Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling.
Cell Mol Life Sci
; 78(24): 8243-8260, 2021 Dec.
Article
in En
| MEDLINE
| ID: mdl-34757442
ABSTRACT
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 Ca2+ release from internal stores. In this manner, TRPC3 participates in cytosolic Ca2+ 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 Ca2+ 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 Ca2+ 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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Phosphatidate Phosphatase
/
Cytokines
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Diglycerides
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TRPC Cation Channels
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Inflammation
Limits:
Animals
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Humans
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Male
Language:
En
Year:
2021
Type:
Article