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 Be²⁺-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 Be²⁺ binds with a micromolar affinity to phosphatidylserine (PS), the major surface marker of apoptotic cells. Isothermal titration calorimetry indicates that, like that of Ca²⁺, binding of Be²⁺ to PS liposomes is largely entropically driven, likely by massive desolvation. Be²⁺ 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 Be²⁺ includes complete neutralization of surface charges at ∼30 μM, accompanied by an increase in the boundary dipole potential. The data suggest that Be²⁺ can displace Ca²⁺ from the surface of PS, and being coordinated in a tight shell of four oxygens, it can mask headgroups from Ca²⁺-mediated recognition by PS receptors. Indeed, 48 μM Be²⁺ added to IC-21 cultured macrophages specifically suppresses binding and engulfment of PS-coated silica beads or aged erythrocytes. We propose that Be²⁺ adsorption at the surface of apoptotic cells may potentially prevent normal phagocytosis, thus causing accumulation of secondary necrotic foci and the resulting chronic inflammation.

中文翻译：

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铍（2+）与磷脂酰丝氨酸的高亲和力相互作用导致交联效应，降低脂质的表面识别

铍具有多种工业应用，但其制造与在肺部发展为慢性铍或慢性铍病的慢性炎症的严重职业风险相关。尽管最近已将Be ²⁺诱导的异常免疫反应与特定的MHC-II等位基因相关联，但尚未完全了解长效肉芽肿的性质。在这里，我们显示Be ²⁺以微摩尔亲和力与凋亡细胞的主要表面标志物磷脂酰丝氨酸（PS）结合。等温滴定量热法表明，像Ca ^2+一样，Be ²⁺与PS脂质体的结合很大程度上受熵驱动，这可能是由于大量去溶剂化所致。是²⁺在PS单层上发挥压实作用，表明通过磷酸酯和羧基在多种构型下的配位可实现交联，这在分子动力学模拟中可以看到。Be ²⁺对PS膜的静电修饰包括在〜30μM处完全中和表面电荷，并伴随着边界偶极电势的增加。数据表明，Be ²⁺可以从PS表面置换Ca ²⁺，并在四个氧的紧密壳中配位，可以掩盖由PS受体引起的Ca ²⁺介导的识别的头基。确实，48μMBe ²⁺加入IC-21培养的巨噬细胞后，可特异性抑制PS包被的二氧化硅微珠或老化的红细胞的结合和吞噬。我们建议凋亡细胞表面的Be ²⁺吸附可能潜在地阻止正常的吞噬作用，从而引起继发性坏死灶的积累和由此引起的慢性炎症。