Targeting IL-6 for Treatment of Chronic Kidney Disease and Cardiovascular Disease

Figure 1. The IL-6 signaling pathway. (a) Production of IL-6 via upstream activation of the NLRP3 inflammasome.53, 54, 55, 56 Arrows (→) indicate activation or downstream signaling steps. Blunt-ended lines (—|) indicate inhibition of a pathway component. Boxes indicate therapeutic agents and their corresponding targets in the IL-6 pathway. (b) The 3 IL-6-mediated signaling modes: classical signaling, trans-signaling, and cluster signaling.57, 58, 59, 60 CRP, C-reactive protein; gp130, glycoprotein 130; IL, interleukin; IL-6R, interleukin-6 receptor; JAK/STAT3, Janus kinase signal transducer and activator of transcription 3; NLRP3, nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing protein 3; sIL-6R, soluble interleukin-6 receptor.

Figure 2. (a) Role of IL-6 in iron metabolism and anemia and (b) therapeutic modulation of iron metabolism and anemia. (a) The IL-6/IL-6R/gp130 complex activates the JAK/STAT3 signaling pathway, leading to the phosphorylation and dimerization of STAT3.112 These STAT3 homodimers translocate to the nucleus and upregulate hepcidin transcription by binding to STAT-responsive elements in its promoter.112 Excess hepcidin causes the proteolysis of ferroportin, thus attenuating iron transport and trapping iron inside cells.112 (b) IL-6 signaling increases hepcidin production and suppresses erythropoiesis, promoting functional iron deficiency and anemia. Dietary iron in the context of inflammation is associated with enhanced IL-6 signaling, which can further amplify hepcidin expression.113,114 In contrast, ESAs lower hepcidin by stimulating erythropoiesis, and IL-6 inhibitors lower hepcidin by blocking IL-6 signaling.112 Thus, hepcidin levels reflect the balance between hepcidin-raising stimuli (inflammation and dietary iron) and hepcidin-lowering stimuli (ESAs and IL-6 inhibitors). When IL-6 levels are elevated, persistent hepcidin elevation despite ESA therapy contributes to ESA…