Neutrophils in systemic onset Juvenile Idiopathic Arthritis display sepsis-like features which can be reverted by IL-1 blockade

5 years ago

Neutrophils in systemic onset Juvenile Idiopathic Arthritis display sepsis-like features which can be reverted by IL-1 blockade

Dirk Foell, Pieter H C Leliefeld, Thomas Vogl, Jorg van Loosdregt, Tamar Tak, Leo Koenderman, Wilco de Jager, Jenny M Meerding, Sebastiaan J Vastert, Michal Mokry, Johannes Roth, Anouk Verwoerd, Nienke M ter Haar, Sytze de Roock, Rianne C Scholman

Objective Neutrophils are the most abundant innate immune cells in the blood, however little is known about their role in (acquired) chronic autoinflammatory diseases. We investigated neutrophils in systemic onset Juvenile Idiopathic Arthritis (sJIA), a prototypical multifactorial autoinflammatory disease, characterized by arthritis and severe systemic inflammation. Methods We analyzed 50 sJIA patients at disease onset and during remission on recombinant IL-1 receptor antagonist (rIL-1RA, anakinra). RNA-sequencing was performed on FACS-sorted neutrophils from 3 active sJIA patients and 3 healthy controls. Expression of activation markers, apoptosis, ROS-production and secretory vesicle degranulation from neutrophils of 17 patients and 15 controls were assessed by flow cytometry. Results Neutrophil counts were markedly increased at disease onset, correlated to levels of inflammatory mediators and normalized within days after initiation of rIL-1RA. RNA-sequencing revealed a substantial upregulation of inflammatory processes in neutrophils from active sJIA patients, significantly overlapping with the transcriptome of sepsis. Correspondingly, neutrophils in active sJIA displayed a primed phenotype characterized by increased ROS-production, CD62L-shedding and secretory vesicle degranulation, which was reversed during remission on rIL-1RA. Patients with a short disease duration had high neutrophil counts, more immature neutrophils and a complete response to rIL-1RA, while patients with symptoms >1 month had normal neutrophil counts and an unsatisfactory response to rIL-1RA. In vitro, rIL-1RA antagonized the priming effect of IL-1β on healthy neutrophils. Conclusions Our data argue strongly for an important role for neutrophils in sJIA, especially in the early inflammatory phase, and show susceptibility of neutrophil numbers and inflammatory activity to IL-1 blockade. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/art.40442