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I.A. de la Rosa et al.
Among the miRNA altered in RA neutrophils, we demonstrate that the miRNA-223, miRNA-126 and miRNA-148 are involved in the modulation of genes involved in processes such as migration, inflammation and cell survival in neutrophils. Finally, biological thera- pies would be able to improve miRNA processing, upreg- ulating the levels of miRNA, which might reduce the acti- vation of the neutrophil.
Beyond the regulation of miRNA in RA neutrophils, there are likely other epigenetic mechanisms that poten- tially contribute to the abnormal activation of these cells in RA context, such as chromatin modification.
This study has several limitations: it is a cross-sectional study in which consecutive patients from standard clini- cal practice were recruited. These patients were treated with standard therapy, including immunosuppressants, at the time of the sample and clinical detail collection. Thus, the effects of specific treatments on the expression levels of miRNA or the molecules involved in their biogenesis in neutrophils was not analyzed.
The isolation of neutrophils with anti-CD15 microbeads is a further potential limitation of this work, however, up to date no unique method for the isolation of neutrophil isolation has been accepted worldwide and differing techniques have shown either some activation or functional impairment of the cells and the presence of small amounts of contaminating cells.
Choosing an adequate method to isolate neutrophils from SF is thus challenging. In our hands, after testing a variety of potential priming/ activation techniques and the percentage of contaminating cells, the isolation of
neutrophils with anti-CD15 microbeads was chosen as a suitable approach to obtain sufficiently numbers of inac- tivated neutrophils. Nevertheless, a consensus on the selection of the right isolation method that allows the comparison of neutrophil paired samples from SF and PB is still needed.
Acknowledgments
We thank all the patients for their kind participation in this study.
Funding
This work was supported by grants from the Instituto de Salud Carlos III (CP15/00158, PI17/01316 and PI18/00837), cofi- nanciado por el fondo europeo de desarrollo regional de la Union Europea, ‘una manera de hacer Europa’, Spain, the Regional Health System (ref. PI 0285 2017), and the Spanish Inflammatory and Rheumatic Diseases Network (RIER, RD16/0012/0015). CL-P was supported by contracts from both the Junta de Andalucia and Spanish Ministry of Science and Innovation (Ramon y Cajal). NB was supported by Ministry of Health postdoctoral fellowship (Miguel Servet Programme). YJ-G was supported by a contract from the University of Cordoba [co-funded by the Research Plan of the University of Cordoba and the Operating Program of the European Regional Development Funds (ERDF) for Andalusia. CL-P was supported by a contract from the Junta de Andalucia] (Nicolas Monardes Programme). YJ-G was supported by a contract from the University of Cordoba (co-funded by the Research Plan of the University of Cordoba and the Operating Program of the European Regional Development Funds [ERDF]) for Andalusia).
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