Neutrophil extracellular traps exacerbate inflammatory arthritis by inhibiting γδ Treg cell differentiation via the AIM2 inflammasome.

Inflammatory arthritis is a set of systemic autoimmune diseases that lead to joint destruction. Recent findings suggest that γδ T cell dysfunction plays a crucial role in the development of inflammatory arthritis, but its underlying mechanisms remain elusive. In this study, we demonstrated that neutrophil extracellular trap (NET) levels were elevated in inflammatory arthritis patients and collagen-induced arthritis (CIA) model mice, which inhibited γδ Treg cell differentiation and contributed to the decreased proportion of γδ Treg cells in these patients and model mice. Inhibition of NET formation with sivelestat (SVT) and CI-amidine restored the proportion of γδ Treg cells and had a therapeutic effect on CIA model mice. In terms of mechanism, the endocytosed NET-associated DNA components bound to an intracellular DNA sensor AIM2, promoting the AIM2 inflammasome activation and the subsequent gasdermin D-mediated mitochondrial dysfunction. This process led to the pathological accumulation of reactive oxygen species, therefore directly inhibiting γδ Treg cell differentiation. Our study reveals the detailed mechanism through which NETs impeded γδ Treg cell differentiation and then exacerbated inflammatory arthritis, suggesting an underlying therapeutic strategy for inflammatory arthritis by targeting the NET-γδ Treg cell axis.