MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains

Lai, Lihua; Azzam, Kathleen M.; Lin, Wan-Chi; Rai, Prashant; Lowe, Julie M.; Gabor, Kristin A.; Madenspacher, Jennifer H.; Aloor, Jim J.; Parks, John S.; Näär, Anders M.; Fessler, Michael B.

doi:10.1074/jbc.m116.723056

Cited by 56 publications

(42 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, miR-33 has also been implicated in the regulation of innate immunity by repressing the ATP-binding cassette A1 and G1 proteins in macrophages (89, 90). One of the main roles of the ABCA1/G1 proteins is to inhibit the assembly and activation of TLR4 (91).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Mediate Radiation-Induced Systemic Bystander Signals in the Bone Marrow and Spleen

et al. 2017

View full text Add to dashboard Cite

Radiation-induced bystander effects refer to the induction of biological changes in cells not directly hit by radiation implying that the number of cells affected by radiation is larger than the actual number of irradiated cells. Recent in vitro studies suggest the role of extracellular vesicles (EVs) in mediating radiation-induced bystander signals, but in vivo investigations are still lacking. Here, we report an in vivo study investigating the role of EVs in mediating radiation effects. C57BL/6 mice were total-body irradiated with X-rays (0.1, 0.25, 2 Gy), and 24 h later, EVs were isolated from the bone marrow (BM) and were intravenously injected into unirradiated (so-called bystander) animals. EV-induced systemic effects were compared to radiation effects in the directly irradiated animals. Similar to direct radiation, EVs from irradiated mice induced complex DNA damage in EV-recipient animals, manifested in an increased level of chromosomal aberrations and the activation of the DNA damage response. However, while DNA damage after direct irradiation increased with the dose, EV-induced effects peaked at lower doses. A significantly reduced hematopoietic stem cell pool in the BM as well as CD4+ and CD8+ lymphocyte pool in the spleen was detected in mice injected with EVs isolated from animals irradiated with 2 Gy. These EV-induced alterations were comparable to changes present in the directly irradiated mice. The pool of TLR4-expressing dendritic cells was different in the directly irradiated mice, where it increased after 2 Gy and in the EV-recipient animals, where it strongly decreased in a dose-independent manner. A panel of eight differentially expressed microRNAs (miRNA) was identified in the EVs originating from both low- and high-dose-irradiated mice, with a predicted involvement in pathways related to DNA damage repair, hematopoietic, and immune system regulation, suggesting a direct involvement of these pathways in mediating radiation-induced systemic effects. In conclusion, we proved the role of EVs in transmitting certain radiation effects, identified miRNAs carried by EVs potentially responsible for these effects, and showed that the pattern of changes was often different in the directly irradiated and EV-recipient bystander mice, suggesting different mechanisms.

show abstract

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Mediate Radiation-Induced Systemic Bystander Signals in the Bone Marrow and Spleen

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The previous study has demonstrated that ABCA1 expression can be negatively regulated by miR-33 [34,35]. Here, we examined whether miR-33 is involved in the augmentation of apigenin on ABCA1 expression and cholesterol efflux.…”

