High-Affinity Interactions of Beryllium(2+) with Phosphatidylserine Result in a Cross-Linking Effect Reducing Surface Recognition of the Lipid.

Beryllium has multiple industrial applications, but its manufacture is associated with a serious occupational risk of developing chronic inflammation in the lungs known as berylliosis, or chronic beryllium disease. Although the Be ²⁺ -induced abnormal immune responses have recently been linked to a specific MHC-II allele, the nature of long-lasting granulomas is not fully understood. Here we show that Be ²⁺ binds with a micromolar affinity to phosphatidylserine (PS), the major surface marker of apoptotic cells. Isothermal titration calorimetry indicates that, like that of Ca ²⁺ , binding of Be ²⁺ to PS liposomes is largely entropically driven, likely by massive desolvation. Be ²⁺ exerts a compacting effect on PS monolayers, suggesting cross-linking through coordination by both phosphates and carboxyls in multiple configurations, which were visualized in molecular dynamics simulations. Electrostatic modification of PS membranes by Be ²⁺ includes complete neutralization of surface charges at ∼30 μM, accompanied by an increase in the boundary dipole potential. The data suggest that Be ²⁺ can displace Ca ²⁺ from the surface of PS, and being coordinated in a tight shell of four oxygens, it can mask headgroups from Ca ²⁺ -mediated recognition by PS receptors. Indeed, 48 μM Be ²⁺ added to IC-21 cultured macrophages specifically suppresses binding and engulfment of PS-coated silica beads or aged erythrocytes. We propose that Be ²⁺ adsorption at the surface of apoptotic cells may potentially prevent normal phagocytosis, thus causing accumulation of secondary necrotic foci and the resulting chronic inflammation.