The intervertebral disc (IVD) consists of an outer fibrocartilaginous annulus fibrosus (AF) that surrounds a gel-like nucleus pulposus (NP). Its main functions are to act as a shock absorber and maintain the backbone mobility, including the cartilaginous endplates that cover this assembly on both the top and bottom sides. The AF is characterised by 15–25 concentric lamellae consisting of fibres of collagen types I and II, with smaller amounts of collagenⅢ, proteoglycans and elastin (Urban and Roberts, 2003; Önnerfjord et al., 2012). A small number of capillaries that penetrate only a few millimetres into the outermost AF (Sakai and Grad, 2015). NP is an avascular tissue. NP is comprised mainly of water along with collagen fibrils (including types VI, IX, and XI), various proteoglycans for shock absorption, and cells of the NP, which are adapted to survive in this hypoxic environment (Urban and Roberts, 2003; Hiyama et al., 2015; Sakai and Grad, 2015). Due to its avascular nature, the nutrients and metabolites are exchanged by diffusion to and from microvessels in the cartilaginous endplates and outer AF (Vo et al., 2016).

With aging, trauma, genetic susceptibility, and other factors, the IVDs gradually degenerate due to many factors, such as microenvironment changes and cell death (Zhang F et al., 2016). During IVD degeneration, the structure of the disc changes and homeostasis in disc become disturbed (Sakai and Grad, 2015). IVD degeneration is linked to low back pain and sciatica, which lead the physical disability of the patients (Urban and Roberts, 2003). Current studies demonstrate that IVD degeneration progresses in consequence of many factors, such as biomolecular damage, inflammatory response, IVD cell loss, extracellular matrix (ECM) degradation increase, and synthesis reduction (Vo et al., 2016; Zhang F et al., 2016).

The frequently reported inflammatory cytokines that are secreted and promote IVD degeneration include tumor necrosis factor-α (TNFα), IL-1 α/β, IL-6, IL-17, IL-8, IL-2, IL-4, IL-10, COX-2, IFN-γ, chemokines, and prostaglandin (PGE)2. Moreover, the factors promoting the extracellular matrix (ECM) degradation often reported are matrix metalloprotease (MMP)-1, -3, -7, -9, and -13, and A disintegrin-like and metalloprotease with thrombospondin type-1 motif (ADAMTS)-1, -4, -5, -9, and -15 (Risbud and Shapiro, 2014; Vo et al., 2016; Willems et al., 2016; Zhang F et al., 2016; Sutovsky et al., 2017). Conversely, TGF-β is essential in maintaining IVD homeostasis (Risbud and Shapiro, 2014; Chen et al., 2019).

Recently, high levels of IL-17A were associated with IVD degeneration (IDD) and IVD herniation (LDH) and IL-17A is considered as the crucial factor in IVD pathology (Shamji et al., 2010; Gabr et al., 2011; Cheng et al., 2013; Suyama et al., 2018). Furthermore, the rat tail suspended or punctured model showed the expression of IL-17A in NP cells and AF cells with tissue degeneration or injury (Han et al., 2015; Wang et al., 2018; Ding and Li, 2020). In this review, based on the current literature, we will focus on the IL-17 signaling pathway, its interaction with other factors, and multiple functions in IVD pathology.

IL-17 (IL-17A, CTLA8) cDNA was isolated and cloned from murine hybridomas in 1993 (Rouvier et al., 1993). IL-17 (also called IL-17A) is produced by the T helper 17 (Th17), a subset of CD4⁺ T cells that are distinct from classic Th1 and Th2 lineages (Gaffen, 2011; Iwakura et al., 2011). These Th17 cells are characterized by the expression of the “master” transcription factor RAR-related orphan receptor gamma (RORγt) and are activated by the IL-12 family cytokine IL-23 (McGeachy et al., 2019). The IL-17A producing CD4⁺ Th17 cells arise from multiple differentiation triggers, including TGFβ, IL-6, IL-1β, and IL-21 (Gaffen, 2011). Besides IL-17A, IL-17 consists of six other family molecules (IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F) with structural identity. IL-17A and IL-17F are closely related linked genes that are usually coproduced by Type 17 cells (Aggarwal and Gurney, 2002).

It was reported that Th17 cells are the major source of IL-17A, and other innate immune cells produce IL-17A in response to pathogens or tissue injury (Cua and Tato, 2010). Overall, IL-17A is produced from Th17 cells and other innate immune cells, inducing various products, including cytokines (IL-6, granulocyte-colony-stimulating factor [G-CSF], TNFα), chemokines (CXCL1, CXCL2, CCL20, among many others), inflammatory effectors (acute-phase proteins, complement), and antimicrobial proteins (defensins, mucins) (Onishi and Gaffen, 2010).

