Interleukin-17 and ischaemic stroke

Abstract

Interleukin-17 (IL-17) is a cytokine family that includes 6 members, IL-17A through IL-17F, most of them are reported to have pro-inflammatory role. Through binding to their receptors (IL-17Rs), IL-17 activates the intracellular signalling pathways to play an important role in autoimmune diseases, including rheumatoid arthritis (RA) and multiple sclerosis (MS). Ischaemic stroke is a complex pathophysiological process mainly caused by regional cerebral ischaemia. Inflammatory factors contribute to the physiological process of stroke that leads to poor prognosis. IL-17 plays a crucial role in promoting inflammatory response and inducing secondary injury in post-stroke. Though immune cells and inflammatory factors have been reported to be involved in the damage of stroke, the functions of IL-17 in this process need to be elucidated. This review focuses on the pathological modulation and the mechanism of IL-17 family in ischaemic stroke and seeking to provide new insights for future therapies.

Keywords: IL-17A; inflammation; interleukin-17 (IL-17); stroke; therapy.

Figure 1

IL‐17 family of cytokines was found. A timeline showing the discovery of IL‐17 and its receptor family. References in 18, 19, 21, 22, 23, 24.

Figure 2

The IL‐17A signalling pathway. IL‐17 binds to its receptor, which is composed of IL17RA and IL‐17RC. Upon ligand binding, activated Act1 phosphorylated TRAF6 and triggers the transcription of TRAF6‐dependent target genes such as NF‐κB, CEBP and MAPK/AP‐1. The IL17A signalling pathway is regulated by many molecules, including TRAF family, HuR and so on. TRAF2‐TRAF5 complex and HuR stabilize the mRNA of IL‐17A target genes and contribute to the pathogenesis of stroke, while TRAF3 and TRAF4 seem to play a negative role. TRAF3 competes with Act1 to IL‐17R, while TRAF4 competes with TRAF6 for Act1. Besides, ERK1/2 and GSK‐3β phosphorylate the Thr188 and Thr179 of C/EBPβ, in turn, inhibits of CEBP pathway. References in 28, 41, 42, 44.

Figure 3

Production and function of IL‐17 after stroke. After stroke, cerebral ischaemia and hypoxia lead nerve cells necrosis and release a large amount of DAMPs and inflammation factors. When DAMPs are combined with TLRs on DCs, it promotes the DC‐derived IL‐23 releasing from DCs and then IL‐23 promotes the release of IL‐17 by γδ T cells, Th17 cells NKT cells and so on. Finally, IL‐17 leads to poor prognosis of stroke in three ways: (1) inducing the secretion of pro‐inflammatory factors; (2) recruiting neutrophils to infiltrate into CNS; (3) impairing the integrity of BBB.