Oxidized Low Density Lipoprotein Induced Caspase-1 Mediated Pyroptotic Cell Death in Macrophages: Implication in Lesion Instability?

Lin, Jing; Shou, Xiling; Mao, Xiaobo; Dong, Jiyang; Mohabeer, Nilesh; Kushwaha, Kishan Kumar; Wang, Lei; Su, Yousu; Fang, Hongcheng; Li, Dazhu

doi:10.1371/journal.pone.0062148

Cited by 64 publications

(65 citation statements)

References 34 publications

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“…Our results also indicated that p65 was activated by ox-LDL, and p65 activation was Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry required for IL-1β production. In addition to IL-1β gene and protein expressions, ox-LDL also promoted its maturation (showed by cleaved IL-1β), which is similar to previous results [35,36]. Caspase-1 is the major regulator that promote IL-1β maturation and is mainly regulated by NLRP3 [37].…”

Section: Discussionsupporting

confidence: 88%

C/EBPβ Acts Upstream of NF-κB P65 Subunit in Ox-LDL-Induced IL-1β Production by Macrophages

Liu

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Interleukin-1β (IL-1β) is one of the critical inflammatory factors during atherogenesis. CCAAT/enhancer binding proteins β (C/EBPβ), a regulator of IL-1β production, recently been evidenced as a key player in the development of atherosclerosis. However, the mechanisms of how C/EBPβ regulates the production of IL-1β are unclear. In this study, we aimed to explore the role of C/EBPβ in regulating IL-1β production in macrophages after oxidized low-density lipoprotein (ox-LDL) exposure and the underlying mechanisms. Methods: RAW264.7 macrophages were treated with 0, 25, 50 or 100 μg/ml ox-LDL for 12, 24 or 48 h. Small interfering RNAs were used to silence related proteins. The gene and protein expression levels were determined by quantitative real-time polymerase chain reaction or western blot (WB). IL-1β secretion was assessed by enzyme-linked immunosorbent assay. The cytoplasmic and nuclear proteins were evaluated by nuclear fractionation followed by WB. Localization of p65 was observed by immunofluorescence. The binding activity of p65 to IL-1β was tested by dual-luciferase reporter assay. Results: Ox-LDL increased IL-1β production, accompanied with increasing C/EBPβ and p65 expression in a dose- and time-dependent manner. Moreover, C/EBPβ deficiency in macrophages blocked ox-LDL-induced increases in IL-1β expression, maturation as well as p65 activation. However, p65 deficiency inhibited the increase in IL-1β production, but not C/EBPβ expression. Dual-luciferase reporter results showed that overexpression of C/EBPβ significantly enhanced binding activity of p65 to IL-1β promoter. In addition, C/EBP 1β deficiency in macrophages abolished the ox-LDL-induced gene transcription increases of IL-1β, IL-6, p65 and caspase-1. Conclusions: Our results demonstrate that C/EBPβ acts upstream of NF-κB p65 subunit in ox-LDL-induced IL-1β production in macrophages and may regulate IL-1β maturation by promoting caspase-1. C/EBPβ may be a promising candidate for the prevention and treatment of atherosclerosis.

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Section: Discussionsupporting

confidence: 88%

C/EBPβ Acts Upstream of NF-κB P65 Subunit in Ox-LDL-Induced IL-1β Production by Macrophages

Liu

Yang

et al. 2018

Cell Physiol Biochem

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“…Moreover, pre‐treatment with a caspase‐1 inhibitor (Z‐YVAD‐FMK) clearly attenuated PA‐induced cell death; therefore, PA‐mediated cytotoxicity partially owed to the induction of pyroptosis. Importantly, mature IL‐1β is one of the key proinflammatory cytokine implicated in many human diseases, including diabetes , AS and neurodegenerative diseases , and ICAM‐1 expression is important for the initiation and progression of AS . Thus, in the present study, we also demonstrated that PA induced IL‐1β maturation and release, as well as ICAM‐1 expression in HUVECs, which were attenuated by Z‐YVAD‐FMK.…”

Section: Discussionmentioning

confidence: 99%

Dihydromyricetin inhibits NLRP3 inflammasome‐dependent pyroptosis by activating the Nrf2 signaling pathway in vascular endothelial cells