Section: The Stimulatory Effects Of Apigenin On Abca1 Expression and mentioning

confidence: 99%

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

Ren

Jiang

Zhou

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The development of atherosclerosis is accompanied by escalating inflammation and lipid accumulation within blood vessel walls. ABCA1 plays a crucial role in mediating cholesterol efflux from macrophages, which protects against atherogenesis. This research was designed to explore the effects and underlying mechanisms of apigenin (4’, 5, 7-trihydroxyflavone) on ABCA1-mediated cellular cholesterol efflux and LPS-stimulated inflammation in RAW264.7 macrophages and apoE^-/- mice. Methods: Expression of genes or proteins was examined by RT-PCR or western blot analysis. Liquid scintillation counting was used to detect percent cholesterol efflux. Cellular cholesterol content was measured using HPLC assay. The secretion levels of pro-inflammatory cytokines were quantified by ELISA assay. Atherosclerotic lesion sizes were determined with Oil Red O staining. The contents of macrophages and smooth muscle cells in atherosclerotic lesion were evaluated using immunohistochemistry. Plasma TC, TG, HDL-C and LDL-C levels in apoE^-/- mice were evaluated using commercial test kits. Results: Apigenin potently increased ABCA1 expression through miR-33 repression in a dose- and time-dependent manner. Treatment with apigenin significantly increased ABCA1-mediated cholesterol efflux, and reduced TC, FC and CE levels in macrophage-derived foam cells. In LPS-treated macrophages, the expression levels of TLR-4, MyD88 and p-IκB-α as well as nuclear NF-κB p65 were decreased by the addition of apigenin. Moreover, apigenin markedly decreased secretion levels of several pro-inflammatory cytokines. Lastly, in LPS-challenged apoE^-/- mice, apigenin administration augmented ABCA1 expression, decreased the contents of macrophages and smooth muscle cells in atherosclerotic lesion, reduced miR-33, TLR-4, and NF-κB p65 levels, improved plasma lipid profile and relieved inflammation, which results in less atherosclerotic lesion size. Conclusions: Taken together, these results suggest that apigenin may attenuate atherogenesis through up-regulating ABCA1-mediated cholesterol efflux and inhibiting inflammation.

show abstract

“…In another recent study, Fessier and colleagues found that miR-33 regulates innate immune response via ABCA1 remodeling of membrane micro-domains. miR-33 augments macrophage lipid raft content and enhances pro-inflammatory cytokine induction and NFκB activation by LPS [47]. In contrast to Ouimet’s study, the authors found that LPS markedly reduces the expression of miR-33, which correlates with a significant downregulation of Srebp2 , the host gene for miR-33 [47].…”

Section: Introductionmentioning

confidence: 99%

“…miR-33 augments macrophage lipid raft content and enhances pro-inflammatory cytokine induction and NFκB activation by LPS [47]. In contrast to Ouimet’s study, the authors found that LPS markedly reduces the expression of miR-33, which correlates with a significant downregulation of Srebp2 , the host gene for miR-33 [47]. In agreement with this observation, numerous studies have shown that SREBP2 expression is significantly reduced in macrophages stimulated with LPS [48, 49].…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs and lipid metabolism

Aryal

Singh²,

Rotllan³

et al. 2017

Current Opinion in Lipidology

176

100

View full text Add to dashboard Cite

Purpose of review Work over the last decade has identified the important role of microRNAs (miRNAS) in regulating lipoprotein metabolism and associated disorders including metabolic syndrome, obesity and atherosclerosis. This review summarizes the most recent findings in the field, highlighting the contribution of miRNAs in controlling low-density lipoprotein (LDL) and high-density lipoprotein (HDL) metabolism. Recent findings A number of miRNAs have emerged as important regulators of lipid metabolism, including miR-122 and miR-33. Work over the last two years has identified additional functions of miR-33 including the regulation of macrophage activation and mitochondrial metabolism. Moreover, it has recently been shown that miR-33 regulates vascular homeostasis and cardiac adaptation in response to pressure overload. In addition to miR-33 and miR-122, recent GWAS have identified single nucleotide polymorphisms (SNP) in the proximity of miRNAs genes associated with abnormal levels of circulating lipids in humans. Several of these miRNA, such as miR-148a and miR-128-1, target important proteins that regulate cellular cholesterol metabolism, including the low-density lipoprotein receptor (LDLR) and the ATP-binding cassette A1 (ABCA1). Summary microRNAs have emerged as critical regulators of cholesterol metabolism and promising therapeutic targets for treating cardiometabolic disorders including atherosclerosis. Here, we discuss the recent findings in the field highlighting the novel mechanisms by which miR-33 controls lipid metabolism and atherogenesis and the identification of novel miRNAs that regulate LDL metabolism. Finally, we summarize the recent findings that identified miR-33 as an important non-coding RNA that controls cardiovascular homeostasis independent of its role in regulating lipid metabolism.

show abstract

MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains

Cited by 56 publications

References 59 publications

Extracellular Vesicles Mediate Radiation-Induced Systemic Bystander Signals in the Bone Marrow and Spleen

Extracellular Vesicles Mediate Radiation-Induced Systemic Bystander Signals in the Bone Marrow and Spleen

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

MicroRNAs and lipid metabolism

Contact Info

Product

Resources

About