Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.
Glia. 2022 Sep;70(9):1666-1680. doi: 10.1002/glia.24188. Epub 2022 May 4.
Astrocytes are glial cells that serve homeostatic functions in the central nervous system (CNS). Recent research, however, suggests that under pathological conditions, astrocytes are stimulated by various factors and actively participate in CNS inflammation. In the present study, we found that astrocytes upregulate various inflammatory factors including prostaglandin E (PGE ) by co-stimulation with tumor necrosis factor-alpha (TNFα) and interleukin-1alpha (IL1α). These TNFα/IL1α-stimulated astrocytes also showed increased Ca release from the endoplasmic reticulum (ER) and increased expression of Orai2, a member of the store-operated calcium channel (SOCC) family. To reveal the role of Orai2, we used astrocytes in which Orai2 was knocked-down (KD) or knocked-out (KO). The expression of the prostaglandin E synthase Ptges and the production of PGE were higher in Orai2-KD astrocytes than in WT astrocytes when stimulated with TNFα and IL1α. Orai2-KO astrocytes also showed increased expression of Ptges and increased PGE production. The expression of Ptgs2, another PGE synthetic enzyme, was also upregulated in Orai2-KO astrocytes. Moreover, Orai2-KO astrocytes showed increased store-operated calcium entry (SOCE) and increased Orai1 expression. These results suggest that Orai2 is upregulated in TNFα/IL1α-stimulated astrocytes and reduces PGE production to some extent, modulating CNS inflammation. Our findings may aid in understanding how astrocytes are associated with inflammatory responses, and the identification of new targets that modulate astrocytic reactivity.
星形胶质细胞是中枢神经系统 (CNS) 中的神经胶质细胞，具有维持内环境稳定的功能。然而，最近的研究表明，在病理条件下，星形胶质细胞受到各种因素的刺激，并积极参与 CNS 炎症反应。在本研究中，我们发现星形胶质细胞通过与肿瘤坏死因子-α (TNFα) 和白细胞介素-1α (IL1α) 共同刺激而上调各种炎症因子，包括前列腺素 E (PGE)。这些 TNFα/IL1α 刺激的星形胶质细胞还显示内质网 (ER) 中 Ca 释放增加，并且储存操作钙通道 (SOCC) 家族成员 Orai2 的表达增加。为了揭示 Orai2 的作用，我们使用了 Orai2 敲低 (KD) 或敲除 (KO) 的星形胶质细胞。当用 TNFα 和 IL1α 刺激时，Orai2-KD 星形胶质细胞中前列腺素 E 合酶 Ptges 的表达和 PGE 的产生高于 WT 星形胶质细胞。Orai2-KO 星形胶质细胞也显示出 Ptges 的表达增加和 PGE 产生增加。另一种 PGE 合成酶 Ptgs2 的表达也在 Orai2-KO 星形胶质细胞中上调。此外，Orai2-KO 星形胶质细胞显示出储存操作钙内流 (SOCE) 的增加和 Orai1 表达的增加。这些结果表明，Orai2 在 TNFα/IL1α 刺激的星形胶质细胞中上调，并在一定程度上减少 PGE 的产生，从而调节 CNS 炎症。我们的发现可能有助于理解星形胶质细胞如何与炎症反应相关联，并确定调节星形胶质细胞反应性的新靶点。
