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

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.

TRP Ion Channels in Immune Cells and Their Implications for Inflammation

“…As cell membrane receptors, TRP ion channels can be regulated by a diverse range of physical stimuli and chemical agents as well as endogenous ligands. Many of these factors coincide with inflammatory elements [ 12 , 20 , 78 , 83 , 93 ]. It has been suggested that there are an abundance of intervention options available at this juncture.…”

“…Upon lipopolysaccharide (LPS) stimulation, M2 macrophages have elevated expression of TRPC1 that supersedes that of Orai1 in these cells [ 19 ]. TRPC3 has been identified as a novel effector for LPS-triggered Ca 2+ signaling in primitive macrophages [ 20 ]. One study indicates that the expression of TRPC5 negatively regulates the transformation of macrophages into the M1 phenotype by inhibiting their polarization [ 21 ].…”

“…LPS is present in endoplasmic reticulum (ER) membranes, where lipin-1 hydrolyzes phosphatidic acid (PA) pools sequentially to evoke macrophages to generate diacylglycerol (DAG), which further activates TRPC3 ion channels to ensure intracellular Ca 2+ elevation. Ultimately, this triggers a cascade of cellular signaling that induces NF-κB translocation to the nucleus and up-regulation of inflammatory genes [ 20 ]. Jing et al identified that overexpression of TRPC3 inhibits T cell activation, particularly CD8 + T lymphocytes, thus promoting inflammation-induced preterm labor [ 65 ].…”

“…TRP ion channels can exhibit divergent roles in inflammation, either promoting or inhibiting the inflammatory response depending on their distribution within distinct immune cell populations. Specifically, resident TRPC3 in macrophages is associated with a pro-inflammatory effect, while its presence in microglia and T lymphocytes contributes to an anti-inflammatory response [ 20 , 39 , 65 ]. TRPM2 is widely expressed in macrophages, microglial cells, neutrophils, and DCs.…”

Function of TRP channels in monocytes/macrophages

“…It has been reported that TRP not only exists in the cell membrane but also in intracellular organelles ( 37 ). In the process of LPS activation, lipoprotein Lipin-1 stimulated the enrichment of endoplasmic reticulum DAG, the activation of endoplasmic reticulum TRPC3 channel, the release of ER calcium, the increase of Ca2+, the activation of NF-κB, and the upregulation of cytokines ( 38 ). Phagocytosis of immune cell function is closely related to TRPML channels ( 39 ).…”