Interleukin-17A: The Key Cytokine in Neurodegenerative Diseases

Abstract

Neurodegenerative diseases are characterized by the loss of neurons and/or myelin sheath, which deteriorate over time and cause dysfunction. Interleukin 17A is the signature cytokine of a subset of CD4⁺ helper T cells known as Th17 cells, and the IL-17 cytokine family contains six cytokines and five receptors. Recently, several studies have suggested a pivotal role for the interleukin-17A (IL-17A) cytokine family in human inflammatory or autoimmune diseases and neurodegenerative diseases, including psoriasis, rheumatoid arthritis (RA), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and glaucoma. Studies in recent years have shown that the mechanism of action of IL-17A is more subtle than simply causing inflammation. Although the specific mechanism of IL-17A in neurodegenerative diseases is still controversial, it is generally accepted now that IL-17A causes diseases by activating glial cells. In this review article, we will focus on the function of IL-17A, in particular the proposed roles of IL-17A, in the pathogenesis of neurodegenerative diseases.

Keywords: astrocytes; glaucoma; interleukin-17A; microglia; neurodegenerative diseases; oligodendrocytes.

Figure 1

Signaling pathway of Interleukin-17A (IL-17A). The heterodimer receptor consists of two subunits, IL-17RA and IL-17RF, which bind to IL-17A, IL-17F, and IL-17AF ligands. The intracellular SEF/IL-17 receptor (SEFIR) domains interact with a corresponding SEFIR motif on the Act1 adaptor (Novatchkova et al., 2003). TNF-receptor associated factor 6 (TRAF6) and TRAF2/5 proteins bind to the TRAF-binding site in Act1. After binding to Act1, TRAF6 mediates the activation of the classical nuclear factor-κB (NF-KB) pathway of MAPK:AP-1. Collectively, these pathways trigger the transcriptional induction of target genes (Qian et al., 2007). In the IL-17 signaling pathway, a pathway of post-transcriptional mRNA stabilization is promoted through the recruitment of TRAF2 and TRAF5 by Act1 (Schwandner et al., 2000). This physiological process is achieved by controlling multiple RNA-binding proteins, such as HuR and Arid5a.

Figure 2

The way of glial cells respond to IL-17A. In central nervous system (CNS) neurodegenerative diseases, IL-17A binds to the receptor on the surface of microglia and activates microglia. Activated microglia secrete cytokines, exacerbating dopaminergic neurons loss. Astrocytes respond to IL-17A through generating chemokines to promote the recruitment of inflammatory cells, such as macrophages and neutrophils. IL-17A reduces the ability of astrocytes to absorb and transform glutamate as well as enhance the excitotoxicity of glutamate. IL-17A inhibits the maturation of oligodendrocyte lineage cells (OPCs) and exacerbates the TNF-α-induced oligodendrocyte apoptosis (Qian et al., ; Stromnes et al., ; Kang et al., ; Ji et al., ; Kang Z. et al., ; Liu et al., ; Rodgers et al., ; Liu Z. et al., 2019).

Figure 3

The relationship between IL-17A and astrocytes. In astrocytes, IL-17A induces expression of macrophage inflammatory protein-α (MIP-1α) through Src/MAPK/PI3K/NF-KB pathways (Yi et al., 2014). IL-17A enhances the excitotoxicity of glutamate by reducing the ability of astrocyte to absorb and transform glutamate (Kostic et al., 2017). In EAE mice, IL-17A triggers the downregulation of miR-497, thereby upregulating the hypoxia-inducible factor-1α (HIF-1α) transcription factor in astrocytes as well as IL-1β and IL-6 secretion by astrocytes. MiR-409-3p and MiR-1896 are involved in the process of IL-17A-mediated secretion of inflammatory cytokines by astrocytes by targeting the SOCS3/STAT3 signaling pathway in EAE mice. Under IL-17A stimulation, miR-873 participates in inflammatory cytokine production in astrocytes through the A20/NF-KB pathway in EAE mice (Liu X. et al., ; Shan et al., ; Liu X. et al., 2019). In EAE mice, proinflammatory gene expression induced by IL-17A is diminished through the abrogation of p38α in astrocytes, which was via the defective activation of MAPK-activated protein kinase 2 (Huang et al., 2015).