Activation of an innate immune receptor, Nod1, accelerates atherogenesis in Apoe-/- mice

• Published in: The Journal of immunology (1950) Vol. 194; no. 2; pp. 773 - 780
• Main Authors: Kanno, Shunsuke, Nishio, Hisanori, Tanaka, Tamami, Motomura, Yoshitomo, Murata, Kenji, Ihara, Kenji, Onimaru, Mitsuho, Yamasaki, Sho, Kono, Hajime, Sueishi, Katsuo, Hara, Toshiro
• Format: Journal Article
• Language: English
• Published: United States 15.01.2015
• Subjects: Adjuvants, Immunologic - pharmacology; Animals; Aorta - immunology; Aorta - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis - genetics; Atherosclerosis - immunology; Atherosclerosis - pathology; Bone Marrow Cells - immunology; Bone Marrow Cells - pathology; Macrophages - immunology; Macrophages - pathology; Mice; Mice, Knockout; Nod1 Signaling Adaptor Protein - genetics; Nod1 Signaling Adaptor Protein - immunology; Oligopeptides - pharmacology; T-Lymphocytes - immunology; T-Lymphocytes - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1302841

Atherosclerosis is essentially a vascular inflammatory process in the presence of an excess amount of lipid. We have recently reported that oral administration of a nucleotide-binding oligomerization domain (Nod)-1 ligand, FK565, induced vascular inflammation in vivo. No studies, however, have proven the association between Nod1 and atherosclerosis in vivo. To investigate a potential role of NOD1 in atherogenesis, we orally administered FK565 to apolipoprotein E knockout (Apoe(-/-)) mice for 4 wk intermittently and performed quantification of atherosclerotic lesions in aortic roots and aortas, immunohistochemical analyses, and microarray-based gene expression profiling of aortic roots. FK565 administration accelerated the development of atherosclerosis in Apoe(-/-) mice, and the effect was dependent on Nod1 in non-bone marrow origin cells by bone marrow transplantation experiments. Immunohistochemical studies revealed the increases in the accumulation of macrophages and CD3 T cells within the plaques in aortic roots. Gene expression analyses of aortic roots demonstrated a marked upregulation of the Ccl5 gene during early stage of atherogenesis, and the treatment with Ccl5 antagonist significantly inhibited the acceleration of atherosclerosis in FK565-administered Apoe(-/-) mice. Additionally, as compared with Apoe(-/-) mice, Apoe and Nod1 double-knockout mice showed reduced development of atherosclerotic lesions from the early stage as well as their delayed progression and a significant reduction in Ccl5 mRNA levels at 9 wk of age. Data in the present study show that the Nod1 signaling pathway in non-bone marrow-derived cells contributes to the development of atherosclerosis.