Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure

Abstract

Heart failure exhibits remarkable pathophysiologic heterogeneity. A large body of evidence suggests that regardless of the underlying etiology, heart failure is associated with induction of cytokines and chemokines that may contribute to the pathogenesis of adverse remodeling, and systolic and diastolic dysfunction. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 have been extensively implicated in the pathogenesis of heart failure. Inflammatory cytokines modulate phenotype and function of all myocardial cells, suppressing contractile function in cardiomyocytes, inducing inflammatory activation in macrophages, stimulating microvascular inflammation and dysfunction, and promoting a matrix-degrading phenotype in fibroblasts. Moreover, cytokine-induced growth factor synthesis may exert chronic fibrogenic actions contributing to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). In addition to their role in adverse cardiac remodeling, some inflammatory cytokines may also exert protective actions on cardiomyocytes under conditions of stress. Chemokines, such as CCL2, are also upregulated in failing hearts and may stimulate recruitment of pro-inflammatory leukocytes, promoting myocardial injury, fibrotic remodeling, and dysfunction. Although experimental evidence suggests that cytokine and chemokine targeting may hold therapeutic promise in heart failure, clinical translation remains challenging. This review manuscript summarizes our knowledge on the role of TNF-α, IL-1, IL-6, and CCL2 in the pathogenesis of heart failure, and discusses the promises and challenges of targeted anti-cytokine therapy. Dissection of protective and maladaptive cellular actions of cytokines in the failing heart, and identification of patient subsets with overactive or dysregulated myocardial inflammatory responses are required for design of successful therapeutic approaches.

Keywords: Chemokine; Cytokine; Heart failure; Inflammation; Interleukin-1; TNF-α.

Fig. 1

Cellular actions of TNF-α and IL-1 in heart failure. The pleiotropic cytokines TNF-α and IL-1 have been implicated in both post-infarction heart failure (HF) and in non-ischemic HF by modulating phenotype and function of cardiomyocytes, immune cells, fibroblasts, and vascular cells. Both TNF-α and IL-1 have negative inotropic actions and induce apoptosis in cardiomyocytes. Moreover, both TNF-α and IL-1 induce MMP expression, promoting degradation of the cardiac extracellular matrix (ECM), and stimulate inflammatory signaling in leukocytes and vascular endothelial cells. However, several studies have suggested that TNF-α may exert protective actions on cardiomyocytes under conditions of stress, by regulating calcium homeostasis and by preserving mitochondrial function. The cartoon was designed using Servier Medical Art (https://smart.servier.com/)

Fig. 2

IL-6 signaling and cellular actions in the failing heart. The wide range of cellular targets of IL-6 and the complexity of IL-6 signaling may explain its pleiotropic actions in heart failure. IL-6 has been reported to exert both pro- and anti-inflammatory actions, stimulates fibroblast proliferation and ECM synthesis, and promotes cardiomyocyte hypertrophy. The potential role of trans-signaling adds a layer of complexity to IL-6 actions. Classically, IL-6 signals through binding to the IL-6 receptor (IL-6R) which in turn associates with the dimerized gp130 receptor subunit gp130 to form a receptor complex that activates Janus kinases and triggers STAT3 phosphorylation. Cells lacking the IL-6R may also be affected by IL-6 through trans-signaling. ADAM proteases can cleave IL-6R from cell surface, generating soluble IL-6R (sIL-6R), which may associate with IL-6, stimulating gp130/STAT3 signaling on cells lacking IL-6R. While classic IL-6 signaling may be anti-inflammatory, trans-signaling has been suggested to exert pro-inflammatory actions. The relative contributions of canonical and trans IL-6 signaling in heart failure have not been systematically studied. This cartoon was designed using Servier Medical Art (https://smart.servier.com/)