Recently, numerous studies in humans and mice have suggested that IL-17A plays a leading role in the pathogenesis of different immune-mediated diseases, including rheumatoid arthritis, psoriasis, asthma, and inflammatory bowel disease (Cua and Tato, 2010; Onishi and Gaffen, 2010; Gaffen, 2011; Amatya et al., 2017).

The IL-17 receptor family includes five members (IL-17RA to IL-17RE) that have such conserved structural characteristics as extracellular fibronectin III-like domains and cytoplasmic expression similar to that of fibroblast growth factor genes and IL-17Rs, and Toll-IL-1R family (SEFIR) domains (Iwakura et al., 2011; Gu et al., 2013).

IL-17A binds the heterodimeric receptor complex composed of IL-17RA and IL-17RC (Toy et al., 2006; Gu et al., 2013) (Figure 1) The initial event in IL-17A receptor signaling is recruitment of NF-κB activator 1 (Act1), a multifunctional signaling protein that also contains a SEFIR domain necessary for IL-17A receptor-Act1 association (Gu et al., 2013; McGeachy, et al., 2019). Then, IL-17A signaling activates several intracellular pathways or factors. For example, the IL-17A signaling activates Activator protein-1 (AP-1), TNF receptor-associated factor (TRAF)6, NF-κB, Jun N-terminal kinase (JNK), Erk1/2 and p38, CCAAT/enhancer-binding proteins (C/EBPs), Janus kinase (JAK) and phosphoinositol-3 kinase (PI3K). It also induces several proinflammatory cytokines (including IL-1β, IL-6, TNFα, and CCL2), antimicrobial peptides (β-defensin), and matrix metalloproteinases (Huang et al., 2007; Gaffen, 2009; Gaffen, 2011; Amatya et al., 2017; Chen et al., 2019; Schinocca et al., 2021).

The major downstream pathway of IL-17A signaling is NF-κB pathway (Xie et al., 2010; Gu et al., 2013). NF-κB activator 1 (Act1) contains a SEFIR domain and TRAF6 binding motif (Chang et al., 2006; Li et al., 2007). After IL-17A binding to IL-17R (IL-17RA/IL-17RC), Act1 interacts with IL-17A receptor through the SEFIR domain, and TRAF6 interacts with the TRAF6 binding motif of Act1; subsequently, TRAF6 activates the transforming growth factor β-activated kinase (TAK)1 and the inhibitor of NF-κB kinase (IKK) complex composed of IKKα, IKKβ, and IKKγ, and then, NF-κB activation occurs (Chang et al., 2006; Li et al., 2007; Amatya et al., 2017) (Figure 1). Because it was reported that IL-17A alone is insufficient for strong activation of NF-κB, IL-17A synergizes with other cytokines like TNFα to stimulate NF-κB and enhances the stabilization of proinflammatory cytokine and chemokine mRNA expression (Hartupee et al., 2007; Onishi and Gaffen, 2010; Gu et al., 2013).

Moreover, IL-17A–IL-17R–TRAF6 can promote the activation of the mitogen-activated protein kinase (MAPK) pathway and AP-1 (Walsh et al., 2015). And IL-17A stimulation recruits TRAF4, which binds the same binding site of TRAF6 on Act-1 competitively (Zepp et al., 2012; Gu et al., 2013). Act1-TRAF4 interaction specifically directs the activation of the MEKK3–MEK5–ERK5 cascade and results in MAPK pathway activation (Wu et al., 2015). Additionally, TRAF3 binds directly to the IL-17RA and interferes with IL-17RA-Act1-TRAF6 interaction (Zhu et al., 2010). These reports show that IL-17A activates the canonical NF-κB pathway but not the noncanonical pathway.

In the NP cells from IDD patient’s tissue, the production of NOx, PEG2, IL-6, and ICAM-1 was upregulated by the synergy of IL-17A and TNFα or IFNγ (Gabr et al., 2011). Similarly, it was reported that IL-17A interacts with many cytokines, such as TNFα or chemokines in IVD cells (Shamji et al., 2010; Wang et al., 2015; Zhang Y et al., 2016; Liu et al., 2019). As mentioned above, IL-6 is necessary for Th17 differentiation to produce IL-17A, and it was also expressed by IL-17A signaling in IVD cells via MAPK pathways (Suyama et al., 2018). Furthermore, IL-1β was reported to induce IL-17A expression in IDD (Johnson et al., 2015; Wang et al., 2020).

