Atheroprone Flow Activation of the Sterol Regulatory Element Binding Protein 2 and Nod-Like Receptor Protein 3 Inflammasome Mediates Focal Atherosclerosis

Abe, Jun; Berk, Bradford C.

doi:10.1161/circulationaha.113.004390

Cited by 22 publications

(19 citation statements)

References 21 publications

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“…76 Indeed, other studies have found that inflammasome activation can occur in endothelial cells. 77–79 However, in Chen et al’s study, the coronary lesions generated after LCWE injection were dramatically smaller than in our study, thus making comparison between the two studies difficult. 76 Additionally, they find evidence for active caspase-1 in the coronary ECs even under naive conditions, which is unusual considering that inflammasome activation is tightly regulated.…”

Section: Discussioncontrasting

confidence: 74%

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

Lee

Wakita

Dagvadorj

et al. 2015

ATVB

104

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Objective Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and IL-1β signaling are required for the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c+ Dendritic Cells (DCs) and macrophages and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling in LCWE-induced KD mouse model of vasculitis. Approach and Results Using mouse knockout models as well as antibody depletion, we found that both IL-1α and IL-1β were required for LCWE-induced KD. Both DCs and macrophages were necessary and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling was critically required in non-endothelial stromal cells, but not hematopoietic cells. Conclusions Our results suggest that IL-1α and IL-1β as well as CD11c+ DCs and macrophages are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, while IL-1 signaling and response is required only in stromal cells, but not in endothelial cells. Determining the role IL-1α and IL-1β and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies.

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Section: Discussioncontrasting

confidence: 74%

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

Lee

Wakita

Dagvadorj

et al. 2015

ATVB

104

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“…In terms of signal transduction, cholesterol depletion-activated SREBP2 showed anti-inflammatory action against excessive production of pro-inflammatory chemokines via EGR-1 and PPAR␥. However, in some studies, SREBP2 is a positive regulator of IL-8 expression by binding to a consensus sequence SRE located in the IL-8 promoter (Ϫ134 to Ϫ125) (32) and triggers IL-1␤-mediated inflammation via formation of NALP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome (33). In contrast to these reports, SREBP2 activation did not contribute to transcription of chemokine expression in cholesterol-depleted enterocytes in the present study.…”

Section: Discussionmentioning

confidence: 99%

Epithelial Cholesterol Deficiency Attenuates Human Antigen R-linked Pro-inflammatory Stimulation via an SREBP2-linked Circuit

Park

Kim

et al. 2016

Journal of Biological Chemistry

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Patients with chronic intestinal ulcerative diseases, such as inflammatory bowel disease, tend to exhibit abnormal lipid profiles, which may affect the gut epithelial integrity. We hypothesized that epithelial cholesterol depletion may trigger inflammation-checking machinery via cholesterol sentinel signaling molecules whose disruption in patients may aggravate inflammation and disease progression. In the present study, sterol regulatory element-binding protein 2 (SREBP2) as the cholesterol sentinel was assessed for its involvement in the epithelial inflammatory responses in cholesterol-depleted enterocytes. Patients and experimental animals with intestinal ulcerative injuries showed suppression in epithelial SREBP2. Moreover, SREBP2-deficient enterocytes showed enhanced pro-inflammatory signals in response to inflammatory insults, indicating regulatory roles of SREBP2 in gut epithelial inflammation. However, epithelial cholesterol depletion transiently induced pro-inflammatory chemokine expression regardless of the well known pro-inflammatory nuclear factor-κB signals. In contrast, cholesterol depletion also exerts regulatory actions to maintain epithelial homeostasis against excessive inflammation via SREBP2-associated signals in a negative feedback loop. Mechanistically, SREBP2 and its induced target EGR-1 were positively involved in induction of peroxisome proliferator-activated receptor γ (PPARγ), a representative anti-inflammatory transcription factor. As a crucial target of the SREBP2-EGR-1-PPARγ-associated signaling pathways, the mRNA stabilizer, human antigen R (HuR) was retained in nuclei, leading to reduced stability of pro-inflammatory chemokine transcripts. This mechanistic investigation provides clinical insights into protective roles of the epithelial cholesterol deficiency against excessive inflammatory responses via the SREBP2-HuR circuit, although the deficiency triggers transient pro-inflammatory signals.

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“…Human atheromata harbor activated inflammasomes (34). Other atherosclerosis-relevant stimuli that can augment inflammasome action include disturbed flow (such as prevails at sites of predilection to atheroma formation and complication) (35,36), and moderate hypoxia and acidosis (common in the core of plaques) (37,38). …”

Section: The Inflammasome Activates Interleukin-1βmentioning

confidence: 99%

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

Libby

2017

Journal of the American College of Cardiology

496

350

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Inflammatory pathways drive atherogenesis and link traditional risk factors to atherosclerosis and its complications. One inflammatory mediator has come to the fore as a therapeutic target in cardiovascular disease. The experimental and clinical evidence reviewed here support interleukin-1 beta (IL-1β) as both a local vascular and systemic contributor in this regard. Intrinsic vascular wall cells and lesional leukocytes alike can produce this cytokine. Local stimuli in the plaque favor the generation of active IL-1β through the action of a molecular assembly known as the inflammasome. Clinically applicable interventions that interfere with IL-1 action can improve cardiovascular outcomes, ushering in a new era of anti-inflammatory therapies for atherosclerosis. The translational path described here illustrates how advances in basic vascular biology may transform therapy. Biomarker-directed application of anti-inflammatory interventions promises to help us achieve a more precise and personalized allocation of therapy for our cardiovascular patients.

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Atheroprone Flow Activation of the Sterol Regulatory Element Binding Protein 2 and Nod-Like Receptor Protein 3 Inflammasome Mediates Focal Atherosclerosis

Cited by 22 publications

References 21 publications

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

Epithelial Cholesterol Deficiency Attenuates Human Antigen R-linked Pro-inflammatory Stimulation via an SREBP2-linked Circuit

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

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