Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease
Interleukin-6 (IL-6) is a pivotal cytokine of innate immunity which enacts a broad set of physiologic 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 interleukin-1 to IL-6 and on to the hepatically derived clinical biomarker C-reactive protein, an expanding literature has led to understanding of the pro-atherogenic role for IL-6 in cardiovascular disease and thus the potential for interleukin-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 pharmacologic inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiologic 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 anti-thrombotic 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 C-reactive protein, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need.