NOD1 and immunometabolic regulation: beyond sensing bacteria and atherosclerosis disease

Abstract

The Pattern Recognition Receptor Nucleotide-Binding Oligomerization Domain-1 (NOD1), mainly known to be activated by infections, has also been linked to other inflammatory and mortal pathologies, such as cardiovascular diseases. Hypercholesterolemia is the most common and an important risk factor for inflammation and immunometabolic disorders. Here we study the role of NOD1 in the regulation of the immune response and metabolic adaptation to hypercholesterolemia. To this purpose, phenotypic and physiological characterization of Nod1−/− mice against Wt was made under a high fat dietary regimen for 6 weeks. Our results show that NOD1 is activated on either immune (spleen, bone marrow), highly metabolic (liver) or atherosclerotic (aorta) tissues. It contributes to the mobilization of myeloid progenitors from the bone marrow to the bloodstream thanks to the upregulation of chemokines. NOD1 activation and the subsequent blood leukocyte influx enhances atheroma lesion. Furthermore, Nod1−/− mice body weight increased compared to Wt as total cholesterol and HDL levels did. Total lipid content in Nod1−/− liver was significantly higher comparing to Wt livers. Accordingly, MAPK and NOD1 cell signalling routes were activated in the liver of Nod1−/− mice. While total lipid content in the spleen differs between both mice genotypes in the red pulp, differences in the white pulp are not statistically significant. In conclusion, we here demonstrate that NOD1 plays an active role in the immunometabolic regulation in response to hypercholesterolemia, promoting vascular recruitment, inflammation and metabolic disorders. Its study beyond its well-known role in bacteria sensing could contribute to understand and fight important immunometabolic disorders.