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Myeloid I?B? deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques.

ABSTRACT: Activation of the transcription factor NF-?B appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-?B inhibitor I?B? in atherosclerosis. Myeloid-specific deletion of I?B? results in larger and more advanced lesions in LDL-R-deficient mice without affecting the compositional phenotype of the plaques or systemic inflammatory markers in the plasma. We show that I?B?-deleted macrophages display enhanced adhesion to an in vitro endothelial cell layer, coinciding with an increased expression of the chemokine CCL5. Also, in vivo we found that I?B?(del) mice had more leukocytes adhering to the luminal side of the endothelial cell layers that cover the atherosclerotic plaques. Moreover, we introduce ER-MP58 in this paper as a new immunohistochemical tool for quantifying newly recruited myeloid cells in the atherosclerotic lesion. This staining confirms that in I?B?(del) mice more leukocytes are attracted to the plaques. In conclusion, we show that I?B? deletion in myeloid cells promotes atherogenesis, probably through an induced leukocyte recruitment to plaques.

SUBMITTER: Goossens P

PROVIDER: S-EPMC3141029 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Myeloid IκBα deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques.

Goossens Pieter P Vergouwe Monique N MN Gijbels Marion J J MJ Curfs Danielle M J DM van Woezik Johannes H G JH Hoeksema Marten A MA Xanthoulea Sofia S Leenen Pieter J M PJ Rupec Rudolf A RA Hofker Marten H MH de Winther Menno P J MP

PloS one 20110721 7

Activation of the transcription factor NF-κB appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-κB inhibitor IκBα in atherosclerosis. Myeloid-specific deletion of IκBα results in larger and more advanced lesions in LDL-R-deficient mice without affecting the compositional phenotype of the plaques or systemic inflammatory markers in the plasma. We show that IκBα-deleted macrophages display enhanced adhesion to an in vitro endothelial cell layer ...[more]

PMID: 21814576

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Project description:AimsAtherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular hypoxic responses, possibly influencing macrophage function in plaque hypoxia. Thus, we aimed to elucidate the role of myeloid PHDs in atherosclerosis.Methods and resultsMyeloid-specific PHD knockout (PHDko) mice were obtained via bone marrow transplantation (PHD1ko, PHD3ko) or conditional knockdown through lysozyme M-driven Cre recombinase (PHD2cko). Mice were fed high cholesterol diet for 6-12 weeks to induce atherosclerosis. Aortic root plaque size was significantly augmented 2.6-fold in PHD2cko, and 1.4-fold in PHD3ko compared to controls but was unchanged in PHD1ko mice. Macrophage apoptosis was promoted in PHD2cko and PHD3ko mice in vitro and in vivo, via the hypoxia-inducible factor (HIF) 1α/BNIP3 axis. Bulk and single-cell RNA data of PHD2cko bone marrow-derived macrophages (BMDMs) and plaque macrophages, respectively, showed enhanced HIF1α/BNIP3 signalling, which was validated in vitro by siRNA silencing. Human plaque BNIP3 mRNA was positively associated with plaque necrotic core size, suggesting similar pro-apoptotic effects in human. Furthermore, PHD2cko plaques displayed enhanced fibrosis, while macrophage collagen breakdown by matrix metalloproteinases, collagen production, and proliferation were unaltered. Instead, PHD2cko BMDMs enhanced fibroblast collagen secretion in a paracrine manner. In silico analysis of macrophage-fibroblast communication predicted SPP1 (osteopontin) signalling as regulator, which was corroborated by enhanced plaque SPP1 protein in vivo. Increased SPP1 mRNA expression upon PHD2cko was preferentially observed in foamy plaque macrophages expressing 'triggering receptor expressed on myeloid cells-2' (TREM2hi) evidenced by single-cell RNA, but not in neutrophils. This confirmed enhanced fibrotic signalling by PHD2cko macrophages to fibroblasts, in vitro as well as in vivo.ConclusionMyeloid PHD2cko and PHD3ko enhanced atherosclerotic plaque growth and macrophage apoptosis, while PHD2cko macrophages further activated collagen secretion by fibroblasts in vitro, likely via paracrine SPP1 signalling through TREM2hi macrophages.

Dataset Information

Myeloid I?B? deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques.

Publications

Myeloid IκBα deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques.

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