The S100A8/A9–NETosis feedback loop in sepsis: potential mechanisms, immune crosstalk, and therapeutic targeting

Sepsis has a high incidence and mortality rate, bringing about a high global burden. Recent research has demonstrated that the S100A8/A9-NETosis feedback loop is considered a central regulator of sepsis. However, few studies have integrated these elements into a unified 'S100A8/A9-NETosis feedback loop'. Meanwhile, a systematic description of this loop in the interaction between myeloid cells and platelets, as well as organ damage, has not been established. This review systematically proposes the S100A8/A9-NETosis positive feedback loop as a core pathological mechanism and explores its potential pathways in sepsis. Specifically, we examine how this loop drives neutrophil-mediated hyperinflammation, monocyte/macrophage polarization, immune paralysis (mediated by dendritic cells and myeloid-derived suppressor cells), and immune thrombosis (triggered by platelets). We also evaluate how this loop contributes to organ-specific injury and discuss potential therapeutic strategies, providing new perspectives for sepsis treatment.