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

Abstract

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 macro vasculature 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. FASEB J. 33, 3912–3921 (2019). http://www.fasebj.org

Deletion or Inhibition of NOD1 Favors Plaque Stability and Attenuates Atherothrombosis in Advanced Atherogenesis

“…In fact, immunohistochemical analysis of human plaques of SMC and macrophages markers revealed elevated expression of NOD1 in both cell types ( Figure 1 c and Figure S2 ). These results, together with our previous studies [ 9 ] suggest a critical role for NOD1 in the key cell players of human and mice atherosclerosis. The accumulation of oxLDLs in the intima is crucial in the plaque lifetime.…”

“…Barcelona, Spain). Double-knockout Apoe −/− Nod1 −/− mice were generated by crossing Apoe −/− mice with Nod1 −/− mice as previously described [ 9 ]. All experiments compared male Apoe −/− mice vs. male Apoe −/− Nod1 −/− littermates.…”

“…Smooth muscle cells (SMC) were harvested from abdominal and thoracic aortas from 2-month-old animals as previously described [ 16 ] and cultured in Dulbecco’s modified Eagle medium (DMEM, GIBCO, Madrid, Spain) containing 20% fetal bovine serum (FBS, Lonza, Barcelona, Spain), L-glutamine and antibiotics (100 units/mL penicillin and 100 µg/mL streptomycin). Bone marrow-derived macrophages (BMDM) were obtained from femoral bone marrow suspensions [ 9 ] differentiated for 7 days in the presence of DMEM plus 10% FBS and 20 ng/mL macrophage colony-stimulating factor (M-CSF, PeproTech, London, UK).…”

“…As a result, platelets and fibrin aggregate to form a thrombus resulting in partial or total ischemic blockage of the artery [ 7 , 8 ]. Therefore, the clinical atherosclerotic lesion is essentially an unresolved inflammatory condition leading to a vulnerable plaque [ 9 , 10 ]. Notably, atherosclerosis is strongly associated with systemic risk factors (e.g., high LDL, infections, diabetes) where the cellular components of the innate immune system are relevant.…”

“…In this regard, the nucleotide-binding oligomerization domain (NOD)-1 receptor of the innate immune system appears to play a key role. Our group has recently identified endothelial NOD1 as proatherogenic in response to oxLDL and a conserved region of bacterial peptidoglycan iE-DAP (γ-D-glutamyl-meso-diaminopimelic acid) [ 9 ]. The downstream interaction of NOD1 with receptor-interacting protein-2 (RIP2 or RICK) activates the canonical nuclear factor kappa B (NF-κB) signaling pathway [ 11 ] that upregulates the expression of adhesion molecules of endothelial cells and the concomitant recruitment of monocytes and neutrophils to the vasculature.…”