Immune Activation Resulting From NKG2D/Ligand Interaction Promotes Atherosclerosis

Abstract

Background The interplay between the immune system and abnormal metabolic conditions sustains and propagates a vicious feedback cycle of chronic inflammation and metabolic dysfunction that is critical for atherosclerotic progression. It is well established that abnormal metabolic conditions, such as dyslipidemia and hyperglycemia, cause various cellular stress responses that induce tissue inflammation and immune cell activation, which in turn exacerbate the metabolic dysfunction. However, molecular events linking these processes are not well understood. Methods and Results Tissues and organs of humans and mice with hyperglycemia and hyperlipidemia were examined for expression of ligands for NKG2D, a potent immune activating receptor expressed by several types of immune cells, and the role of NKG2D in atherosclerosis and metabolic diseases was probed using mice lacking NKG2D or by blocking NKG2D with monoclonal antibodies. NKG2D ligands were upregulated in multiple organs, particularly atherosclerotic aortae and inflamed livers. Ligand upregulation was induced in vitro by abnormal metabolites associated with metabolic dysfunctions. Using ApoE-/- mouse models we demonstrated that preventing NKG2D functions resulted in a dramatic reduction in plaque formation, suppressed systemic and organ inflammation mediated by multiple immune cell types, and alleviated abnormal metabolic conditions. Conclusions The NKG2D/ligand interaction is a critical molecular link in the vicious cycle of chronic inflammation and metabolic dysfunction that promotes atherosclerosis and might be a useful target for therapeutic intervention in the disease.

Molecular Biology of Atherosclerosis

“…In addition, hyperlipidemia, diabetes, infection, and injury can stimulate expression of various ligands of the KLRK1 receptor on endothelial cells and macrophages, among other cells. Activation of the KLRK1 receptor causes vigorous production of cytokines by NK, NKT, and other cells while KO of KLRK1 markedly reduced atherosclerosis as noted previously (1118,1989).…”

“…Expression of KLRK1 ligands were markedly increased in hyperlipidemic as well as diabetic mice. KLRK1 KO markedly decreased atherosclerosis by 80% (1989). The KLRK1 receptor and ligand system seems to work similarly to TLR ligation to induce rapid and generous production of inflammatory cytokines including IFN-␥, TNF-␣, CXCL1, IL-1␤, IL-6, and IL-12 (1118).…”

MICA/B expression in macrophage foam cells infiltrating atherosclerotic plaques

“…Previous work showed that MICA/B is expressed in endothelial cells and foam cells in atherosclerotic lesions of type 2 diabetic patients (Xia et al, 2011). To examine whether MICA/B is expressed in atherosclerotic lesions in general, we performed immunohistochemical staining of MICA/B in 10 autopsy-derived aortic samples.…”

“…Recently, inhibition of NKG2D functions was shown to suppress inflammation by immune cells and reduce aortic plaque formation in mice (Xia et al, 2011). The same work also showed that endothelial cells and macrophages infiltrating atherosclerotic plaques express MICA/B in patients with type 2 diabetes (Lin et al, 2012;Xia et al, 2011). were used as MDMs.…”

Shed NKG2D ligand boosts NK cell immunity

“…Interestingly, the authors detected a very high concentration of shed MULT1 in the sera of Apoe -/-mice exhibiting severe atherosclerosis and liver inflammation. Given that these autoimmune injuries observed in this mouse model depend on NKG2D activity [5], it was unlikely that shed MULT1 exert an inhibitory effect on immunity.…”