Zhang

et al. 2017

BioFactors

146

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Increasing evidence demonstrates that pyroptosis, pro-inflammatory programmed cell death, is linked to atherosclerosis; however, the underlying mechanisms remain to be elucidated. Dihydromyricetin (DHM), a natural flavonoid, was reported to exert anti-oxidative and anti-inflammatory bioactivities. However, the effect of DHM on atherosclerosis-related pyroptosis has not been studied. In the present study, palmitic acid (PA) treatment led to pyroptosis in human umbilical vein endothelial cells (HUVECs), as evidenced by caspase-1 activation, LDH release, and propidium iodide-positive staining; enhanced the maturation and release of proinflammatory cytokine IL-1β and activation of the NLRP3 inflammasome; and markedly increased intracellular reactive oxygen species (ROS) and mitochondrial ROS (mtROS) levels. Moreover, NLRP3 siRNA transfection or treatment with inhibitors efficiently suppressed PA-induced pyroptosis, and pretreatment with total ROS scavenger or mtROS scavenger attenuated PA-induced NLRP3 inflammasome activation and subsequent pyroptosis. However, DHM pretreatment inhibited PA-induced pyroptotic cell death by increasing cell viability, decreasing LDH and IL-1β release, improving cell membrane integrity, and abolishing caspase-1 cleavage and subsequent IL-1β maturation. We also found that DHM pre-treatment remarkably reduced the levels of intracellular ROS and mtROS and activated the Nrf2 signaling pathway. Moreover, knockdown of Nrf2 by siRNA abrogated the inhibitory effects of DHM on ROS generation and subsequent PA-induced pyroptosis. Together, these results indicate that the Nrf2 signaling pathway plays a role, as least in part, in the DHM-mediated improvement in PA-induced pyroptosis in vascular endothelial cells, which implies the underlying medicinal value of DHM targeting immune/inflammatory-related diseases, such as atherosclerosis. © 2017 BioFactors, 44(2):123-136, 2018.

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“…Although apoptosis is well documented in atherosclerosis, recent studies showed that pyroptosis also plays an important role in atherosclerosis and plaque stability . Pyroptosis is a caspase‐1‐dependent apoptotic process characterized by the presence of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow‐specific caspase‐1/11 deficiency inhibits atherosclerosis development in Ldlr^−/− mice

et al. 2015

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Recent investigations have suggested that inflammasome activation plays an important role during atherosclerosis. Upon activation, the inflammasome induces processing and release of pro‐inflammatory cytokines interleukin 1β (IL‐1β) and interleukin 18 (IL‐18) via activation of caspase‐1/11. Previously, it was shown that complete caspase‐1 deficiency is protective against atherosclerosis development. However, while macrophages are the main inflammatory cells involved in atherosclerosis, the exact role of macrophage‐specific caspase‐1/11 activation during development of cardiovascular disease has never been investigated. We hypothesized that hematopoietic caspase‐1/11 deficiency leads to reduced atherosclerosis development. To investigate the specific contribution of hematopoietic caspase‐1/11 activation to atherosclerosis development, Ldlr−/− mice received a transplant (tp) of wild‐type (WT) or caspase‐1/11−/− bone marrow, to create WT‐tp mice and caspase‐1/11−/−‐tp mice, and fed a high‐fat, high‐cholesterol diet for 12 weeks. Our results showed an increase in anti‐inflammatory blood leukocytes in caspase‐1/11−/−‐tp mice compared with WT‐tp mice, as indicated by a decreased level of Ly6Chigh monocytes and an increased level of Ly6Clow monocytes. In line with our hypothesis, hematopoietic deletion of caspase‐1/11 resulted in a strong reduction in atherosclerotic plaque size. Furthermore, necrotic core content was dramatically decreased in caspase‐1/11−/−‐tp mice. Our data indicate that hematopoietic caspase‐1/11 activation is involved in vascular inflammation and atherosclerosis, and plays an important role in cardiovascular disease progression.

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Oxidized Low Density Lipoprotein Induced Caspase-1 Mediated Pyroptotic Cell Death in Macrophages: Implication in Lesion Instability?

Cited by 64 publications

References 34 publications

C/EBPβ Acts Upstream of NF-κB P65 Subunit in Ox-LDL-Induced IL-1β Production by Macrophages

C/EBPβ Acts Upstream of NF-κB P65 Subunit in Ox-LDL-Induced IL-1β Production by Macrophages

Dihydromyricetin inhibits NLRP3 inflammasome‐dependent pyroptosis by activating the Nrf2 signaling pathway in vascular endothelial cells

Bone marrow‐specific caspase‐1/11 deficiency inhibits atherosclerosis development in Ldlr^−/− mice

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Oxidized Low Density Lipoprotein Induced Caspase-1 Mediated Pyroptotic Cell Death in Macrophages: Implication in Lesion Instability?

Cited by 64 publications

References 34 publications

C/EBPβ Acts Upstream of NF-κB P65 Subunit in Ox-LDL-Induced IL-1β Production by Macrophages

C/EBPβ Acts Upstream of NF-κB P65 Subunit in Ox-LDL-Induced IL-1β Production by Macrophages

Dihydromyricetin inhibits NLRP3 inflammasome‐dependent pyroptosis by activating the Nrf2 signaling pathway in vascular endothelial cells

Bone marrow‐specific caspase‐1/11 deficiency inhibits atherosclerosis development in Ldlr−/− mice

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Bone marrow‐specific caspase‐1/11 deficiency inhibits atherosclerosis development in Ldlr^−/− mice