Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation

Abstract

To determine the roles of nuclear localization of pro-caspase-1 in human aortic endothelial cells (HAECs) activated by proatherogenic lipid lysophosphatidylcholine (LPC), we examined cytosolic and nuclear localization of pro-caspase-1, identified nuclear export signal (NES) in pro-caspase-1 and sequenced RNAs. We made the following findings: 1) LPC increases nuclear localization of procaspase-1 in HAECs. 2) Nuclear pro-caspase-1 exports back to the cytosol, which is facilitated by a leptomycin B-inhibited mechanism. 3) Increased nuclear localization of pro-caspase-1 by a new NES peptide inhibitor upregulates inflammatory genes in oxidative stress and Th17 pathways; and SUMO activator N106 enhances nuclear localization of pro-caspase-1 and caspase-1 activation (p20) in the nucleus. 4) LPC plus caspase-1 enzymatic inhibitor upregulates inflammatory genes with hypercytokinemia/hyperchemokinemia and interferon pathways, suggesting a novel capsase-1 enzyme-independent inflammatory mechanism. 5) LPC in combination with NES inhibitor and caspase-1 inhibitor upregulate inflammatory gene expression that regulate Th17 activation, endotheli-1 signaling, p38-, and ERK- MAPK pathways. To examine two hallmarks of endothelial activation such as secretomes and membrane protein signaling, LPC plus NES inhibitor upregulate 57 canonical secretomic genes and 76 exosome secretomic genes, respectively, promoting four pathways including Th17, IL-17 promoted cytokines, interferon signaling and cholesterol biosynthesis. LPC with NES inhibitor also promote inflammation via upregulating ROS promoter CYP1B1 and 11 clusters of differentiation (CD) membrane protein pathways. Mechanistically, all the LPC plus NES inhibitor-induced genes are significantly downregulated in CYP1B1-deficient microarray, suggesting that nuclear caspase-1-induced CYP1B1 promotes strong inflammation. These transcriptomic results provide novel insights on the roles of nuclear caspase-1 in sensing DAMPs, inducing ROS promoter CYP1B1 and in regulating a large number of genes that mediate HAEC activation and inflammation. These findings will lead to future development of novel therapeutics for cardiovascular diseases (CVD), inflammations, infections, transplantation, autoimmune disease and cancers. (total words: 284).

Aorta in Pathologies May Function as an Immune Organ by Upregulating Secretomes for Immune and Vascular Cell Activation, Differentiation and Trans-Differentiation—Early Secretomes may Serve as Drivers for Trained Immunity

“…We and others reported that the Nod-like receptor family 3 (NLRP3) promotes human aortic EC activation ( 41 ) induced by oxLDL and LPC ( 8 , 10 , 73 ). The inflammatory cell death (pyroptosis) ( 9 ) carried out by caspase 1 ( 38 ) canonical, caspase 4 (humans)/caspase 11 (mice) noncanonical inflammasomes ( 74 )-gasdermin D ( 75 ) pathway has been reported to mediate EC pyroptosis (inflammatory cell death) ( 76 ).…”

Editorial: Endothelial cells as innate immune cells

“…However, immunological characters of endothelial cells have been poorly characterized due to the fact that endothelial cells have not been recognized as innate immune cells in the field. To fill in this significant knowledge gap, ten years ago based on more than ten major innate immune functional aspects that are shared by the prototypic innate immune cell type -macrophages and endothelial cells, we proposed a new concept that endothelial cells are innate immune cells (2,4), which was further supported by our experimental data (5)(6)(7)(8)(9)(10)(11)(12)(13) analyses (Shao et al,15). The Molecular Innate Immunity field is continuously evolving, and we greatly appreciate the Molecular Innate Immunity section editors gave us this opportunity to organize this Research Topic and work with other investigators to explore this important topic further.…”

Lp-PLA 2 (Lipoprotein-Associated Phospholipase A 2 ) Deficiency Lowers Cholesterol Levels and Protects Against Atherosclerosis in Rabbits

“…60 The broad anti-inflammatory effects of Lp-PLA 2 deficiency were highly correlated with the decrease of the 2 key downstream inflammatory lipid mediators, especially lysophosphatidylcholine. Studies have shown that lysophosphatidylcholine could target endothelial cells to induce oxidative stress and innate immune activation, 61,62 affect cell viability and homing of inflammatory cells, 1 mediate inflammasome activation in microglia and astrocytes. 63 Recent studies have shown that Lp-PLA 2 deficiency reduced the concentrations of reactive oxygen species and inhibited ceramide-induced NLRP3 (the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome activation, the authors suspected that Lp-PLA 2 might be an important regulator of inflammasome.…”