{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Birla H"],"funding":["National Institute of Neurological Disorders and Stroke","NINDS NIH HHS"],"pagination":["102619"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9928533"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["105"],"pubmed_abstract":["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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> response and had no effect on thapsigargin (Ca<sup>2+</sup>-ATPase inhibitor)-induced store-dependent Ca<sup>2+</sup> 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 Ca<sup>2+</sup> level and SOCE after exposure to astrocytes. Moreover, elevating extracellular Ca<sup>2+</sup> concentration increased cytosolic Ca<sup>2+</sup> level, which was almost eliminated in Orai1 KO astrocytes. Our study reports novel findings that Orai1 acts as a Ca<sup>2+</sup> leak channel regulating the basal Ca<sup>2+</sup> 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."],"journal":["Cell calcium"],"pubmed_title":["Toll-like receptor 4 activation enhances Orai1-mediated calcium signal promoting cytokine production in spinal astrocytes."],"pmcid":["PMC9928533"],"funding_grant_id":["R01NS087033","R01 NS117484","R01NS117484","R01 NS087033"],"pubmed_authors":["Xia J","Patel S","Hu H","Birla H","Wang F","Gao X","Bekker A","Tao YX","Zhao H","Amponsah A"],"additional_accession":[]},"is_claimable":false,"name":"Toll-like receptor 4 activation enhances Orai1-mediated calcium signal promoting cytokine production in spinal astrocytes.","description":"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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> response and had no effect on thapsigargin (Ca<sup>2+</sup>-ATPase inhibitor)-induced store-dependent Ca<sup>2+</sup> 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 Ca<sup>2+</sup> level and SOCE after exposure to astrocytes. Moreover, elevating extracellular Ca<sup>2+</sup> concentration increased cytosolic Ca<sup>2+</sup> level, which was almost eliminated in Orai1 KO astrocytes. Our study reports novel findings that Orai1 acts as a Ca<sup>2+</sup> leak channel regulating the basal Ca<sup>2+</sup> 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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Jul","modification":"2025-04-04T00:35:37.062Z","creation":"2025-04-04T00:35:37.062Z"},"accession":"S-EPMC9928533","cross_references":{"pubmed":["35780680"],"doi":["10.1016/j.ceca.2022.102619"]}}