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Ferrata Storti Foundation
Haematologica 2020 Volume 105(9):2250-2261
Granulocyte Biology & its Disorders
Impaired microRNA processing in neutrophils from rheumatoid arthritis patients confers their pathogenic profile. Modulation by biological therapies
Ivan Arias de la Rosa,1* Carlos Perez-Sanchez,2* Patricia Ruiz-Limon,3* Alejandra Patiño-Trives,1 Carmen Torres-Granados,1 Yolanda Jimenez-Gomez,1 Maria del Carmen Abalos-Aguilera,1 Irene Cecchi,4 Rafaela Ortega,1
Miguel Angel Caracuel,1 Jerusalem Calvo-Gutierrez,1 Alejandro Escudero- Contreras,1 Eduardo Collantes-Estevez,1# Chary Lopez-Pedrera1#
and Nuria Barbarroja#1,5
1Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain; 2Deparment of Medicine, University of Cambridge, School of Clinical Medicine, Addenbroke’s Hospital, Cambridge Institute for Medical Research, Cambridge, UK; 3Biomedical Research Institute (IBIMA), Service of Endocrinology and Nutrition, Malaga Hospital Complex (Virgen de la Victoria), Malaga, Spain; 4Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Valle d’Aosta Network for Rare Diseases, Turin, Italy and 5CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
ABSTRACT
The aim of this study was to investigate the microRNA (miRNA) expression pattern in neutrophils from rheumatoid arthritis (RA) patients and its contribution to their pathogenic profile and to ana- lyze the effect of specific autoantibodies or inflammatory components in the regulation of miRNA in RA neutrophils and its modulation by biological therapies. Neutrophils were isolated from paired peripheral blood (PB) and synovial fluid samples of 40 patients with RA and from PB of 40 healthy donors. A miRNA array was performed using nCounter technology. Neutrophils from healthy donors were treated in vitro with antibodies to cit- rullinated protein antigens isolated from RA patients and tumor necrosis factor-a (TNF-a) or interleukin-6. A number of cytokines and chemokines were analyzed. In vitro treatments of RA-neutrophils with tocilizumab or infliximab were carried out. Transfections with pre-miRNA and DICER downregulation experiments were further performed. RA-neutrophils showed a global downregulation of miRNA and genes involved in their bio- genesis, alongside with an upregulation of various potential mRNA targets related to migration and inflammation. Decreased levels of miRNA and DICER correlated with autoimmunity, inflammation and disease activity. Citrullinated protein antigens and TNF-a decreased the expression of numerous miRNA and their biogenesis-related genes, increasing their potential mRNA targets. Infliximab reversed those effects. Transfections with pre-miRNA-223, -126 and -148a specifically modulated genes regulat- ing inflammation, survival and migration whereas DICER depletion influ- enced the inflammatory profile of neutrophils. Taken together RA-neu- trophils exhibited a global low abundance of miRNA induced by autoanti- bodies and inflammatory markers, which potentially contributed to their pathogenic activation. miRNA biogenesis was significantly impaired in RA- neutrophils and further associated with a greater downregulation of miRNA mainly related to migration and inflammation in synovial fluid neu- trophils. Finally, anti-TNF-a and anti-interleukin-6 receptor treatments can modulate miRNA levels in the neutrophils, minimizing their inflammatory profile.
*IAR, CPS and PRL contributed equally as co-first authors. #ECE, CLP and NB contributed equally as co-senior authors.
Correspondence:
NURIA BARBARROJA
nuria.barbarroja.exts@juntadeandalucia.es
Received: August 22, 2018. Accepted: January 10, 2020. Pre-published: January 16, 2020.
doi:10.3324/haematol.2018.205047 ©2020 Ferrata Storti Foundation
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