From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection

Abstract

Plasma levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) predict vascular risk with an effect estimate as large as that of total or high-density lipoprotein cholesterol. Further, randomized trial data addressing hsCRP have been central to understanding the anti-inflammatory effects of statin therapy and have consistently demonstrated on-treatment hsCRP levels to be as powerful a predictor of residual cardiovascular risk as on-treatment levels of low-density lipoprotein cholesterol. Yet, although hsCRP is clinically useful as a biomarker for risk prediction, most mechanistic studies suggest that CRP itself is unlikely to be a target for intervention. Moving upstream in the inflammatory cascade from CRP to interleukin (IL)-6 to IL-1 provides novel therapeutic opportunities for atheroprotection that focus on the central IL-6 signaling system and ultimately on inhibition of the IL-1β-producing NOD-like receptor family pyrin domain containing 3 inflammasome. Cholesterol crystals, neutrophil extracellular traps, atheroprone flow, and local tissue hypoxia activate the NOD-like receptor family pyrin domain containing 3 inflammasome. As such, a unifying concept of hsCRP as a downstream surrogate biomarker for upstream IL-1β activity has emerged. From a therapeutic perspective, small ischemia studies show reductions in acute-phase hsCRP production with the IL-1 receptor antagonist anakinra and the IL-6 receptor blocker tocilizumab. A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1β, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with little change in atherogenic lipids. Canakinumab in now being tested as a method to prevent recurrent cardiovascular events in a randomized trial of 10 065 post-myocardial infarction patients with elevated hsCRP that is fully enrolled and due to complete in 2017. Clinical trials using alternative anti-inflammatory agents active against the CRP/IL-6/IL-1 axis, including low-dose methotrexate and colchicine, are being explored. If successful, these trials will close the loop on the inflammatory hypothesis of atherosclerosis and serve as examples of how fundamental biologic principles can be translated into personalized medical practice.

Keywords: atherosclerosis; clinical trials; cytokines; inflammation; prevention.

Figure 1

Relationship of baseline plasma levels of hsCRP to risks of future myocardial infarction, stroke, and cardiovascular death in the prospective Physicians’ Health Study among those randomly allocated to aspirin or placebo (left). Risk estimates associated with elevated hsCRP levels are stable over long periods of time (right). Adapted from N Engl J Med 1997;336:973-9.

Figure 2

Meta-analysis of the relationship of hsCRP levels in healthy individuals to future risks of coronary heart disease and vascular deaths (left). The magnitude of cardiovascular risk associated with a one standard deviation change in hsCRP is at least as large as that associated with a similar change in systolic blood pressure, total cholesterol, or non-HDL cholesterol (right). Adapted from Lancet 2010;375:132-40.

Figure 3

Relationship of plasma levels of IL-6 to future risks of cardiovascular disease in 25 prospective epidemiologic cohorts. Overall, for each SD increase in log IL-6, there is a 25 percent increase in risk of future vascular events (95%CI 1.19-1.32). Adapted from Eur Heart J 2014;35:578-89.

Figure 4

Mendelian Randomization studies demonstrate that polymorphism in the IL-6 signaling pathway at rs2228145 and rs7529229 concordantly associate with both lifetime lower levels of hsCRP and lifetime lower risks of coronary heart disease. Adapted from Lancet 2012;379:1214-24 and Lancet 2012;379:1205-13.

Figure 5

Activation of the NLRP3 inflammasome by cholesterol crystals, neutrophil extracellular traps, hypoxia, and atheroprone flow result in production of pro-IL-1β to IL-1β with consequent downstream effects on IL-6 and CRP, as well as increased vascular atheroma. Potential targets for intervention include canakinumab, anakinra, tocilizumab, methotrexate, and colchicine. PAI-1 = plasminogen activator inhibitor-1; SREBP2 = sterol regulatory binding protein 2. (Illustration credit: Ben Smith).

Figure 6

Dose dependent effects of canakinumab at 4 months for CRP, IL-6, and fibrinogen among 556 diabetic patients at high risk for vascular disease. Adapted from Circulation 2012;116:2739-48.

Figure 7

Design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Adapted from Am Heart J 2011;162:597-605.