Regarding the cooperation of IL-17A and TNFα in IVD pathology, besides the IL-17A receptor- NF-κB pathway, the TNF receptor TNFR1 and TNFR2 are involved in the IL-17A response. TNFR1 can be activated either by tmTNFα (transmembrane TNFα) or sTNFα (a soluble form), whereas TNFR2 is activated mainly by sTNFα. Under tmTNFα and sTNFα stimulation, the TNFR1/SODD complex releases the inhibitory SODD protein, and TNFR1 becomes activated. Then TNFR1 binds TNF receptor-associated death domain, recruiting other adaptor proteins, including TNF receptor-associated factor 2 (TRAF2), receptor-interacting protein-1 (RIP-1), and cellular inhibitor of apoptosis protein (cIAP) 1, resulting in the formation of complex I that signal through either the NF-κB or MAPK pathways to activate p65 or AP-1 (Johnson et al., 2015; Wang et al., 2020). TNFR2 recruits TRAF3, TRAF2, cIAP1/2, and TRAF1 to establish a complex that also activates NF-κB, AP-1, and ERK, and it activates PI3K/AKT consequently (Wang et al., 2020). This regulation concerns many responses of IL-17A in IVD cells. Further, these pathways regulate the production of pro-inflammatory mediators such as TNFα, IL-1β or IL-6, and these mediators can recruit Th17 cells, which produce IL-17A, again (Figure 2). Indeed, when the factor that inhibits TNFα-TNFR1 signaling was suppressed in murine models of IDD, IL-17A expression was significantly increased by TNFα stimulating the NF-κB and MAPK pathways via TNFα receptors (Wang et al., 2018). TNFα can stimulate IVD cells directly, and it affects IL-17A signaling. Therefore, it results in IDD progression.

IL-17A plays an important role in IDD and LDH. IL-17A regulates many factors, including inflammatory cytokines, chemokines, PGE2, and the factors promoting ECM degradation, consequently promoting IVD pathology. However, there are many unknowns in IL-17A about their function, interaction, and gene regulation without immune cells or antagonists. It has yet been unclear how IL-17A is produced from IVD cells, though, it was reported that exposing degenerated disc cells to IL-1β or TNFα stimulates IL-17A production (Yang et al., 2015; Wang et al., 2020). These reports indicate the possibility that several cells can produce IL-17A in disc tissue. Similarly, Risbud and Shapiro suggested that resident disc cells may contribute to the production of lymphokine, including IL-17A (Risbud and Shapiro, 2014) because Shamji et al. showed the prominent IL-17 staining in non-degenerate control tissues (Shamji et al., 2010).

NF-κB and MAPK pathways which IL-17A effected on, regulate pro-inflammatory mediators such as TNF-α, IL-1β or IL-6, as both pathways have been identified as master regulators of inflammation and catabolism in IDD and LDH (Sakai and Grad, 2015). Furthermore, other cytokines or chemokines may be involved in IL-17A functions. Therefore, IL-17A could be used for therapy targets of IVD diseases.

According to current reports, IL-17A receptors are at the surface of NP cells, it indicates that IL-17A inhibitor, such as biologicals or small molecule compounds likely to be efficacious against IDD. These findings show the practical utility of IL-17A inhibitor. The therapy of IL-17A regulation may effect on pro-inflammatory cytokines including TNFα, IL-6, and IL-1β, and may suppress the degradation of ECM. Further, it was suggested the possibility that IL-17A correlates with IVD disease patients’ pain intensity, IL-17A is expected to be a biological marker of curative effects. It suggests the possibility that IL-17A inhibitors can be used as the medication for IDD to suppress the inflammation and the degradation of ECM by improving the IVD specific microenvironment via the related pathways in NP cells. It may lead to the improvement of physical functioning and quality of life of IDD patients. Indeed, as the reports of IL-17A medication in other diseases, it was reported that the treatment with IL-17A blockers improved joint symptoms of psoriatic arthritis compared with placebo (Mease et al., 2017; Nash et al., 2017; Blauvelt and Chiricozzi. 2018).

Additionally, although only IL-17A has been associated with IVD, the IL-17 family contains six members (IL-17A–IL-17F) (Iwakura et al., 2011; McGeachy et al., 2019). Therefore, the involvement of additional members of the IL-17 family in IVD could be reported in the future.