。然后，我们确定 lnc-CAST 对 PAMs 中 CXCL8 的表达具有正向影响。lnc-CAST 的过表达导致 CXCL8 产生增加，这反过来又增强了上皮细胞的迁移和中性粒细胞的募集。相反，抑制 lnc-CAST 的表达会导致 PAMs 中 CXCL8 产生减少，从而降低上皮细胞和中性粒细胞的迁移水平。从机制上讲，我们发现位于核内的 lnc-CAST 促进了 CXCL8 启动子区域中组蛋白 H3K27ac 的富集，从而以顺式调节方式刺激 CXCL8 的转录。总之，我们的研究强调了 lnc-CAST 在调节 CXCL8 产生中的关键作用，为 PRRSV 感染期间趋化因子调节和肺损伤提供了有价值的见解。
