Department of Geriatric Respiratory Medicine, Hunan Provincial People's Hospital, The First-Affiliated Hospital of Hunan Normal University, Changsha 410016, China; Institute of Respiratory Disease, Hunan Provincial People's Hospital, The First-Affiliated Hospital of Hunan Normal University, Changsha 410016, China.
Institute of Respiratory Disease, Hunan Provincial People's Hospital, The First-Affiliated Hospital of Hunan Normal University, Changsha 410016, China.
Biochim Biophys Acta Mol Basis Dis. 2020 Dec 1;1866(12):165920. doi: 10.1016/j.bbadis.2020.165920. Epub 2020 Aug 12.
Neutrophils are key inflammatory cells in the immunopathogenesis of asthma. Neutrophil migration can be initiated through activation of the CXCR1 and CXCR2 receptors by CXC chemokines, such as IL-8. Although transcription factor KLF2 has been found to maintain T cell migration patterns through repression of several chemokine receptors, whether KLF2 can regulate neutrophil migration via modulation of CXCR1 and CXCR2 is unknown. Here, we aimed to explore the functions of KLF2, CXCR1 and CXCR2 in neutrophil migration in asthma and to establish a regulatory role of KLF2 for CXCR1/2. We demonstrate that with asthma aggravation, the percentages and migration rates of peripheral blood neutrophils gradually increased in asthmatic patients and the guinea pig asthma model. Correspondingly, both the KLF2 mRNA and protein levels in neutrophils were gradually reduced. While CXCR1 and CXCR2 expression was negatively correlated with KLF2. In vitro knockdown of KLF2 dramatically increased the migration of HL-60-drived neutrophil-like cells, which was accompanied by an increase in the CXCR1 and CXCR2 mRNA and protein expression levels. Taken together, our results indicate that decreased KLF2 aggravates asthma progression by promoting neutrophil migration, which is associated with the transcriptional upregulation of CXCR1 and CXCR2. The KLF2 and/or CXCR1/2 expression levels may represent an indicator of asthma severity.
中性粒细胞是哮喘免疫发病机制中的关键炎症细胞。中性粒细胞的迁移可以通过 CXC 趋化因子（如 IL-8）激活 CXCR1 和 CXCR2 受体来启动。虽然转录因子 KLF2 已被发现通过抑制几种趋化因子受体来维持 T 细胞迁移模式，但 KLF2 是否可以通过调节 CXCR1 和 CXCR2 来调节中性粒细胞迁移尚不清楚。在这里，我们旨在探讨 KLF2、CXCR1 和 CXCR2 在哮喘中性粒细胞迁移中的作用，并确定 KLF2 对 CXCR1/2 的调节作用。我们证明，随着哮喘的加重，哮喘患者和豚鼠哮喘模型外周血中性粒细胞的百分比和迁移率逐渐增加。相应地，中性粒细胞中的 KLF2 mRNA 和蛋白水平也逐渐降低。而 CXCR1 和 CXCR2 的表达与 KLF2 呈负相关。体外敲低 KLF2 可显著增加 HL-60 诱导的中性粒细胞样细胞的迁移，同时 CXCR1 和 CXCR2 的 mRNA 和蛋白表达水平也增加。总之，我们的结果表明，KLF2 的减少通过促进中性粒细胞迁移加重哮喘进展，这与 CXCR1 和 CXCR2 的转录上调有关。KLF2 和/或 CXCR1/2 的表达水平可能是哮喘严重程度的一个指标。
