Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24):
e2536989123
Systemic inflammation is accompanied by overwhelming neutrophil activation, resulting in extensive formation of neutrophil extracellular traps (NETs). Although NETs are beneficial for pathogen entrapment, they become detrimental; therefore, their endogenous regulation is pivotal for survival. In this context, the observation that healthy individuals' red blood cells (RBCs) can inhibit NET formation induced by lipopolysaccharide (LPS)-primed neutrophils is noteworthy. However, during systemic inflammation, NET formation in the vasculature is robust despite constant neutrophil exposure to RBCs. Herein, we reveal that for RBCs and neutrophils from septic individuals, but not from those with local inflammation, interactions cease and NET inhibition is abolished. This is observed even if only one cell type originates from an inflamed individual, and occurs in both human and murine cells. Moreover, 6 to 10 d post-sepsis induction (mice) or diagnosis (humans), during the resolution of inflammation, interactions are restored and hence fail during the critical stages of inflammation. Mechanistically, this is not due to passive LPS absorption by RBCs, which would limit its availability for neutrophils. In contrast, the cessation of NET inhibition is due to inflammation-induced RBC desialylation (removal of α2,3-linked sialic acids) and decreased expression of inhibitory Siglec-E/9 and -G, but not Siglec-F/5, on neutrophils. Accordingly, concurrent addition of exogenous polysialic acid (PolySia) and pharmacologically controlled accumulation of Siglec molecules on neutrophils preserves the ability of erythrocytes to inhibit PAD4-dependent NET formation upon interaction with neutrophils of endotoxemic mice. These findings open avenues for clinically controlling NET formation during systemic inflammation, given the abundance of erythrocytes in the blood.
Keywords: erythrocytes; neutrophil extracellular traps (NETs); neutrophils; sepsis; siglec receptors