The metabolism-modulating activity of IL-17 signaling in health and disease

Abstract

IL-17 was discovered nearly 30 yr ago, but it has only been recently appreciated that a key function of this cytokine is to orchestrate cellular and organismal metabolism. Indeed, metabolic regulation is integrated into both the physiological and the pathogenic aspects of IL-17 responses. Thus, understanding the interplay between IL-17 and downstream metabolic processes could ultimately inform therapeutic opportunities for diseases involving IL-17, including some not traditionally linked to this cytokine pathway. Here, we discuss the emerging pathophysiological roles of IL-17 related to cellular and organismal metabolism, including metabolic regulation of IL-17 signal transduction.

Figure 1.

Overview of IL-17–mediated metabolic regulation. IL-17–driven metabolic pathways deliver vital signals for tissue homeostasis. In parallel, metabolic regulation underlies many IL-17–driven pathologies. Cellular and organismal metabolic homeostasis cannot be sustained without appropriate temporally and spatially regulated IL-17 signaling, at the risk of damage to tissues with critical metabolic functions.

Figure 2.

IκBζ mediates IL-17–driven metabolic and immunological responses. (A) Cellular metabolism generates energy and regulates cell function in numerous ways. Glucose metabolism creates intermediates that supply different metabolic pathways. For example, pyruvate is converted to acetyl-CoA, which feeds into the TCA cycle to generate ATP. Oxaloacetate and citrate are used for nucleotide and lipid synthesis, respectively. Fatty acids are metabolized through β-oxidation to acetyl-CoA, whereas glutamine is metabolized via glutaminolysis to α-ketoglutarate. Some metabolites (e.g., itaconate) directly influence IL-17 responses. (B) IL-17 activates downstream signaling pathways through distinct TRAF proteins. TRAF6 induces IκBζ, NF-κB, C/EBPs, and MAPK pathways. Together, these pathways upregulate transcription of IL-17–dependent target genes. Additionally, IL-17 controls posttranscriptional events that increase target mRNA levels through various RBPs (e.g., Act1, HuR, Arid5a, Regnase-1). (C) IL-17 promotes stromal cell survival in lymph nodes (e.g., FRCs) through cell metabolic regulation involving an IκBζ-dependent increase in glycolysis and mitochondrial activity.

Figure 3.

IL-17–mediated metabolic regulation in adipose tissue. The IL-17 pathway exerts an antiadipogenic role by suppressing adipocyte differentiation through decreased expression of proadipogenic TFs. IL-17A promotes thermogenesis in BAT by supporting a UCP1-dependent thermogenic response. Moreover, IL-17 synergizes with TNF-α to induce IL-33 by stromal adipose cells, leading to T reg cell expansion. IL-17F is reported to trigger sympathetic innervation and norepinephrine (NE) release.