Ikegame, A.; Kondo, A.; Morinishi, T.; Yamaguchi, Y.; Okutani, Y.; Maegawa, C.; Tada, S.

Presepsin (P-SEP), a soluble subtype of CD14, has been widely reported as a useful biomarker for sepsis in clinical studies. However, the cytological mechanism underlying its production remains poorly understood. Previous research has demonstrated that P-SEP is generated when M1 macrophages (M1 M{Phi}s) phagocytose neutrophil extracellular traps (NETs) and degrade internalized CD14. In this study, we demonstrated that M1 M{Phi}s phagocytose NETs and that proteinase 3 (PR3) within M1 M{Phi}s degrades NET-derived CD14, resulting in the production of P-SEP. Furthermore, we observed a strong correlation between the amount of NETs and P-SEP levels, indicating that NET phagocytosis is a key process in P-SEP generation. Our findings also suggest that PR3 released extracellularly along with NETs may degrade CD14 in plasma, contributing to elevated P-SEP levels. This mechanism may contribute to increased P-SEP concentrations observed in autoimmune diseases associated with NET accumulation, proposing P-SEP as a potential biomarker of disease activity beyond sepsis.