Investigation of the role of endogenous ligands for toll-like receptors in the increased risk of cardiovascular disease in patients with Chronic Kidney Disease

Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality, but the mechanisms are not fully understood. Notably, atherosclerosis, an inflammation-driven thickening of the vascular wall which underlies most CV events, is aggravated in CKD. This work identified 4 known endogenous TLR agonists, Damage-Associated Molecular Patterns (DAMPs), namely Hsp70, Calprotectin, Hyaluronic acid and HMGB-1, elevated in CKD plasma and demonstrated that these DAMPs can differentially drive key cellular functions and responses in endothelial cells, monocytes and macrophages that are associated with worsening of atherosclerosis. Specifically, CKDassociated DAMPs induced loss of trans-endothelial resistance, enhanced chemokine-driven monocyte migration, increased cytokine production and atherosclerosis-associated gene expression by macrophages, and promoted foam cell formation by reducing cholesterol efflux. These activities were mostly mediated by TLR2 and TLR4. In mice, CKD induction also led to increased DAMP plasma levels and induced a range of short and long-term systemic inflammatory, immune and atherosclerosis-promoting responses that are known to drive CVD. In vivo, both a multi-TLR inhibition approach and a Calprotectin-specific targeting approach reduced or prevented CKD-induced systemic inflammatory and pro-atherogenic responses, such as cytokine production, gene expression and increase inflammatory leukocyte proportions. Furthermore, Calprotectin inhibition robustly reduced the CKD induced increased aortic expression of atherosclerotic-promoting genes. These findings identify specific DAMPs elevated in CKD that can critically promote pro-inflammatory and atherogenic responses and demonstrate that specific targeting within the DAMP/TLR pathway is a promising therapeutic strategy to reduce chronic inflammation and lower the atherosclerotic burden in CKD, ultimately reducing CV risk in this patient population