Lipid nanotubes unmask neutrophils for complement attack Open Access

• Neutrophils exposed to shear stress form lipid nanotubes that lack complement inhibitors, allowing deposition of complement components.

• Complement-decorated nanotubes activate resting neutrophils, revealing a new mechanism of pro-inflammatory cell-cell communication.

Neutrophils, critical components of innate immunity, undergo significant morphological changes during phagocytosis. In this study, we demonstrate that neutrophils exposed to shear stress generate lipid nanotubes (NTs) with an unique composition. Compared to the proteome of whole neutrophils, NTs notably lack cytoskeletal elements and the complement-inhibiting transmembrane protein CD46. Consequently, these NTs are recognized by the complement system and selectively opsonized the complement component C3b. Biophysical characterization of NTs confirmed that their integrity relies on lipid-lipid interactions and that they pinch off from neutrophils to form NT-derived vesicles (NTDVs). We detected C3b+ NTDVs in plasma from patients and animal models experiencing diverse inflammatory conditions, including metastatic melanoma, vasculitis, and polytrauma. Further functional experiments indicate that resting neutrophils phagocytose complement-opsonized NTDVs, leading to cell activation, including the production of reactive oxygen species (ROS). In conclusion, our data suggest a significant role for neutrophil-derived NTs in a wide range of inflammatory diseases and reveal a previously unknown mode of cell-cell communication.