Endothelial NOD1 directs myeloid cell recruitment in atherosclerosis through VCAM-1

Atherosclerosis is a chronic disease characterized by vascular lipid retention and inflammation, and pattern recognition receptors (PRRs) are important contributors in early stages of the disease. Given the implication of the intracellular PRR nucleotide-binding oligomerization domain 1 (NOD1) in cardiovascular diseases, we investigated its contribution to early atherosclerosis. We evidenced NOD1 induction in atherosclerotic human and mouse tissues, predominantly in vascular endothelial cells. Accordingly, NOD1 genetic inactivation in Apoe-/- mice reduced not only atherosclerosis burden, but also monocyte and neutrophil accumulation in atheromata. Of note, in the presence of either peptidoglycan or oxidized LDLs, endothelial NOD1 triggered VCAM-1 up-regulation through the RIP2-NF-κB axis in an autocrine manner, enhancing firm adhesion of both sets of myeloid cells to the inflamed micro- and macrovasculature in vivo. Our data define a major proatherogenic role for endothelial NOD1 in early leukocyte recruitment to the athero-prone vasculature, thus introducing NOD1 as an innovative therapeutic target and potential prognostic molecule.-González-Ramos, S., Paz-García, M., Rius, C., del Monte-Monge, A., Rodríguez, C., Fernández-García, V., Andrés, V., Martínez-González, J., Lasunción, M. A., Martín-Sanz, P., Soehnlein, O., Boscá, L. Endothelial NOD1 directs myeloid cell recruitment in atherosclerosis through VCAM-1.This work was supported by the the Ministry of Science, Innovation and Universities (Grants SAF2015-64767-R, SAF2016-79490-R, SAF2015-70747-R, SAF2016-75004-R, SAF2017-82436-R/RTC2017-6283-1), the Center for Biomedical Research Network Consortium in Cardiovascular Diseases (Grants CB16/11/00257, CB16/11/00405, CB/11/00222), Community of Madrid Grant BMD/3686, the German Research Foundation (Grants SFB914 TP A02/B08/B09/Z03, SFB1123 TP A06/B05/B08/Z01), and the Netherlands Organization for Scientific Research (VIDI project 91712303). This project was also financed, in part, by the European Regional Development Fund. O.S. and L.B. contributed equally as senior authors. The authors declare no conflicts of interes