ArticleCellular & molecular immunology2017
Extracellular calcium elicits feedforward regulation of the Toll-like receptor-triggered innate immune response.
Article in Cellular & molecular immunology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
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- Emerging Potential of Ras-proximate-1 (Rap1) in Mediating Neurodegenerative Diseases.Current neuropharmacology · 2026Review
- An arthropod transporter IsOATP4056 exerts inhibitory effect on its interacting membrane protein to facilitate rickettsial pathogen survival in ticks.Cell communication and signaling : CCS · 2025Article
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- Loss of STIM1 and STIM2 in Salivary Glands Disrupts ANO1 Function but Does Not Induce Sjogren's Disease.Function (Oxford, England) · 2025Article
- The role of toll-like receptors (TLRs) and their therapeutic applications in glomerulonephritis.International urology and nephrology · 2023Review
- Understanding the Photodynamic Therapy Induced Bystander and Abscopal Effects: A Review.Antioxidants (Basel, Switzerland) · 2023Review
- RasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth.Nature communications · 2022Article
- Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses.Nature communications · 2022Article
- Thromboinflammation in Myeloproliferative Neoplasms (MPN)-A Puzzle Still to Be Solved.International journal of molecular sciences · 2022Review
- Calcium Ions Signaling: Targets for Attack and Utilization by Viruses.Frontiers in microbiology · 2022Review
- Ion channel Piezo1 activation promotes aerobic glycolysis in macrophages.Frontiers in immunology · 2022Article
- Cannabidiol selectively modulates interleukin (IL)-1β and IL-6 production in toll-like receptor activated human peripheral blood monocytes.Toxicology · 2021Article
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- Airway Administration of Flagellin Regulates the Inflammatory Response toAmerican journal of respiratory cell and molecular biology · 2021Article
- Monocyte Gene Expression Distinguishes Enhancing Brain Parenchymal Cysticercal Granulomas From Tuberculomas.Open forum infectious diseases · 2021Article
- Endoplasmic reticulum & mitochondrial calcium homeostasis: The interplay with viruses.Mitochondrion · 2021Article
- The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress.Cell death & disease · 2021Article
- Integration of Rap1 and Calcium Signaling.International journal of molecular sciences · 2020Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Despite the expanding knowledge on feedback regulation of Toll-like receptor (TLR) signaling, the feedforward regulation of TLR signaling for the proper innate response to invading microbes is not fully understood. Here, we report that extracellular calcium can coordinate the activation of the small GTPases Ras and Ras-proximate-1 (Rap1) upon TLR stimulation which favors activation of macrophages through a feedforward mechanism. We show that different doses of TLR agonists can trigger different levels of cytokine production, which can be potentiated by extracellular calcium but are impaired by the chelating reagent ethylene glycol tetraacetic acid (EGTA) or by knockdown of stromal interaction molecule 1 (STIM1). Upon TLR engagement, GTP-bound Ras levels are increased and GTP-bound Rap1 is decreased, which can be reversed by EGTA-mediated removal of extracellular calcium. Furthermore, we demonstrate that Rap1 knockdown rescues the inhibitory effects of EGTA on the TLR-triggered innate response. Examination of the TLR signaling pathway reveals that extracellular calcium may regulate the TLR response via feedforward activation of the extracellular signal-regulated kinase signaling pathway. Our data suggest that an influx of extracellular calcium, mediated by STIM1-operated calcium channels, may transmit the information about the intensity of extracellular TLR stimuli to initiate innate responses at an appropriate level. Our study may provide mechanistic insight into the feedforward regulation of the TLR-triggered innate immune response.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.