Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease

• Published in: Circulation research Vol. 128; no. 11; pp. 1728 - 1746
• Main Authors: Ridker, Paul M., Rane, Manas
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 28.05.2021
• Subjects: Aneurysm - etiology; Animals; Antibodies, Monoclonal, Humanized - therapeutic use; Atherosclerosis - etiology; Atherosclerosis - metabolism; C-Reactive Protein - metabolism; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - therapy; Cell Differentiation; Cell Proliferation; Disease Models, Animal; Humans; Immunity, Cellular; Immunity, Innate; Inflammasomes; Inflammation - complications; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - metabolism; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - genetics; Interleukin-6 - immunology; Interleukin-6 - metabolism; Mice; Myocardial Ischemia - therapy; NLR Family, Pyrin Domain-Containing 3 Protein; Receptors, Interleukin-6 - antagonists & inhibitors; Receptors, Interleukin-6 - metabolism; Renal Dialysis; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - therapy; Thrombosis - etiology; atherosclerosis; ligands; inflammation; humans; interleukin-6
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.121.319077

IL (interleukin)-6 is a pivotal cytokine of innate immunity, which enacts a broad set of physiological functions traditionally associated with host defense, immune cell regulation, proliferation, and differentiation. Following recognition of innate immune pathways leading from the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome to IL-1 to IL-6 and on to the hepatically derived clinical biomarker CRP (C-reactive protein), an expanding literature has led to understanding of the proatherogenic role for IL-6 in cardiovascular disease and thus the potential for IL-6 inhibition as a novel method for vascular protection. In this review, we provide an overview of the mechanisms by which IL-6 signaling occurs and how that impacts upon pharmacological inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiological data outlining the utility of IL-6 as a biomarker of vascular risk; outline genetic data suggesting a causal role for IL-6 in systemic atherothrombosis and aneurysm formation; and then detail the potential role of IL-6 inhibition in stable coronary disease, acute coronary syndromes, heart failure, and the atherothrombotic complications associated with chronic kidney disease and end-stage renal failure. Finally, we review anti-inflammatory and antithrombotic findings for ziltivekimab, a novel IL-6 ligand inhibitor being developed specifically for use in atherosclerotic disease and poised to be tested formally in a large-scale cardiovascular outcomes trial focused on individuals with chronic kidney disease and elevated levels of CRP, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need.