Early growth response-1 is involved in foam cell formation and is upregulated by the TLR9–MyD88–ERK1/2 pathway

Kim, Jinsik; Park, Dae-Weon; Lee, Hyung-Kyoung; Kim, Jae-Ryong; Baek, Suk‐Hwan

doi:10.1016/j.bbrc.2009.09.009

Cited by 21 publications

(21 citation statements)

References 23 publications

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“…Several reports have indicated that Egr family members are induced by Dectin-1 ligands in macrophages and DCs (34,58) or neutrophils (59) in a calcineurin/NF-AT-dependent manner, which is likely also the case after Mincle stimulation. Although there are a number of reports on genes regulated by EGR family members in innate immune cells (60)(61)(62), the direct targets of EGRs in macrophages and DCs, especially in response to CLR activation, are currently unknown. We used expression of Egrs in this study primarily as a readout for early Mincle-dependent gene expression.…”

Section: Discussionmentioning

confidence: 99%

Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α

Schoenen

Huber

Sonda

et al. 2014

The Journal of Immunology

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Trehalose-6,6-dimycolate (TDM), the mycobacterial cord factor, and its synthetic analog Trehalose-6,6-dibehenate (TDB) bind to the C-type lectin receptors macrophage-inducible C-type lectin (Mincle) and Mcl to activate macrophages. Genetically, the transcriptional response to TDB/TDM has been defined to require FcRγ-Syk-Card9 signaling. However, TDB/TDM-triggered kinase activation has not been studied well, and it is largely unknown which transcriptional regulators bring about inflammatory gene expression. In this article, we report that TDB/TDM caused only weak Syk-phosphorylation in resting macrophages, consistent with low basal Mincle expression. However, LPS-priming caused MYD88-dependent upregulation of Mincle, resulting in enhanced TDB/TDM-induced kinase activation and more rapid inflammatory gene expression. TLR-induced Mincle expression partially circumvented the requirement for Mcl in the response to TDB/TDM. To dissect transcriptional responses to TDB/TDM, we mined microarray data and identified early growth response (Egr) family transcription factors as direct Mincle target genes, whereas upregulation of Cebpb and Hif1a required new protein synthesis. Macrophages and dendritic cells lacking C/EBPβ showed nearly complete abrogation of TDB/TDM responsiveness, but also failed to upregulate Mincle. Retroviral rescue of Mincle expression in Cebpb-deficient cells restored induction of Egr1, but not of G-CSF. This pattern of C/EBPβ dependence was also observed after stimulation with the Dectin-1 ligand Curdlan. Inducible expression of hypoxia-inducible factor 1α (HIF1α) also required C/EBPβ. In turn, HIF1α was not required for Mincle expression, kinase activation, and Egr1 or Csf3 expression, but critically contributed to NO production. Taken together, we identify C/EBPβ as central hub in Mincle expression and inflammatory gene induction, whereas HIF1α controls Nos2 expression. C/EBPβ also connects TLR signals to cord factor responsiveness through MYD88-dependent upregulation of Mincle.

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Section: Discussionmentioning

confidence: 99%

Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α

Schoenen

Huber

Sonda

et al. 2014

The Journal of Immunology

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“…In vitro data describing CpG DNA-mediated activation of macrophages stimulating foam cell formation 16,29,30 imply that TLR9 might rather contribute to the development of atherosclerosis. However, in contrast to this, our in vivo studies demonstrate that TLR9 has a protective role against atherosclerosis in the ApoE −/− mouse model.…”

Section: Discussionmentioning

confidence: 99%

Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Koulis

Chen

Hausding

et al. 2014

ATVB

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Objective— Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9 has a role in the development of atherosclerosis in apolipoprotein E–deficient (ApoE −/− ) mice. Approach and Results— Newly generated double-knockout ApoE −/− :TLR9 −/− mice and control ApoE −/− mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE −/− :TLR9 −/− mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4 + T cells. Although ApoE −/− :TLR9 −/− mice exhibited an increase in plasma very low-density lipoprotein/low-density-lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE −/− :TLR9 −/− mice, CD4 + T-cell accumulation was further investigated and depletion of these cells in ApoE −/− :TLR9 −/− mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9 agonist (type B CpG oligodeoxynucleotide 1668) to ApoE −/− mice resulted in a reduction of lesion severity. Conclusions— Genetic deletion of the innate immune receptor TLR9 exacerbated atherosclerosis in ApoE −/− mice fed a high-fat diet. CD4 + T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9 agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.

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“…The contribution of endosomal TLR7 is beginning to emerge as a mediator of vascular remodeling and foam cell accumulation (Karper et al, 2012). Finally, endosomal TLR9 has been observed to propagate inflammation in response to vascular injury (Erridge et al, 2008;Lopez et al, 2012;Hirata et al, 2013), foam cell accumulation, and lesion formation (Niessner et al, 2006;Kim et al, 2009a;Sorrentino et al, 2010;Karper et al, 2012) and in LDL receptor-deficient mice (Ding et al, 2013).…”

Section: A Atherosclerosismentioning

confidence: 99%

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

2015

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Early growth response-1 is involved in foam cell formation and is upregulated by the TLR9–MyD88–ERK1/2 pathway

Cited by 21 publications

References 23 publications

Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α

Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α

Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

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