Cardiolipotoxicity, Inflammation, and Arrhythmias: Role for Interleukin-6 Molecular Mechanisms

FIGURE 1. Functional crosstalk between macrophages and cardiomyocytes. The schematic shows functional coupling between macrophages and cardiomyocytes through gap junctional channels. Small molecules including ATP are exchanged between cells with implications for inflammatory response. Macrophages have been shown to express ion channels that are similar to depolarizing (ICa, INa) and repolarizing mechanisms in heart (IKr, IKs, and IK1). Previously Van Wagoner and others (Das et al., 2009), reported functional expression of Cav1.2 channels in macrophages, that could be blocked by known Ca channel blockers (amlodipine and verapamil), but were voltage-independent. Macrophages also express IHERG-like currents, that are unrelated to cardiac IKr (Pennefather et al., 1998; Zhou et al., 1998), and inwardly rectifying K channels (Moreno et al., 2013; Kan et al., 2016). What role, if any do the expression of these channels play in mediating the effects of SFFAs on cardiac electrical activity? Despite the lack of clarity, macrophages are likely to influence cardiac electrical function to help maintain homeostatic control. This influence could be via direct (TL4R-cytokine release) or indirect…

FIGURE 2. Cardiac and macrophage inflammatory pathways. In metabolic disorders, enlargement of adipocytes contributes to the activation of macrophages and release of SFFAs through lipolysis (Watanabe et al., 2013). The exposure of cells to increased levels of these inflammatory molecules leads to the activation of inflammatory pathways. The cartoon representation shows the activation of the TLR signaling pathways (MyD88-dependent and -independent), by SFFAs in both macrophages and cardiomyocytes. Infiltration of cardiomyocytes by M1 pro-inflammatory macrophages may lead to cardiac electrical dysfunction, cause arrythmias leading to cardiomyopathies of metabolic disorders. The MyD88-dependent pathway involves sequentially, activation of IRAK4, phosphorylation of IRAK1/2, and TRAF6, followed by activation of IKK and NF-κB, and the subsequent production or secretion of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β). The MyD88-independent pathway also involves the secretion of pro-inflammatory cytokines through activation of TRAF6 by TRAM/TRIF. SFFA, Saturated free-fatty acid; TLR, Toll-like receptor; MD-2, myeloid differentiation protein-2; TIR, Toll/interleukin-1 receptor; TRIF,…

FIGURE 3. Cartoon depiction illustrating potential saturated free-fatty acid mechanisms that may underlie arrhythmogenic events. High-fat diet induce elevations of saturated free-fatty acids (SFFAs) leading to increased expression of proinflammatory cytokines in macrophages. Cardiac macrophages sense high concentrations of SFFAs through the toll-like receptor 2 (TLR2) and/or toll-like receptor 4 (TLR4) which induces expression of inflammatory target genes including tumor necrosis factor (TNF)-α and interleukin-6 (IL-6), by regulating the activities of nuclear factor-κB (NF-κB) (Youssef-Elabd et al., 2012). SFFAs also induce interleukin-1β secretion via the NLRP3 inflammasome in macrophages, which is independent of the TLR4 pathway (Henao-Mejia et al., 2012). Hemichannels control the exchange of small molecules including ATP (Willebrords et al., 2016). The released ATP binds to the cell-surface purinergic receptors P2X7R, and can control inflammation by regulating the release of pro-inflammatory cytokines (including IL-1β) (Gicquel et al., 2017). There is a paucity of lipid studies involving the IL-6 signaling pathway, and therefore the molecular mechanisms of IL-6 modulation of cardiac…