title: Regulation of neutrophil senescence by microRNAs.
abstract: Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease.
authors.affiliation: MRC Centre for Developmental and Biomedical Genetics, School of Medicine and Biomedical Science, The University of Sheffield, Sheffield, United Kingdom.
authors.forename: Jon R
authors.initials: JR
authors.lastname: Ward
authors.forename: Paul R
authors.initials: PR
authors.lastname: Heath
authors.forename: James W
authors.initials: JW
authors.lastname: Catto
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: Marta
authors.initials: M
authors.lastname: Milo
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
mesh_terms: D000199:Actins / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D018925:Chemokines / Q000235:genetics; D019295:Computational Biology; D016207:Cytokines / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D046228:Microarray Analysis; D009504:Neutrophils / Q000166:cytology*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D015854:Up-Regulation; D018631:ras Proteins / Q000235:genetics
chemical_list: D000199:Actins; D018925:Chemokines; D016207:Cytokines; D035683:MicroRNAs; D012333:RNA, Messenger; D018631:ras Proteins