Abstract
ABSTRACTNeutrophilic inflammation is essential for defending against invading pathogens, but can also be detrimental in many clinical settings. The hematopoietic-specific small Rho-GTPase Rac2 regulates multiple pathways that are essential for neutrophil activation, including adhesion, migration, degranulation and production of reactive oxygen species. This study tested the hypothesis that partially suppressing rac2 in zebrafish neutrophils by using a microRNA (miRNA) would inhibit neutrophil migration and activation, which would reduce the immunological damage caused by systemic inflammation. We have generated a transgenic zebrafish line that overexpresses microRNA-722 (miR-722) in neutrophils. Neutrophil motility and chemotaxis to tissue injury or infection are significantly reduced in this line. miR-722 downregulates the transcript level of rac2 through binding to seed-matching sequence in the rac2 3′UTR. Furthermore, miR-722-overexpressing larvae display improved outcomes in both sterile and bacterial systemic models, which correlates with a robust upregulation of the anti-inflammatory cytokines in the whole larvae and isolated neutrophils. Finally, an miR-722 mimic protects zebrafish from lethal lipopolysaccharide challenge. Together, these results provide evidence for and the mechanism of an anti-inflammatory miRNA that restrains detrimental systemic inflammation.
Highlights
How to dampen immune activation is a major challenge in modern medicine
This study tested the hypothesis that partially suppressing rac2 in neutrophils with a microRNA would inhibit neutrophil migration and activation, which will reduce the immunological damage caused by systemic inflammation
To test the efficacy of microRNAs as next-generation therapeutics that would restrain neutrophil migration and inflammation, we looked into microRNAs that can suppress rac2 expression
Summary
How to dampen immune activation is a major challenge in modern medicine. Neutrophils are the most abundant white blood cells in the circulation and the first line of defense against infections. Recent evidence suggests that neutrophils, in addition to mediating acute inflammation, are a critical regulator of the inflammatory landscape. They live longer than previously recognized (Pillay et al, 2010). They initiate (Sreeramkumar et al, 2014), disseminate (Woodfin et al, 2011), and critically regulate the magnitude of inflammation (Warnatsch et al, 2015) while bridging innate and adaptive immunity (Abi Abdallah et al, 2011; Lim et al, 2015) in both sterile inflammation and infection. There is an urgent need to develop antineutrophil therapies that would benefit a diverse population suffering from inflammatory ailments
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