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Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling

Exposure to Gram-negative bacterial LPS exacerbates host immune responses and may lead to sepsis, a life-threatening condition. Despite its high mortality and morbidity, no drugs specifically directed to treating sepsis are currently available. Using human cell genetic depletion, pharmacological inh...

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Autores principales: Casas, Javier, Meana, Clara, López-López, José Ramón, Balsinde, Jesús, Balboa, María A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629864/
https://www.ncbi.nlm.nih.gov/pubmed/34757442
http://dx.doi.org/10.1007/s00018-021-03999-0
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author Casas, Javier
Meana, Clara
López-López, José Ramón
Balsinde, Jesús
Balboa, María A.
author_facet Casas, Javier
Meana, Clara
López-López, José Ramón
Balsinde, Jesús
Balboa, María A.
author_sort Casas, Javier
collection PubMed
description Exposure to Gram-negative bacterial LPS exacerbates host immune responses and may lead to sepsis, a life-threatening condition. Despite its high mortality and morbidity, no drugs specifically directed to treating sepsis are currently available. Using human cell genetic depletion, pharmacological inhibition, live-cell microscopy and organelle-targeted molecular sensors we present evidence that the channel TRPC3 is activated intracellularly during macrophage exposure to LPS and is essential for Ca(2+) release from internal stores. In this manner, TRPC3 participates in cytosolic Ca(2+) elevations, activation of the transcription factor NF-κB and cytokine upregulation. We also report that TRPC3 is activated by diacylglycerol generated by the phosphatidic acid phosphatase lipin-1. In accord with this, lipin-1-deficient cells exhibit reduced Ca(2+) responses to LPS challenge. Finally, pharmacological inhibition of TRPC3 reduces systemic inflammation induced by LPS in mice. Collectively, our study unveils a central component of LPS-triggered Ca(2+) signaling that involves intracellular sensing of lipin-1-derived DAG by TRPC3, and opens new opportunities for the development of strategies to treat LPS-driven inflammation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-021-03999-0.
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spelling pubmed-86298642021-12-15 Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling Casas, Javier Meana, Clara López-López, José Ramón Balsinde, Jesús Balboa, María A. Cell Mol Life Sci Original Article Exposure to Gram-negative bacterial LPS exacerbates host immune responses and may lead to sepsis, a life-threatening condition. Despite its high mortality and morbidity, no drugs specifically directed to treating sepsis are currently available. Using human cell genetic depletion, pharmacological inhibition, live-cell microscopy and organelle-targeted molecular sensors we present evidence that the channel TRPC3 is activated intracellularly during macrophage exposure to LPS and is essential for Ca(2+) release from internal stores. In this manner, TRPC3 participates in cytosolic Ca(2+) elevations, activation of the transcription factor NF-κB and cytokine upregulation. We also report that TRPC3 is activated by diacylglycerol generated by the phosphatidic acid phosphatase lipin-1. In accord with this, lipin-1-deficient cells exhibit reduced Ca(2+) responses to LPS challenge. Finally, pharmacological inhibition of TRPC3 reduces systemic inflammation induced by LPS in mice. Collectively, our study unveils a central component of LPS-triggered Ca(2+) signaling that involves intracellular sensing of lipin-1-derived DAG by TRPC3, and opens new opportunities for the development of strategies to treat LPS-driven inflammation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-021-03999-0. Springer International Publishing 2021-11-10 2021 /pmc/articles/PMC8629864/ /pubmed/34757442 http://dx.doi.org/10.1007/s00018-021-03999-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Casas, Javier
Meana, Clara
López-López, José Ramón
Balsinde, Jesús
Balboa, María A.
Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling
title Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling
title_full Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling
title_fullStr Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling
title_full_unstemmed Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling
title_short Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling
title_sort lipin-1-derived diacylglycerol activates intracellular trpc3 which is critical for inflammatory signaling
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629864/
https://www.ncbi.nlm.nih.gov/pubmed/34757442
http://dx.doi.org/10.1007/s00018-021-03999-0
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