Dataset Information

P2X7 receptor antagonism modulates IL-1? and MMP9 in human atherosclerotic vessels.

ABSTRACT: In atherosclerosis, matrix metallopeptidases (MMPs) contribute to plaque rupture through weakening of the fibrous cap. Pleiotropic P2X purinoceptor 7 (P2X7), expressed in the carotid plaque (PL), is involved in interleukin 1 beta (IL-1?) release that may influence MMP9 generation, thus their possible modulation through acting on P2X7 was investigated. P2X7-related machinery was characterized and the effects of P2X7 antagonists (A740003, KN62) and MMPs inhibitors (Batimastat, Ro28-2653) were studied in ex-vivo tissue cultures of human PL's vs. non-atherosclerotic internal mammary artery (IMA) by using molecular biology, immune-biochemical and microscopy methodologies. We highlighted atherosclerosis-related differences between PLs and IMAs molecular patterns, and their responsivity to P2X7 antagonism. High IL-1? tissue content was associated with PLs morphology and instability/vulnerability. We demonstrated that A740003, but not KN62, decreased IL-1? and MMP9 independently from NLR family pyrin domain containing 3, but in relationship with patient's smoking status. Acting downstream P2X7 by MMPs inhibitors, diminished IL-1? mRNA without transcriptional effect at MMP9, possibly because the assumption of statin by patients. These data firstly demonstrated A740003 suitability as a specific tool to decrease inflammatory status in human vessels and might support the design of studies applying P2X7 antagonists for the local targeting and tailored therapy of atherosclerosis.

SUBMITTER: Lombardi M

PROVIDER: S-EPMC5501842 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels.

Lombardi Maria M Mantione Maria Elena ME Baccellieri Domenico D Ferrara David D Castellano Renata R Chiesa Roberto R Alfieri Ottavio O Foglieni Chiara C

Scientific reports 20170707 1

In atherosclerosis, matrix metallopeptidases (MMPs) contribute to plaque rupture through weakening of the fibrous cap. Pleiotropic P2X purinoceptor 7 (P2X7), expressed in the carotid plaque (PL), is involved in interleukin 1 beta (IL-1β) release that may influence MMP9 generation, thus their possible modulation through acting on P2X7 was investigated. P2X7-related machinery was characterized and the effects of P2X7 antagonists (A740003, KN62) and MMPs inhibitors (Batimastat, Ro28-2653) were stud ...[more]

PMID: 28687781

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Project description:BACKGROUND:Toxoplasma gondii can invade and replicate in all nucleated cells in a wide range of host species, and infection induces IL-1β production. IL-1β plays central roles in the stimulation of the innate immune system and inflammation. However, little is known of the innate immune responses in human fetal small intestinal epithelial cells (FHs 74 Int cells) after T. gondii infection. METHODS:FHs 74 Int cells were infected with the T. gondii GFP-RH strain. Then, IL-1β production and its mechanisms of action were evaluated using ELISA, MTT cell viability assays, Western blotting, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), and gene-specific small interfering RNA (siRNA) transfection. RESULTS:Infection of FHs 74 Int cells by T. gondii triggered significant time- and dose-dependent IL-1β production. Although T. gondii activated NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes in FHs 74 Int cells, NLRP3 levels were consistently and significantly time-dependently increased, while the other inflammasomes were not. Transfection with siRNA targeting NLRP3, cleaved caspase-1 (Casp-1) or ASC significantly reduced T. gondii-induced IL-1β production, whereas T. gondii proliferation was markedly increased. Toxoplasma gondii infection activated P2X7 receptor (P2X7R) levels in FHs 74 Int cells in a time-dependent manner; however, transfection with siRNA targeting P2X7R significantly reduced T. gondii-induced IL-1β secretion and substantially increased T. gondii proliferation, which is mediated by decreased protein expression levels of NLRP3, cleaved Casp-1 and ASC. Collectively, NLRP3-dependent IL-1β secretion is mediated by P2X7R in small intestinal epithelial cells in response to T. gondii infection, thereby controlling parasite proliferation. CONCLUSIONS:This study revealed that the P2X7R/NLRP3 pathway plays important roles in IL-1β secretion and inhibition of T. gondii proliferation in small intestinal epithelial cells. These results not only contribute to our understanding of the mucosal immune mechanisms of T. gondii infection but also offer new insight into the identification of innate resistance in the gut epithelium.

Dataset Information

P2X7 receptor antagonism modulates IL-1? and MMP9 in human atherosclerotic vessels.

Publications

P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels.

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