Myeloid IkBa Deficiency Promotes Atherogenesis by Enhancing Leukocyte Recruitment to the Plaques

Abstract

Activation of the transcription factor NF-kB appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-kB inhibitor IkBa in atherosclerosis. Myeloid-specific deletion of IkBa 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 IkBa-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 IkBa 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 IkBa del mice more leukocytes are attracted to the plaques. In conclusion, we show that IkBa deletion in myeloid cells promotes atherogenesis, probably through an induced leukocyt