S1P/S1P2 Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

Abstract

The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P receptor subtype involved and underlying regulatory mechanisms. During the priming stage, S1P induced NLRP3 upregulation in BMDMs only when primed with lipopolysaccharide (LPS). In this event, S1P2, but not S1P1, was involved based on the attenuated NLRP3 upregulation with JTE013 (S1P2 antagonist) or S1P2 knockdown. During the activation stage, S1P induced NLRP3 inflammasome activation in LPS-primed BMDMs via caspase-1 activation, interleukin 1β maturation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, and IL-1β secretion. Such NLRP3 inflammasome activation was blocked by either pharmacological inhibition or genetic knockdown of S1P2. NF-κB, PI3K/Akt, and ERK1/2 were identified as effector pathways underlying S1P/S1P2 signaling in the regulation of NLRP3 upregulation in LPS-primed BMDMs. Further, reactive oxygen species (ROS) production was dependent on the S1P/S1P2 signaling axis in these cells, and the ROS generated regulate NLRP3 inflammasome activation, but not NLRP3 priming. Collectively, our findings suggest that S1P promotes NLRP3 upregulation and NLRP3 inflammasome activation in LPS-primed BMDMs via S1P2 and subsequent effector pathways.

Sphingosine 1‐phosphate elicits a ROS‐mediated proinflammatory response in human endometrial stromal cells via ERK5 activation

“…This is in agreement with a previous study performed in human pulmonary alveolar epithelial cells showing that S1P increased the inflammatory response through a NADPH oxidase/ROS‐dependent NF‐κB activation mechanism 52 . Moreover, in bone marrow‐derived macrophages, S1P/S1P 2 signaling axis was responsible for ROS production and NLRP3 inflammasome activation 53 . Thus, our data, in keeping with other reports, 52–54 support the evidence that S1P is a lipid engaging a redox‐based signaling.…”

“…52 Moreover, in bone marrow-derived macrophages, S1P/ S1P 2 signaling axis was responsible for ROS production and NLRP3 inflammasome activation. 53 Thus, our data, in keeping with other reports, [52][53][54] support the evidence that S1P is a lipid engaging a redox-based signaling. Here, the identification of S1P 1/3 as responsible for ROS generation in endometrial cells in response to S1P treatment further highlights that the signaling mediated by S1PR is cell-specific.…”

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

“…GSDMD is a soluble, inactive precursor protein consisting of GSDMD-N and GSDMD-C, two structural domains that can be separated by a bendable inter-domain linker [ 14 ]. Activated inflammatory cysteine aspartic proteases (Caspase-1, 4, and 5 in humans; Caspase-1 and 11 in mice) cleave GSDMD in structural interdomain linkers, resulting in the translocation of GSDMD-N into endoplasmic membrane leaflets and the subsequent pinching of two plasma membrane leaflets to aggregate into oligomers, resulting in large GSDMD pores that lead to cell permeability swelling and spontaneous cell death [ 47 , 48 ]. Previous studies have revealed that liver injury resulted in abundant damage and associated molecular patterns (DAMPs) being released, and further up-regulated and activated NLRP3 inflammasome, which led to pyroptosis [ 49 ].…”

Integrative network fusion-based multi-omics study for biomarker identification and patient classification of rheumatoid arthritis

“…As the activation of the NLRP3 inflammasome and the occurrence of pyroptosis, the metabolic levels of the body may also be disturbed, especially the changes in lipid metabolites [ 55 ]. Ceramide is the main metabolite of the sphingolipid metabolic pathway and one of the important synthetic substrates for NLRP3, which can be supplemented by S1P through ceramidase and sphingosine kinase [ 56 ]. According to our metabonomics data, we found that the contents of “Sphingolipid metabolism” related differential metabolites were significantly increased.…”