Abstract
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 RAR-related orphan receptor alpha (roraa). 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 roraa 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.
Highlights
The two abundant neutrophil miRNAs, miR-223 and let-7e, were used as controls to demonstrate that this overexpression did not disrupt physiological microRNA levels. miR-99 overexpression did not affect the total neutrophil numbers in embryos (Figures 1C, D) but reduced neutrophil recruitment to either the tail injury or ear infection sites (Figures 1E–H)
We sought to determine whether miR-99 inhibits human neutrophil migration
Our current finding suggests that miR-99 overexpression or receptor a (RORa) inhibition suppresses neutrophil chemotaxis
Summary
Inflammation is essential for the restoration of tissue homeostasis after injury and infection. Neutrophils, the primary effector cells of acute inflammation, are the first to infiltrate inflammation sites. They combat disease by phagocytosing foreign particles and secreting cytokines, antimicrobial molecules, and chromatin while contributing to collateral tissue injury [1]. Neutrophils are a heterogeneous population with pro-and antiinflammatory phenotypes that cooperate to resolve inflammation [2, 3]. In line with their multifaceted roles, neutrophils contribute to dangerous, chronic inflammatory conditions in humans, including those associated with tumors, chronic obstructive pulmonary disease, arthritis, and adipose inflammation.
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