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

Circ Res. 2021 May 28;128(11):1728-1746. doi: 10.1161/CIRCRESAHA.121.319077. Epub 2021 May 17.

Abstract

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.

Keywords: atherosclerosis; humans; inflammation; interleukin-6; ligands.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 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

Substances

  • Antibodies, Monoclonal, Humanized
  • Inflammasomes
  • Interleukin-1beta
  • Interleukin-6
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Receptors, Interleukin-6
  • ziltivekimab
  • canakinumab
  • C-Reactive Protein