Polysialic acid interacts with lactoferrin and supports its activity to inhibit the release of neutrophil extracellular traps

•Lactoferrin is a novel binding partner of polysialic acid.•Lactoferrin/polysialic acid complexes are present in several bodily fluids.•Polysialic acid increase the impact of lactoferrin to inhibit the NET-release. Polysialic acid (polySia) is a linear carbohydrate polymer consisting of N-acetylneuraminic acid residues and is involved in several physiological processes. In the present study, we identified the multifunctional protein lactoferrin as a novel interaction partner for polySia. Lactoferrin co-precipitated when polySia was isolated from human blood, milk, and semen samples. The interaction between polySia and lactoferrin was verified using a native gel electrophoresis application, demonstrating that such interaction depends on the degree of polymerization. The interaction between the molecules could be inhibited by an antibody against lactoferricin (LFcin), which suggests that the LFcin domain of lactoferrin represents the potential binding area for sialic acid polymers. Because lactoferrin inhibits the formation of neutrophil extracellular traps (NETs), the potential impact of polySia on this function of lactoferrin was tested. Intriguingly, we observed that polySia increases the efficiency of lactoferrin to prevent the release of NET fibers. PolySia alone shows no activity. Therefore, together with lactoferrin, polySia may represent a natural regulatory system of NET release.