Essential Role of Neutrophils in the Initiation and Progression of a Murine Model of Rheumatoid Arthritis

TLDR

Neutrophils are prominent in human rheumatoid arthritis joint inflammation, yet their role in the early inductive phase remains unclear, and the K/B×N mouse model demonstrates that transfer of autoreactive Ig induces rapid, joint‑specific inflammation resembling human RA. The study aimed to determine whether neutrophils are required for the early inflammatory response following transfer of arthritogenic serum from K/B×N transgenic mice. Mice were treated with a neutrophil‑depleting monoclonal antibody before and after serum transfer, and clinical scores of ankle joint and forepaw swelling were recorded. Neutrophil depletion prevented and even reversed joint inflammation, while mice lacking inducible NO synthase 2 or gp91phox still mounted normal inflammatory responses, establishing neutrophils as the critical initiators and sustainers of joint inflammation in this model.

Abstract

Abstract Neutrophils are prominent participants in the joint inflammation of human rheumatoid arthritis (RA) patients, but the extent of their role in the inductive phase of joint inflammation is unknown. In the K/B×N mouse RA model, transfer of autoreactive Ig from the K/B×N mouse into mice induces a rapid and profound joint-specific inflammatory response reminiscent of human RA. We observed that after K/B×N serum transfer, the earliest clinical signs of inflammation in the ankle joint correlated with the presence of neutrophils in the synovial regions of recipient mouse ankle joints. In this study, we investigated the role of neutrophils in the early inflammatory response to transferred arthritogenic serum from the K/B×N transgenic mouse. Mice were treated with a neutrophil-depleting mAb before and following transfer of arthritogenic serum and scored for clinical indications of inflammation and severity of swelling in ankle joints and front paws. In the absence of neutrophils, mice were completely resistant to the inflammatory effects of K/B×N serum. Importantly, depletion of neutrophils in diseased recipient mice up to 5 days after serum transfer reversed the inflammatory reaction in the joints. Transfer of serum into mice deficient in the generation of nitrogen or oxygen radicals (inducible NO synthase 2 or gp91phox genes, respectively) gave normal inflammatory responses, indicating that neither pathway is essential for disease induction. These studies have identified a critical role for neutrophils in initiating and maintaining inflammatory processes in the joint.