Toll-like receptor 4 activation enhances Orai1-mediated calcium signal promoting cytokine production in spinal astrocytes.

Birla, Hareram; Xia, Jingsheng; Gao, Xinghua; Zhao, Hui; Wang, Fengying; Patel, Shivam; Amponsah, Akwasi; Bekker, Alex; Tao, Yuan‐Xiang; Hu, Huijuan

doi:10.1016/j.ceca.2022.102619

Cited by 8 publications

(7 citation statements)

References 81 publications

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“…Growing evidence has suggested that nerve injury and inflammation can modulate the functions of sensory SGCs, which are notably linked with pain sensation through TLR4 activation and GFAP upregulation-associated production of proinflammatory cytokines [ 2 ]. Recent studies have remarkably demonstrated that LPS-induced upregulation of SOCE increases proinflammatory cytokine production in spinal astrocytes, and initiates inflammatory signaling pathways in a mouse hippocampal cell line [ 19 , 38 ]. In contrast, we found that LPS diminished SOCE by downregulating Orai1 and STIM1 expression in the sympathetic ganglia.…”

Section: Discussionmentioning

confidence: 99%

“…While SOCE has been extensively studied in various glial cells within the central nervous system, including astrocytes, oligodendrocytes, microglia, and Muller glia [ 13 - 18 ], information on glial Ca 2+ signaling and its mechanisms in the autonomic ganglia remains scarce. Evidence suggests that dysregulation of SOCE in astrocytes and microglia occurs under conditions like lipopolysaccharide (LPS)-induced inflammation [ 17 , 19 ]. As an initial exploration into the physiological and pathophysiological roles of glial Ca 2+ signaling in autonomic ganglia, we examined the presence of SOCE and its machinery in rat superior cervical ganglia (SCG).…”

Section: Introductionmentioning

confidence: 99%

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Store-operated calcium entry in the satellite glial cells of rat sympathetic ganglia

Kim,

Kang,

Nguyen

et al. 2024

Korean J Physiol Pharmacol

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Satellite glial cells (SGCs), a major type of glial cell in the autonomic ganglia, closely envelop the cell body and even the synaptic regions of a single neuron with a very narrow gap. This structurally unique organization suggests that autonomic neurons and SGCs may communicate reciprocally. Glial Ca 2+ signaling is critical for controlling neural activity. Here, for the first time we identified the machinery of store-operated Ca 2+ entry (SOCE) which is critical for cellular Ca 2+ homeostasis in rat sympathetic ganglia under normal and pathological states. Quantitative real-time PCR and immunostaining analyses showed that Orai1 and stromal interaction molecules 1 (STIM1) proteins are the primary components of SOCE machinery in the sympathetic ganglia. When the internal Ca 2+ stores were depleted in the absence of extracellular Ca 2+ , the number of plasmalemmal Orai1 puncta was increased in neurons and SGCs, suggesting activation of the Ca 2+ entry channels. Intracellular Ca 2+ imaging revealed that SOCE was present in SGCs and neurons; however, the magnitude of SOCE was much larger in the SGCs than in the neurons. The SOCE was significantly suppressed by GSK7975A, a selective Orai1 blocker, and Pyr6, a SOCE blocker. Lipopolysaccharide (LPS) upregulated the glial fibrillary acidic protein and Toll-like receptor 4 in the sympathetic ganglia. Importantly, LPS attenuated SOCE via downregulating Orai1 and STIM1 expression. In conclusion, sympathetic SGCs functionally express the SOCE machinery, which is indispensable for intracellular Ca 2+ signaling. The SOCE is highly susceptible to inflammation, which may affect sympathetic neuronal activity and thereby autonomic output.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Store-operated calcium entry in the satellite glial cells of rat sympathetic ganglia

Kim,

Kang,

Nguyen

et al. 2024

Korean J Physiol Pharmacol

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“…TLR4 activation promotes the migration and proliferation of breast cancer cells [ 9 , 10 ]. Previous studies have reported that some actions of TLR4 are enhanced by SOCE in other cells, such as microglia and astrocytes [ 20 , 21 ]. Our study herein was designed to evaluate whether the SOCE pathway can influence the TLR4 signaling in breast cancer cells and ultimately affect inflammation-induced cancer progression processes.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have illustrated the vital role of SOCE in immune signaling [ 19 ]. The inhibition of the SOCE pathway results in impaired TLR4-mediated immune responses in the microglia [ 20 ] and astrocytes [ 21 ]. However, it is not known how SOCE affects the TLR4 signaling in breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Targeting Store-Operated Calcium Entry Regulates the Inflammation-Induced Proliferation and Migration of Breast Cancer Cells

