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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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Detalles Bibliográficos
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
Descripción
Sumario: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.