Impaired microRNA processing in neutrophils from rheumatoid arthritis patients confers their pathogenic profile. Modulation by biological therapies
Ivan Arias de la Rosa,
Carlos Perez-Sanchez,
Patricia Ruiz-Limon,
Alejandra Patiño-Trives,
Carmen Torres-Granados,
Yolanda Jimenez-Gomez,
Maria del Carmen Abalos-Aguilera,
Irene Cecchi,
Rafaela Ortega,
Miguel Angel Caracuel,
Jerusalem Calvo-Gutierrez,
Alejandro Escudero-Contreras,
Eduardo Collantes-Estevez,
Chary Lopez-Pedrera,
Nuria Barbarroja
Affiliations
Ivan Arias de la Rosa
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Carlos Perez-Sanchez
Deparment of Medicine, University of Cambridge, School of Clinical Medicine, Addenbroke’s Hospital, Cambridge Institute for Medical Research, Cambridge, UK
Patricia Ruiz-Limon
Biomedical Research Institute (IBIMA), Service of Endocrinology and Nutrition, Malaga Hospital Complex (Virgen de la Victoria), Malaga, Spain
Alejandra Patiño-Trives
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Carmen Torres-Granados
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Yolanda Jimenez-Gomez
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Maria del Carmen Abalos-Aguilera
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Irene Cecchi
Department 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
Rafaela Ortega
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Miguel Angel Caracuel
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Jerusalem Calvo-Gutierrez
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Alejandro Escudero-Contreras
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Eduardo Collantes-Estevez
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Chary Lopez-Pedrera
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain
Nuria Barbarroja
Rheumatology service, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
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 analyze 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 vitrowith antibodies to citrullinated 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 biogenesis, 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 regulating inflammation, survival and migration whereas DICER depletion influenced the inflammatory profile of neutrophils. Taken together RA-neutrophils exhibited a global low abundance of miRNA induced by autoantibodies and inflammatory markers, which potentially contributed to their pathogenic activation. miRNA biogenesis was significantly impaired in RAneutrophils and further associated with a greater downregulation of miRNA mainly related to migration and inflammation in synovial fluid neutrophils. Finally, anti-TNF-a and anti-interleukin-6 receptor treatments can modulate miRNA levels in the neutrophils, minimizing their inflammatory profile.