Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization

Shu, Fei; Chen, Jiahuan; Ma, Xiaojie; Fan, Yunzhou; Yu, Li; Zheng, Wenfeng; Amrein, Matthias; Xia, Tie; Shi, Yan

doi:10.3389/fimmu.2018.01163

Cited by 21 publications

(13 citation statements)

References 64 publications

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“…We found that cells containing cholesterol crystals appeared aggregated within decidual tissue, rather than randomly scattered, suggesting that cholesterol crystal mediated inflammation may be localized to specific regions in the decidua. Previous studies have suggested that the size of cholesterol crystals and their clusters may be an important factor in the inflammatory potential ( 44 , 45 ), but this hypothesis was not substantiated for decidual inflammation in the current study. The amount and size of cholesterol crystals in the decidua did not differ between normal and preeclamptic pregnancies.…”

Section: Discussioncontrasting

confidence: 95%

Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies

et al. 2020

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Preeclampsia is a hypertensive and inflammatory pregnancy disorder associated with cholesterol accumulation and inflammation at the maternal-fetal interface. Preeclampsia can be complicated with fetal growth restriction (FGR) and shares risk factors and pathophysiological mechanisms with cardiovascular disease. Cholesterol crystal mediated NLRP3 inflammasome activation is central to cardiovascular disease and the pathway has been implicated in placental inflammation in preeclampsia. Direct maternal-fetal interaction occurs both in the uterine wall decidua and at the placental surface and these aligned sites constitute the maternal-fetal interface. This study aimed to investigate cholesterol crystal accumulation and NLRP3 inflammasome expression by maternal and fetal cells in the uterine wall decidua of normal and preeclamptic pregnancies. Pregnant women with normal ( n = 43) and preeclamptic pregnancies with ( n = 28) and without ( n = 19) FGR were included at delivery. Cholesterol crystals were imaged in decidual tissue by both second harmonic generation microscopy and polarization filter reflected light microscopy. Quantitative expression analysis of NLRP3, IL-1β and cell markers was performed by immunohistochemistry and automated image processing. Functional NLRP3 activation was assessed in cultured decidual explants. Cholesterol crystals were identified in decidual tissue, both in the tissue stroma and near uterine vessels. The cholesterol crystals in decidua varied between pregnancies in distribution and cluster size. Decidual expression of the inflammasome components NLRP3 and IL-1β was located to fetal trophoblasts and maternal leukocytes and was strongest in areas of proximity between these cell types. Pathway functionality was confirmed by cholesterol crystal activation of IL-1β in cultured decidual explants. Preeclampsia without FGR was associated with increased trophoblast dependent NLRP3 and IL-1β expression, particularly in the decidual areas of trophoblast and leukocyte proximity. Our findings suggest that decidual accumulation of cholesterol crystals may activate the NLRP3 inflammasome and contribute to decidual inflammation and that this pathway is strengthened in areas with close maternal-fetal interaction in preeclampsia without FGR.

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Section: Discussioncontrasting

confidence: 95%

Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies

et al. 2020

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“…GSDMD pores also facilitate the release of mature IL‐1β and IL‐18, and this has recently been suggested to occur immediately prior to pyroptotic cell death . It is worth mentioning that caspase‐1 and GSDMD are not essential for cell death to all inflammasome triggers . In fact, in certain cases NLRP3 itself is dispensable, such as upon exposure to lysosomal‐disrupting agents, crystalline and particulate matter .…”

Section: Introductionmentioning

confidence: 99%

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Yabal

Calleja

Simpson

et al. 2018

Journal of Leukocyte Biology

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Inflammasomes are multimeric protein complexes that induce the cleavage and release of bioactive IL-1 and cause a lytic form of cell death, termed pyroptosis. Due to its diverse triggers, ranging from infectious pathogens and host danger molecules to environmental irritants, the NOD-like receptor protein 3 (NLRP3) inflammasome remains the most widely studied inflammasome to date. Despite intense scrutiny, a universal mechanism for its activation remains elusive, although, recent research has focused on mitochondrial dysfunction or potassium (K + ) efflux as key events. In this review, we give a general overview of NLRP3 inflammasome activation and explore the recently emerging noncanonical and alternative pathways to NLRP3 activation. We highlight the role of the NLRP3 inflammasome in the pathogenesis of metabolic disease that is associated with mitochondrial and oxidative stress. Finally, we interrogate the mechanisms proposed to trigger NLRP3 inflammasome assembly and activation. A greater understanding of how NLRP3 inflammasome activation is triggered may reveal new therapeutic targets for the treatment of inflammatory disease. K E Y W O R D Scaspases, inflammasome, metabolism, mitochondria, reactive oxygen species Abbreviations: AIM2, absent in Melanoma; AMPK, AMP-activated protein kinase; APAF-1, apoptosis protease activating factor-1; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; BMDCs, bone marrow dendritic

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“…LDL was obtained from Alfa (Thermo Fisher Scientific, Heysham, Lancashire, UK). Cholesterol crystals (CCs) were prepared according to a previous report [ 27 ]. Human and mouse IFN-α and interferon gamma (IFN-γ) was obtained from PBL Biomedical Laboratories (Piscataway, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial protein CMPK2 regulates IFN alpha-enhanced foam cell formation, potentially contributing to premature atherosclerosis in SLE

et al. 2021

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Background Premature atherosclerosis occurs in patients with SLE; however, the mechanisms remain unclear. Both mitochondrial machinery and proinflammatory cytokine interferon alpha (IFN-α) potentially contribute to atherogenic processes in SLE. Here, we explore the roles of the mitochondrial protein cytidine/uridine monophosphate kinase 2 (CMPK2) in IFN-α-mediated pro-atherogenic events. Methods Foam cell measurements were performed by oil red O staining, Dil-oxLDL uptake and the BODIPY approach. The mRNA and protein levels were measured by qPCR and Western blotting, respectively. Isolation of CD4+ T cells and monocytes was performed with monoclonal antibodies conjugated with microbeads. Manipulation of protein expression was conducted by either small interference RNA (siRNA) knockdown or CRISPR/Cas9 knockout. The expression of mitochondrial reactive oxygen species (mtROS) was determined by flow cytometry and confocal microscopy. Results IFN-α enhanced oxLDL-induced foam cell formation and Dil-oxLDL uptake by macrophages. In addition to IFN-α, several triggers of atherosclerosis, including thrombin and IFN-γ, can induce CMPK2 expression, which was elevated in CD4+ T cells and CD14+ monocytes isolated from SLE patients compared to those isolated from controls. The analysis of cellular subfractions revealed that CMPK2 was present in both mitochondrial and cytosolic fractions. IFN-α-induced CMPK2 expression was inhibited by Janus kinase (JAK)1/2 and tyrosine kinase 2 (Tyk2) inhibitors. Both the knockdown and knockout of CMPK2 attenuated IFN-α-mediated foam cell formation, which involved the reduction of scavenger receptor class A (SR-A) expression. CMPK2 also regulated IFN-α-enhanced mtROS production and inflammasome activation. Conclusions The study suggests that CMPK2 plays contributing roles in the pro-atherogenic effects of IFN-α.

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Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization

Cited by 21 publications

References 64 publications

Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies

Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Mitochondrial protein CMPK2 regulates IFN alpha-enhanced foam cell formation, potentially contributing to premature atherosclerosis in SLE

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