Elevated serum gasdermin D N-terminal implicates monocyte and macrophage pyroptosis in adult-onset Still's disease

Objectives. Elevation of serum IL-18 in adult-onset Still's disease (AOSD) and systemic JIA (sJIA) suggests the role of the inflammasome in these diseases. Gasdermin D is a pore-forming protein playing central roles in inflammasome-mediated inflammation, but its role in rheumatic disease is unknown. We aimed to elucidate the auto-inflammatory mechanisms in AOSD and sJIA. Methods. Patients with AOSD, sJIA, hemophagocytic lymphohistiocytosis (HLH) and Behget's disease followed at Yokohama City University (YCU), or US National Institutes of Health (NIH) were included in the study. Disease activity was evaluated by the modified Pouchot score. Ferritin and N-terminal gasdermin D levels in serum and culture supernatant were measured by ELISA. Primary monocytes (Mo) were stimulated with GM-CSF or M-CSF and differentiated into M1 macrophages (M phi) or M2M phi, respectively. The number of Mo/M phi and their viability were monitored over time. Results. Patients with active AOSD and sJIA had increased levels of serum gasdermin D N-terminal, which correlated with serum ferritin and IL-18 levels. Mo-derived M phi from active AOSD patients showed reduced cell viability and increased cell death. The number of cultured M phi cells on day nine was negatively correlated with the serum ferritin and gasdermin D levels. Higher ferritin and gasdermin D levels were observed in the M1M phi culture super-natant of active AOSD patients. Gasdermin D inhibitors reduced the pyroptosis-mediated ferritin release in Mo. Conclusion. Elevation of serum gasdermin D N-terminal provides evidence for inflammasome activation triggering gasdermin D-mediated Mo and Mcp pyroptosis in AOSD and possibly sJIA.