Toll-like receptor 4 activation enhances Orai1-mediated calcium signal promoting cytokine production in spinal astrocytes.
Toll-like receptor 4 activation enhances Orai1-mediated calcium signal promoting cytokine production in spinal astrocytes.
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toll样受体4激活增强orai1介导的钙信号，促进脊髓星形胶质细胞细胞因子的产生。
DOI：
10.1016/j.ceca.2022.102619
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发表时间：
2022-07
期刊：
影响因子：
4
通讯作者：
Hu, Huijuan
中科院分区：
文献类型：
--
作者：
Birla, Hareram;Xia, Jingsheng;Gao, Xinghua;Zhao, Hui;Wang, Fengying;Patel, Shivam;Amponsah, Akwasi;Bekker, Alex;Tao, Yuan -Xiang;Hu, Huijuan
Toll样受体4（TLR 4）与包括慢性疼痛在内的病理状况有关。星形胶质细胞TLR的活化导致促炎细胞因子如白细胞介素6（IL-6）和肿瘤坏死因子-α（TNF-α）的合成，其可引起中枢神经系统中的病理性炎症和组织损伤。然而，TLR 4介导的细胞因子从星形胶质细胞释放的机制还不完全清楚。我们以前的研究表明，Orai 1，钙释放激活的钙通道（CRACs）的关键组成部分，介导的星形胶质细胞中的Ca 2+内流。Orai 1如何促进TLR 4信号转导尚不清楚。我们发现Orai 1缺陷显著减弱脂多糖（LPS）诱导的星形胶质细胞中TNF-α和IL-6的产生。急性LPS处理不诱导Ca 2+反应，对毒胡萝卜素（Ca 2 +-ATP酶抑制剂）诱导的钙池依赖性Ca 2+内流没有影响。Orai 1的抑制或敲除显示LPS诱导的p-ERK 1/2、p-c-Jun N-末端激酶或p-p38 MAPK活化没有减少。有趣的是，Orai 1蛋白水平在LPS暴露后显著增加，这可通过抑制NF-κB活性来阻断。LPS可显著增加星形胶质细胞的基础Ca ~（2+）水平和SOCE。此外，升高细胞外Ca 2+浓度增加胞浆Ca 2+水平，这在Orai 1 KO星形胶质细胞中几乎被消除。我们的研究报告了新的发现，Orai 1作为一个Ca 2+泄漏通道调节基础Ca 2+水平和增强炎症条件下星形胶质细胞中细胞因子的产生。这些发现强调了Orai 1在星形胶质细胞TRL 4功能中的重要作用，并可能表明Orai 1可能是神经炎性疾病（包括慢性疼痛）的潜在治疗靶点。
Toll-like receptor 4 (TLR4) has been implicated in pathological conditions including chronic pain. Activation of astrocytic TLRs leads to the synthesis of pro-inflammatory cytokines like interleukin 6 (IL-6) and tumor necrosis factor-ɑ (TNF-α), which can cause pathological inflammation and tissue damage in the central nervous system. However, the mechanisms of TLR4-mediated cytokine releases from astrocytes are incomplete understood. Our previous study has shown that Orai1, a key component of calcium release activated calcium channels (CRACs), mediates Ca2+ entry in astrocytes. How Orai1 contributes to TLR4 signaling remains unclear. Here we show that Orai1 deficiency drastically attenuated lipopolysaccharides (LPS)-induced TNF-α and IL-6 production in astrocytes. Acute LPS treatment did not induce Ca2+ response and had no effect on thapsigargin (Ca2+-ATPase inhibitor)-induced store-dependent Ca2+ entry. Inhibition or knockdown of Orai1 showed no reduction in LPS-induced p-ERK1/2, p-c-Jun N-terminal kinase, or p-p38 MAPK activation. Interestingly, Orai1 protein level was significantly increased after LPS exposure, which was blocked by inhibition of NF-κB activity. LPS significantly increased basal Ca2+ level and SOCE after exposure to astrocytes. Moreover, elevating extracellular Ca2+ concentration increased cytosolic Ca2+ level, which was almost eliminated in Orai1 KO astrocytes. Our study reports novel findings that Orai1 acts as a Ca2+ leak channel regulating the basal Ca2+ level and enhancing cytokine production in astrocytes under the inflammatory condition. These findings highlight an important role of Orai1 in astrocytic TRL4 function and may suggest that Orai1 could be a potential therapeutic target for neuroinflammatory disorders including chronic pain.
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影响因子：
4
作者：
Berry CT;May MJ;Freedman BD
通讯作者：
Freedman BD
影响因子：
7.4
作者：
Gao YJ;Xu ZZ;Liu YC;Wen YR;Decosterd I;Ji RR
通讯作者：
Ji RR
DOI：
10.1073/pnas.1502264112
发表时间：
2015-05-05
影响因子：
11.1
作者：
Davis, Felicity M.;Janoshazi, Agnes;Putney, James W., Jr.
通讯作者：
Putney, James W., Jr.
影响因子：
6.2
作者：
Gao, Yong-Jing;Zhang, Ling;Ji, Ru-Rong
通讯作者：
Ji, Ru-Rong
DOI：
10.1016/j.bbrc.2015.01.160
发表时间：
2015-03-13
影响因子：
3.1
作者：
Du Shi-lin;Xue Yuan;Tong Chao-yang
通讯作者：
Tong Chao-yang