Cholesterol crystals activate Syk and PI3 kinase in human macrophages and dendritic cells

Corr, Emma M.; Cunningham, C; Dunne, Aisling

doi:10.1016/j.atherosclerosis.2016.06.035

Cited by 40 publications

(38 citation statements)

References 25 publications

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“…The rationale for measuring IL-18 is that cholesterol crystals activate the NLRP3 inflammasome in atheroma, and IL-18 is a hallmark of inflammasome activation (Duewell et al, 2010;Baldrighi et al, 2017;Hoseini et al, 2017;Karasawa and Takahashi, 2017). The rationale for evaluating levels of MMP-2, MMP-3, and MMP-8 is that cholesterol crystals induce MMP expression in macrophages, and MMPs are abundant in atheroma (Beaudeux et al, 2004;Watanabe and Ikeda, 2004;Lenglet et al, 2013;Corr et al, 2016). Multiplex immunoassay analyses revealed that OPN is present in areas of liquefactive necrosis for at least 8 weeks following stroke ( Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

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Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin dependent mechanism

Chung

Frye

Zbesko

et al. 2018

Preprint

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The response to ischemic injury in the brain is different to the response to ischemic injury in other organs and tissues. Almost exclusive to the brain, and for unknown reasons, dead tissue liquefies in response to ischemia by the process of liquefactive necrosis. However, the data we present here indicate that at the macroscopic, microscopic, and molecular level, liquefactive necrosis strongly resembles atherosclerosis. We show that chronic stroke infarcts contain foamy macrophages, cholesterol crystals, high levels of osteopontin and matrix metalloproteinases, and a similar cytokine profile to atherosclerosis. Excessive cholesterol loading of macrophages is a principal driver of atherosclerosis. Therefore, because cholesterol is an important structural component of myelin, liquefactive necrosis in response to stroke may be caused by an inflammatory response to myelin debris that is prolonged by the formation of cholesterol crystals within macrophages. We propose that this results in the chronic production of high levels of proteases, which in a partially osteopontin dependent mechanism, causes secondary neurodegeneration and encephalomalacia of the surrounding tissue. In support of this, we show that genetically ablating osteopontin substantially reduces the production of degradative enzymes following stroke, reduces secondary neurodegeneration, and improves recovery.These findings suggest that treatments that prevent atherosclerosis or target the regression of All rights reserved. No reuse allowed without permission.

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Section: Resultsmentioning

confidence: 99%

“…Cholesterol crystals cause physical damage to organelles by destabilization of the lysosomal compartment, rupture plasma membranes, and activate nucleotide-binding domain and leucinerich repeat containing protein 3 (NLRP3) inflammasome signaling (Abela and Aziz, 2005;Duewell et al, 2010;Moore et al, 2013;Corr et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin dependent mechanism

Chung

Frye

Zbesko

et al. 2018

Preprint

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“…Duewell and colleagues [21] confirmed that CCs also activate the NLRP3 inflammasome to trigger the secretion of mature interleukin (IL)-1β and α from macrophages, leading to cell necrosis. In addition, Corr et al report that CCs induce IL-α/β production through the activation of Syk and PI3K in human macrophages and dendritic cells [22]. Moreover, a recent study shows that CCs directly bind to the human macrophage-inducible C-type lectin (hMincle) and induce pro-inflammatory cytokine, such as tumor necrosis factor(TNF)and macrophage inflammatory protein 2(MIP-2), release [23].…”

Section: Pathogenesismentioning

confidence: 99%

Cholesterol Crystal Embolism and Chronic Kidney Disease

Bayliss

Zhuang

2017

IJMS

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Renal disease caused by cholesterol crystal embolism (CCE) occurs when cholesterol crystals become lodged in small renal arteries after small pieces of atheromatous plaques break off from the aorta or renal arteries and shower the downstream vascular bed. CCE is a multisystemic disease but kidneys are particularly vulnerable to atheroembolic disease, which can cause an acute, subacute, or chronic decline in renal function. This life-threatening disease may be underdiagnosed and overlooked as a cause of chronic kidney disease (CKD) among patients with advanced atherosclerosis. CCE can result from vascular surgery, angiography, or administration of anticoagulants. Atheroembolic renal disease has various clinical features that resemble those found in other kidney disorders and systemic diseases. It is commonly misdiagnosed in clinic, but confirmed by characteristic renal biopsy findings. Therapeutic options are limited, and prognosis is considered to be poor. Expanding knowledge of atheroembolic renal disease due to CCE opens perspectives for recognition, diagnosis, and treatment of this cause of progressive renal insufficiency.

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“…The binding of CCs to the human macrophage-inducible C-type lectin receptors on the surface of macrophages and dendritic cells induces secretion of proinflammatory cytokine tumor necrosis factor (TNF) and macrophage inflammatory protein 2 [9]. CCs can also activate Syk and PI3K in human macrophages and dendritic cells and induce IL-1α/β [10]. However, the contribution of CCs to inflammation and necrosis in CCE remains obscure to date, mostly owing to the lack of suitable animal models of the disease.…”

Section: Type 1 Crystalline Nephropathy: Renal Cholesterol Embolismmentioning

confidence: 99%

Novel Insights into Crystal-Induced Kidney Injury

Mulay

Shi

et al. 2018

Kidney Dis

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Background: The entity of crystal nephropathies encompasses a spectrum of different kidney injuries induced by crystal-formed intrinsic minerals, metabolites, and proteins or extrinsic dietary components and drug metabolites. Depending on the localization and dynamics of crystal deposition, the clinical presentation can be acute kidney injury, progressive chronic kidney disease, or renal colic. Summary: The molecular mechanisms involving crystal-induced injury are diverse and remain poorly understood. Type 1 crystal nephropathies arise from crystals in the vascular lumen (cholesterol embolism) or the vascular wall (atherosclerosis) and involve kidney infarcts or chronic ischemia, respectively. Type 2 crystal nephropathies arise from intratubular crystal deposition causing obstruction, interstitial inflammation, and tubular cell injury. NLRP3 inflammasome and necroptosis drive renal necroinflammation in acute settings. Type 3 is represented by crystal and stone formation in the draining urinary tract, i.e., urolithiasis, causing renal colic and chronic obstruction. Key Messages: Dissecting the types of injury is the first step towards a better understanding of the pathophysiology of crystal nephropathies. Crystal-induced activation of the inflammasome and necroptosis, crystal adhesion, crystallization inhibitors, extratubulation, and granuloma formation are only a few of certainly many involved pathomechanisms that deserve further studies to eventually form the basis for innovative cures for these diseases.

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Cholesterol crystals activate Syk and PI3 kinase in human macrophages and dendritic cells

Cited by 40 publications

References 25 publications

Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin dependent mechanism

Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin dependent mechanism

Cholesterol Crystal Embolism and Chronic Kidney Disease

Novel Insights into Crystal-Induced Kidney Injury

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