Hsu Alan Y, Wang Tianqi, Syahirah Ramizah, Liu Sheng, Li Kailing, Zhang Weiwei, Wang Jiao, Cao Ziming, Tian Simon, Matosevic Sandro, Staiger Christopher J, Wan Jun, Deng Qing
Department of Biological Sciences, Purdue University, West Lafayette, IN, United States.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States.
Front Immunol. 2022 Mar 4;13:756034. doi: 10.3389/fimmu.2022.756034. eCollection 2022.
Neutrophil migration and activation are essential for defense against pathogens. However, this process may also lead to collateral tissue injury. We used microRNA overexpression as a platform and discovered protein-coding genes that regulate neutrophil migration. Here we show that miR-99 decreased the chemotaxis of zebrafish neutrophils and human neutrophil-like cells. In zebrafish neutrophils, miR-99 directly targets the transcriptional factor . Inhibiting RORα, but not the closely related RORγ, reduced chemotaxis of zebrafish and primary human neutrophils without causing cell death, and increased susceptibility of zebrafish to bacterial infection. Expressing a dominant-negative form of Rorα or disrupting the locus specifically in zebrafish neutrophils reduced cell migration. At the transcriptional level, RORα regulates transmembrane signaling receptor activity and protein phosphorylation pathways. Our results, therefore, reveal previously unknown functions of miR-99 and RORα in regulating neutrophil migration and anti-microbial defense.
中性粒细胞的迁移和激活对于抵御病原体至关重要。然而，这一过程也可能导致附带的组织损伤。我们以微小RNA过表达为平台，发现了调控中性粒细胞迁移的蛋白质编码基因。在此我们表明，miR-99降低了斑马鱼中性粒细胞和人中性粒细胞样细胞的趋化性。在斑马鱼中性粒细胞中，miR-99直接靶向转录因子。抑制RORα而非密切相关的RORγ，可降低斑马鱼和原代人中性粒细胞的趋化性且不导致细胞死亡，并增加斑马鱼对细菌感染的易感性。在斑马鱼中性粒细胞中特异性表达显性负性形式的Rorα或破坏该基因座会减少细胞迁移。在转录水平上，RORα调节跨膜信号受体活性和蛋白质磷酸化途径。因此，我们的结果揭示了miR-99和RORα在调控中性粒细胞迁移和抗菌防御方面此前未知的功能。
