The endoplasmic reticulum Ca2+‐ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis,Glia

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The endoplasmic reticulum Ca2+‐ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis
Glia ( IF 5.4 ) Pub Date : 2020-10-26 , DOI: 10.1002/glia.23931
Juan M Morales-Ropero ₁ , Sandra Arroyo-Urea ₁ , Veronika E Neubrand ₁ , David Martín-Oliva ₁ , José L Marín-Teva ₁ , Miguel A Cuadros ₁ , Peter Vangheluwe ₂ , Julio Navascués ₁ , Ana M Mata ₃ , M Rosario Sepúlveda ₁

Affiliation

Activation of microglia is an early immune response to damage in the brain. Although a key role for Ca²⁺ as trigger of microglial activation has been considered, little is known about the molecular scenario for regulating Ca²⁺ homeostasis in these cells. Taking into account the importance of the endoplasmic reticulum as a cellular Ca²⁺ store, the sarco(endo)plasmic reticulum Ca²⁺‐ATPase (SERCA2b) is an interesting target to modulate intracellular Ca²⁺ dynamics. We found upregulation of SERCA2b in activated microglia of human brain with Alzheimer's disease and we further studied the participation of SERCA2b in microglial functions by using the BV2 murine microglial cell line and primary microglia isolated from mouse brain. To trigger microglia activation, we used the bacterial lipopolysaccharide (LPS), which is known to induce an increase of cytosolic Ca²⁺. Our results showed an upregulated expression of SERCA2b in LPS‐induced activated microglia likely associated to an attempt to restore the increased cytosolic Ca²⁺ concentration. We analyzed SERCA2b contribution in microglial migration by using the specific SERCA inhibitor thapsigargin in scratch assays. Microglial migration was strongly stimulated with thapsigargin, even more than with LPS‐induction, but delayed in time. However, phagocytic capacity of microglia was blocked in the presence of the SERCA inhibitor, indicating the importance of a tight control of cytosolic Ca²⁺ in these processes. All together, these results provide for the first time compelling evidence for SERCA2b as a major player regulating microglial functions, affecting migration and phagocytosis in an opposite manner.

中文翻译：

内质网 Ca2+-ATPase SERCA2b 在活化的小胶质细胞中上调，其抑制对迁移和吞噬作用产生相反的影响

小胶质细胞的激活是对大脑损伤的早期免疫反应。尽管已经考虑了 Ca ^{2+作为小胶质细胞活化触发的关键作用，但对于调节这些细胞中 Ca}²⁺稳态的分子方案知之甚少。考虑到内质网作为细胞 Ca ²⁺储存的重要性，肌（内）质网 Ca ²⁺ -ATP 酶 (SERCA2b) 是调节细胞内 Ca ^{2+的有趣靶标}动力学。我们发现 SERCA2b 在患有阿尔茨海默病的人脑激活的小胶质细胞中上调，我们通过使用 BV2 小鼠小胶质细胞系和从小鼠脑中分离的原代小胶质细胞进一步研究了 SERCA2b 对小胶质细胞功能的参与。^{为了触发小胶质细胞活化，我们使用了已知会诱导细胞溶质 Ca 2+}增加的细菌脂多糖 (LPS) 。我们的结果显示 LPS 诱导的活化小胶质细胞中 SERCA2b 的表达上调，这可能与试图恢复增加的细胞溶质 Ca ^2+相关。专注。我们通过在划痕试验中使用特定的 SERCA 抑制剂毒胡萝卜素来分析 SERCA2b 在小胶质细胞迁移中的贡献。毒胡萝卜素强烈刺激小胶质细胞迁移，甚至超过 LPS 诱导，但时间延迟。然而，在 SERCA 抑制剂的存在下，小胶质细胞的吞噬能力被阻断，表明在这些过程中严格控制胞质 Ca ^{2+的重要性。}总之，这些结果首次为 SERCA2b 作为调节小胶质细胞功能的主要参与者提供了令人信服的证据，以相反的方式影响迁移和吞噬作用。

更新日期：2020-10-26

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