- 作者: Patricia Ruiz-Limon, Maria Lourdes Ladehesa-Pineda, Maria del Carmen Castro-Villegas, Maria del Carmen Abalos-Aguilera, Clementina Lopez-Medina, Chary Lopez-Pedrera, Nuria Barbarroja, Daniel Espejo-Peralbo, Jose Antonio Gonzalez-Reyes, Jose Manuel Villalba, Carlos Perez-Sanchez, Alejandro Escudero-Contreras, Eduardo Collantes-Estevez, Pilar Font-Ugalde and Yolanda Jimenez-Gomez
- 作者服務機構: 1. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Avda. Menéndez Pidal s/n, 14004, Córdoba, Spain 2. Unidad de Gestión Clínica Reumatología, Hospital Universitario Reina Sofía, Avda. Menéndez Pidal s/n, 14004, Córdoba, Spain 3.Departamento de Medicina (Medicina, Dermatología y Otorrinolaringología), Universidad de Córdoba, Avda. Menéndez Pidal s/n, 14004, Córdoba, Spain 4. Unidad de Gestión Clínica Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Clínico Virgen de la Victoria, Campus Teatinos s/n, 29010, Málaga, Spain 5. Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario ceiA3, Campus de Rabanales, Edificio Severo Ochoa, 3ª planta, 14014, Córdoba, Spain
- 中文摘要:
- 英文摘要:
Background
Radiographic axial spondyloarthritis (r-axSpA) is a chronic inflammatory form of arthritis in which tumor necrosis factor (TNF)-α, a potent inducer of inflammatory response and a key regulator of innate immunity and of Th1 immune responses, plays a central role. NETosis is a mechanism of innate immune defense that is involved in diverse rheumatology diseases. Nevertheless, spontaneous NETosis generation in r-axSpA, its association to disease pathogenesis, and the NETosis involvement on anti-TNF-α therapy’s effects has never been explored.
Methods
Thirty r-axSpA patients and 32 healthy donors (HDs) were evaluated. Neutrophil extracellular trap (NET) formation, mediators of signal-transduction cascade required for NETosis induction and cell-free NETosis-derived products were quantified. An additional cohort of 15 r-axSpA patients treated with infliximab (IFX) for six months were further analyzed. In vitro studies were designed to assess the effects of IFX in NETosis generation and the inflammatory profile triggered.
Results
Compared to HDs, neutrophils from r-axSpA patients displayed augmented spontaneous NET formation, elevated expression of NET-associated signaling components, nuclear peptidylarginine deiminase 4 translocation and increased citrullinated histone H3. Furthermore, patients exhibited altered circulating levels of cell-free NETosis-derived products (DNA, nucleosomes and elastase). Additional studies revealed that cell-free NETosis-derived products could be suitable biomarkers for distinguish r-axSpA patients from HDs. Correlation studies showed association between cell-free NETosis-derived products and clinical inflammatory parameters. Besides, nucleosomes displayed potential as a biomarker for discriminate patients according to disease activity.
IFX therapy promoted a reduction in both NETosis generation and disease activity in r-axSpA patients. Mechanistic in vitro studies further unveiled the relevance of IFX in reducing NET release and normalizing the augmented inflammatory activities promoted by NETs in mononuclear cells.
Conclusions
This study reveals that NETosis is enhanced in r-axSpA patients and identifies the NETosis-derived products as potential disease activity biomarkers. In addition, the data suggests the potential role of NET generation analysis for assessment of therapeutic effectiveness in r-axSpA. - 中文關鍵字:
- 英文關鍵字: Biomarkers/NETosis/neutrophils/immunotherapy/pathogenesis/radiographic axial spondyloarthritis