Interleukin-17 as a key player in neuroimmunometabolism

Abstract

In mammals, interleukin (IL)-17 cytokines are produced by innate and adaptive lymphocytes. However, the IL-17 family has widespread expression throughout evolution, dating as far back as cnidaria, molluscs and worms, which predate lymphocytes. The evolutionary conservation of IL-17 suggests that it is involved in innate defence strategies, but also that this cytokine family has a fundamental role beyond typical host defence. Throughout evolution, IL-17 seems to have a major function in homeostatic maintenance at barrier sites. Most recently, a pivotal role has been identified for IL-17 in regulating cellular metabolism, neuroimmunology and tissue physiology, particularly in adipose tissue. Here we review the emerging role of IL-17 signalling in regulating metabolic processes, which may shine a light on the evolutionary role of IL-17 beyond typical immune responses. We propose that IL-17 helps to coordinate the cross-talk among the nervous, endocrine and immune systems for whole-body energy homeostasis as a key player in neuroimmunometabolism.

Fig. 1 |. Timeline of major neuroimmunometabolic discoveries involving IL-17.

Since the discovery of IL-17A in 1993, our understanding of the role of this proinflammatory cytokine has slowly become more focused towards metabolism (immunological timeline). The first indication that IL-17 regulates systemic metabolism was observed when mice deficient for IL-17 displayed enhanced glucose handling (2010; metabolism timeline). Subsequent studies have also described a neuromodulatory role for IL-17 in which it regulates behavioural expression in C. elegans and mice (neuromodulation timeline).

Fig. 2 |. IL-17-mediated signalling in target cells.

IL-17A and IL-17F initiate downstream signalling events by ligating receptor complexes composed of IL-17RA and IL-17RC. Following ligation, IL-17RA–IL-17RC recruits the adaptor protein ACT1, an essential member of the cytosolic IL-17 cascade. ACT1 in turn associates with members of the TRAF family of adaptor proteins, activating multiple transcription factors that direct inflammation, cellular metabolism and tissue repair. Additionally, IL-17 signals through TRAF2 and TRAF5 to stabilize specific mRNA targets.

Fig. 3 |. Structural relationships between IL-17A, IL-17F and an archetypal neurotrophic factor.

At the level of their 3D protein structures, IL-17A and IL-17F resemble neuronal growth factors, each adopting a similar β-sheet framework and the characteristic cystine knot motif of neurotrophins. Conversely, IL-17 cytokines are structurally distinct from prototypical interleukins, including IL-10 and IL-6.

Fig. 4 |. IL-17 signalling modulates cellular metabolism in a host of non-immune target cells.

IL-17 is expressed by cells of the immune system such as γδ T cells, T_H17 cells, and ILC3s, while IL-17 receptor expression is predominantly limited to non-immune cells such as adipocytes, fibroblasts and epithelial cells. IL-17 signalling regulates the expression of genes involved in a variety of metabolic pathways, including lipolysis (adipocytes), lipogenesis (gut epithelial cells), oxidative phosphorylation (fibroblasts) and glycolysis (skin epithelial cells). The outcome of metabolic rewiring by IL-17 signalling is cell-type specific and affects higher-order functions including thermogenesis, weight fluctuation and wound healing.

Fig. 5 |. Evidence for evolutionarily conserved roles for IL-17 signalling beyond immunity.

Studies across species, including worms, fish, molluscs, mice and humans, indicate that IL-17 may play a conserved role in several processes. IL-17 plays an apparent role in feeding behaviour, as circulating IL-17 levels increase shortly after feeding, which regulates glucose metabolism and food consumption. The role of IL-17 in feeding behaviour may in part be linked to nervous system modulation, as IL-17 signalling regulates the sensory response to feeding in the nematode, while ensuring appropriate innervation of metabolic organs such as adipose tissue. Finally, underexpression or overexpression of IL-17 consistently detrimentally impacts tissue development. Loss of IL-17 signalling impairs adipose tissue neurogenesis and limits gastrointestinal development, whereas overexpression of IL-17 has been linked to the development of autism-like behaviour via abnormal cortex development. BDNF, brain-derived neurotrophic factor; CTX, cortex; HPC, hippocampus; HY, hypothalamus; SNS, sympathetic nervous system.