Pro-inflammatory S100A8 Protein Exhibits a Detergent-like Effect on Anionic Lipid Bilayers, as Imaged by High-Speed AFM

Neuronal cell death induced by cell membrane damage is one of the major hallmarks of neurodegenerative diseases. Neuroinflammation precedes the loss of neurons; however, whether and how inflammation-related proteins contribute to the loss of membrane integrity remains unknown. We employed a range of biophysical tools, including high-speed atomic force microscopy, fluorescence spectroscopy, and electrochemical impedance spectroscopy, to ascertain whether the pro-inflammatory protein S100A8 induces alterations in biomimetic lipid membranes upon interaction. Our findings underscore the crucial roles played by divalent cations and membrane charge. We found that apo-S100A8 selectively interacts with anionic lipid membranes composed of phosphatidylserine (PS), causing membrane disruption through a detergent-like mechanism, primarily affecting regions where phospholipids are less tightly packed. Interestingly, the introduction of Ca²⁺ ions inhibited S100A8-induced membrane disruption, suggesting that the disruptive effects of S100A8 are most pronounced under conditions mimicking intracellular compartments, where calcium levels are low, and PS concentrations in the inner leaflet of the membrane are high. Overall, our results present a mechanistic basis for understanding the molecular interactions between S100A8 and the plasma membrane, emphasizing S100A8 as a potential contributor to the onset of neurodegenerative diseases.