KLF2 regulates neutrophil migration by modulating CXCR1 and CXCR2 in asthma
KLF2 regulates neutrophil migration by modulating CXCR1 and CXCR2 in asthma
复制标题
KLF2 通过调节哮喘中的 CXCR1 和 CXCR2 来调节中性粒细胞迁移
DOI：
10.1016/j.bbadis.2020.165920
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发表时间：
2020-12-01
影响因子：
6.2
通讯作者：
Wang，Zi
中科院分区：
文献类型：
--
作者：
Zhu，Li-ming;Zeng，Dan;Wang，Zi
中性粒细胞是哮喘免疫发病机制中的关键炎症细胞。中性粒细胞迁移可通过CXC趋化因子（如IL-8）激活CXCR1和CXCR2受体而启动。虽然已经发现转录因子KLF2通过抑制几种趋化因子受体来维持T细胞的迁移模式，但KLF2是否可以通过调节CXCR1和CXCR2来调节中性粒细胞的迁移尚不清楚。本研究旨在探讨KLF2、CXCR1和CXCR2在哮喘中性粒细胞迁移中的功能，并确定KLF2对CXCR1/2的调控作用。我们发现随着哮喘的加重，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KLF2 mRNA和蛋白水平逐渐降低。而CXCR1和CXCR2的表达与KLF2呈负相关。体外敲除KLF2显著增加hl -60驱动的中性粒细胞样细胞的迁移，同时CXCR1和CXCR2 mRNA和蛋白表达水平升高。综上所述，我们的研究结果表明，KLF2的降低通过促进中性粒细胞迁移而加剧哮喘的进展，这与CXCR1和CXCR2的转录上调有关。KLF2和/或CXCR1/2表达水平可能是哮喘严重程度的一个指标。
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.