et al. 2023

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Persistent challenges complicating the treatment of breast cancer remain, despite some recent undeniable successes. Sufficient evidence currently exists demonstrating the crucial role of inflammation, characterized by the enhanced activation of Toll-like receptor 4 (TLR4) and the COX-2/PGE2 pathway, in the migration and proliferation of breast cancer cells. Interestingly, the store-operated calcium entry (SOCE) pathway was shown to be essential for the TLR4 activity and COX-2 expression in immune cells such as macrophages and microglia. However, whether SOCE influences inflammatory signaling and the inflammation-induced proliferation and migration of breast cancer cells is still unknown. Thus, the current study intended to delineate the role of SOCE in the TLR4-induced inflammation, migration, and proliferation of breast cancer cells. To this end, MDA-MB-231 breast cancer cells were treated with lipopolysaccharide (LPS) to activate TLR4, BTP2 to inhibit SOCE, and Thapsigargin to induce SOCE. Following these treatments, several experiments were conducted to evaluate the proliferation and migration rates of the MDA-MB-231 cells and the expression of several inflammatory and oncogenic genes, including COX-2, PGE2, IL-6, IL-8, and VEGF. Different techniques were used to achieve the aims of this study, including qRT-PCR, Western blotting, ELISA, MTT, and wound healing assays. This study shows that SOCE inhibition using BTP2 suppressed the LPS-induced migration and proliferation of breast cancer cells. Additionally, treatment with LPS caused approximately six- and three-fold increases in COX-2 mRNA and protein expression, respectively, compared to the controls. The LPS-induced elevations in the COX-2 mRNA and protein levels were suppressed by BTP2 to the control levels. In addition to its effect on COX-2, BTP2 also suppressed the LPS-induced productions of PGE2, IL-6, IL-8, and VEGF. Conversely, SOCE induction using Thapsigargin enhanced the LPS-induced inflammation, migration, and proliferation of breast cancer cells. Collectively, these results provide evidence for the potentially important role of SOCE in inflammation-induced breast cancer progression processes. Thus, we argue that the current study may provide novel targets for designing new therapeutic approaches for the treatment of breast cancer.

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“…Through mitogen‐activated protein kinases, TLRs activate a signaling pathway, which in turn results in NF‐kB activation (Nicotra et al, 2012; Schroder et al, 2006). Under inflammatory conditions this pathway induces activation of Orai1 (a key member of the calcium release‐activated calcium channels; Kraft, 2015) in astrocytes, resulting in increased intracellular calcium levels (Birla et al, 2022). Since microglia also express Orai1, it is conceivable that a similar mechanism modulates the LPS‐mediated BEST‐1 upregulation (Michaelis et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide augments microglial GABA uptake by increasing GABA transporter‐1 trafficking and bestrophin‐1 expression

Palma

Serpe

Luca

et al. 2023

Glia

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Gamma‐aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the brain, affects numerous immune cell functions. Microglia, the brain's resident innate immune cells, regulate GABA signaling through GABA receptors and express the complete GABAergic machinery for GABA synthesis, uptake, and release. Here, the use of primary microglial cell cultures and ex vivo brain tissue sections allowed for demonstrating that treatment with lipopolysaccharide (LPS) increased microglial GABA uptake as well as GABA transporter (GAT)‐1 trafficking. This effect was not entirely abolished by treatment with GAT inhibitors (GAT‐Is). Notably, LPS also induced microglial upregulation of bestrophin‐1 (BEST‐1), a Ca2+‐activated Cl− channel permeable to GABA. Combined administration of GAT‐Is and a BEST‐1 inhibitor completely abolished LPS‐induced microglial GABA uptake. Interestingly, increased microglial GAT‐1 membrane turnover via syntaxin 1A was detected in LPS‐treated cultures after BEST‐1 blockade. Altogether, these findings provided evidence for a novel mechanism through which LPS may trigger the inflammatory response by directly altering microglial GABA clearance and identified the GAT‐1/BEST‐1 interplay as a potential novel mechanism involved in brain inflammation.

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Toll-like receptor 4 activation enhances Orai1-mediated calcium signal promoting cytokine production in spinal astrocytes.

Cited by 8 publications

References 81 publications

Store-operated calcium entry in the satellite glial cells of rat sympathetic ganglia

Store-operated calcium entry in the satellite glial cells of rat sympathetic ganglia

Targeting Store-Operated Calcium Entry Regulates the Inflammation-Induced Proliferation and Migration of Breast Cancer Cells

Lipopolysaccharide augments microglial GABA uptake by increasing GABA transporter‐1 trafficking and bestrophin‐1 expression

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