Therapeutic Dilemmas: Exploring the Dual Nature of IL-17 in Immune Responses

The interleukin 17 (IL-17) family of pro-inflammatory cytokines consists of six structurally related members: IL-17A to IL17F. Of the six cytokines, IL-17A is the most studied and will therefore be the major focus of this discussion.

IL-17A, previously known as cytotoxic T-lymphocyte-associated antigen 8 (CTLA8), is one of the major cytokines produced by a distinct subset of CD4⁺ T cells called T helper 17 (Th17) cells. While Th17 cells are the primary cells for secretion of IL-17A, production of this cytokine has also been identified from other cell types including γδ T, natural killer T (NKT), and group 3 innate lymphoid cells (ILC3).

The expression of IL-17A is induced by the binding of IL-23, a cytokine mainly produced by dendritic cells or macrophages, to its cognate receptor on Th17 cells. Secreted IL-17A subsequently binds to its receptors on other cells, such as epithelial cells, to activate the IL-17A signaling pathway.

Dysregulation of IL-17A production and signaling have been linked to both inflammatory and autoimmune diseases. Therefore, IL-17A signaling has been used as a primary therapeutic target to treat these illnesses. In this blog, we will discuss the pathological implications associated with IL-17A and current therapeutic treatments for diseases.

What Is the Function of IL-17A And Its Role in Disease?

IL-17A serves a vital function in immune responses, particularly in protecting epithelial tissues from microbial infections. When IL-17A binds to its receptor, which consists of a heteromeric IL-17RA/RC complex, it recruits a factor called Act 1 adaptor protein (ACT1). ACT1 subsequently activates another protein, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), to form a protein complex. The ACT1-TRAF6 complex then activates the canonical nuclear factor kappa B (NF-κB) pathway and induces the expression of inflammatory chemokines, such as C-X-C motif chemokine ligand 1 (CXCL1).

Interestingly, IL-17A signaling also has a synergistic effect with the signaling pathway initiated by a different cytokine, TNF-α (Chiricozzi et al. 2011). This combined activation not only stabilizes mRNA but also amplifies the expression of inflammatory cytokines, including IL-6 (Herjan et al. 2018).

While IL-17A plays a pivotal role in antimicrobial defense, prolonged production of IL-17A can contribute to chronic illnesses. Studies have linked the accumulation of IL-17-producing cells to Crohn’s disease (CD), a chronic inflammatory bowel condition. Additionally, patients with autoimmune diseases, such as psoriasis — a chronic skin disorder — and multiple sclerosis (MS) — with persistent damage to the central nervous system — show elevated levels of IL-17A. As a result, IL-17A signaling has emerged as a promising avenue for therapeutic strategies.

Therapies for IL-17A-Induced Diseases

Therapies targeting IL-17A signaling, including both the IL-17A cytokine and its receptor, IL-17RA, have been developed to treat diseases. Secukinumab and ixekizumab, monoclonal antibodies that block IL-17A, are effective in treating psoriasis. Additionally, the monoclonal antibody brodalumab, which blocks IL-17RA, offers a receptor-focused therapy.

However, IL-17A-targeted therapy is not equally effective for all patients, and the efficacy of the treatment also varies depending on the type of disease. For instance, CD patients who received treatment of either secukinumab or brodalumab not only show limited efficacy in the therapeutic outcomes but have worsened symptoms associated with increased microbial infection (Hueber et al., 2012).

This disparate response to IL-17A-targeted therapy between different diseases underscores the complexity of IL-17A signaling. IL-17A is not only crucial for the regulation of the immune response, but also for the maintenance of epithelial tight junctions that serve as protective barriers against pathogens.

Another potential reason for resistance to anti-IL-17A therapy in these patients could be due to the excessive abundance of a factor known as SH2 containing protein tyrosine phosphatase-2 (SHP2). The continuous release of IL-17A results in sustained expression of SHP2, which then interacts with ACT1 and leads to persistent activation of an IL-17A-independent signaling pathway (Luo et al. 2023). Indeed, treatment with iguratimod, a drug that can block the interaction between ACT1 and SHP2, effectively reduces the expression of IL-17A-mediated chemokines (e.g., CXCL1). More importantly, administering iguratimod to animals slows the progression of experimental autoimmune encephalomyelitis (EAE), an animal model for MS.

In light of these challenges, researchers have explored targeting pathways upstream of IL-17A signaling. Ustekinumab, an antibody against the p40 subunit of IL-23, offers an alternative therapeutic strategy. Clinical evidence shows that ustekinumab effectively treats CD and psoriasis with minimal adverse effects. This upstream targeting provides an alternative for patients unresponsive to IL-17A inhibition and offers broader therapeutic options with improved safety.

Apart from inflammatory and autoimmune diseases, hallmarks of IL-17A signaling have also been found in patients with certain cancers such as colorectal cancer (CRC). Notably, when CRC patients are treated with a combination of anti-IL-17A and checkpoint blockade, a type of immunotherapy, they exhibit enhanced anti-tumor response (Liu et al. 2021).

Therapeutic Designs for IL-17A-Related Diseases: Future Outlook

IL-17A acts as a double-edged sword. This cytokine is a key player in maintaining tissue homeostasis and defending against microbial infections but can also contribute to the development of diseases. While many monoclonal antibodies are available to target IL-17A pathways, these treatments are expensive and can result in various side effects. Therefore, the emergence of small molecule treatments targeting IL-17A signaling presents a potential alternative and provides lower-cost options with fewer off-target effects. By developing more effective therapies, these small molecules can not only help minimize treatment-related risks for patients with IL-17A-induced inflammatory and autoimmune diseases but could also lead to better clinical outcomes.