Structure, Signaling, and Targeting Strategies of IL-17A

Keywords: IL-17A, IL-17R, Act1, NF-κB, Th17 effector, dual-target antibody

IL-17A is the most functionally critical member of the IL-17 family and the core effector molecule of Th17 immune responses. Unlike the upstream regulator IL-23, IL-17A directly acts on target tissues (e.g., skin keratinocytes, synovial fibroblasts, intestinal epithelial cells), inducing the expression of chemokines, cytokines, and antimicrobial peptides, and driving neutrophil recruitment and tissue inflammation. Aberrant expression of IL-17A is a direct pathological driver of diseases such as psoriasis, ankylosing spondylitis, and psoriatic arthritis. This article systematically elaborates on the molecular structure of IL-17A, receptor complexes, signal transduction mechanisms, and strategies for targeting it as a drug.

The IL-17 family includes six members: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F. Among them, IL-17A and IL-17F share the highest homology (approximately 55% amino acid sequence identity) and are functionally most related.

IL-17A is a homodimeric protein composed of 155 amino acids, with each monomer adopting a cystine knot fold structure. The two monomers are covalently linked by two interchain disulfide bonds (Cys92-Cys92' and Cys40-Cys115'), forming a stable dimer. The topology of the IL-17A dimer differs from that of typical four-helix bundle cytokines, with its receptor-binding interface located on one side of the dimer and containing multiple conserved residues.

IL-17F and IL-17A can form the heterodimer IL-17A/F, which is also biologically active in vivo, with affinity and signaling strength intermediate between IL-17A and IL-17F. This discovery has driven the development of bispecific antibodies targeting both IL-17A and IL-17F.

The IL-17 receptor family includes five members: IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE. IL-17A signaling is mediated by the heterodimeric complex formed by IL-17RA and IL-17RC.

IL-17RA is the common subunit, composed of approximately 866 amino acids, with an extracellular region containing a fibronectin type III domain and a SEFIR domain (similar to the TIR domain). IL-17RC has a structure similar to IL-17RA. Unlike typical cytokine receptors, the assembly of the IL-17 receptor complex is unique: the IL-17A dimer binds to both receptor chains simultaneously, but the binding order and affinity differ. It is generally believed that IL-17A first binds to IL-17RA with high affinity, followed by the recruitment of IL-17RC to form a ternary complex.

IL-17RA is widely expressed in various cell types, including fibroblasts, epithelial cells, endothelial cells, and immune cells, explaining the broad tissue spectrum of IL-17A action. The expression profile of IL-17RC is relatively limited, correlating with the tissue-specific pathological effects of IL-17A.

After IL-17A binds to IL-17RA/IL-17RC, the SEFIR domains in the intracellular regions of the receptors undergo conformational changes, recruiting the adaptor protein Act1 (also known as TRAF3IP2). Act1 binds to the receptor SEFIR domains via its SEFLEX domain, while its TRAF6-binding motif recruits the E3 ubiquitin ligase TRAF6. TRAF6 catalyzes the formation of K63-linked polyubiquitin chains, thereby activating the canonical and non-canonical NF-κB pathways.

NF-κB pathway activation: Ubiquitinated TRAF6 recruits the TAK1-TAB1/TAB2 complex, and TAK1 phosphorylates and activates the IKK complex (IKKα/IKKβ/NEMO). The IKK complex phosphorylates IκBα, promoting its proteasomal degradation and releasing the NF-κB dimer (p50/p65) for nuclear translocation, initiating inflammatory gene transcription.

MAPK pathway activation: TAK1 simultaneously activates the MKK3/6-p38 and MKK4/7-JNK pathways, participating in cytokine production and cellular stress responses.

mRNA stability regulation: Act1 also recruits TRAF2 and TRAF5, activating the MEKK3-ERK5 pathway, which phosphorylates and inhibits mRNA stability regulators (e.g., AUF1, TTP), prolonging the half-life of chemokine and cytokine mRNAs.

The final transcriptional output of IL-17A signaling includes: chemokines (CXCL1, CXCL2, CXCL8/IL-8, CCL20), cytokines (IL-6, G-CSF, GM-CSF), antimicrobial peptides (β-defensin, S100 proteins), and matrix metalloproteinases (MMP1, MMP3, MMP13).

Recent studies have revealed unique autocrine activation mechanisms in IL-17R signaling. Under chronic inflammatory conditions, IL-17A can induce high expression of SHP2 (SH2 domain-containing protein tyrosine phosphatase 2). SHP2 interacts with Act1, forming the IL-17R-Act1-SHP2 complex. Although SHP2 is not a classical ubiquitin ligase, it mediates K63 ubiquitination of Act1, activating downstream signaling pathways. The pathological significance of this mechanism lies in the fact that even after IL-17A ligand withdrawal, SHP2-driven autocrine activation can sustain signaling. This discovery explains the reduced long-term efficacy of anti-IL-17A monoclonal antibody therapy in some patients and provides a new direction for targeting the SHP2-Act1 interface.

IL-17 signaling is also subject to negative feedback regulation. Act1 itself can be degraded by the proteasome as a signal termination mechanism. TRAF3 can competitively bind Act1, inhibiting TRAF6 recruitment. SOCS3 (suppressor of cytokine signaling 3) can also be induced to negatively regulate IL-17 signaling.

Drug development strategies targeting the IL-17 pathway can be divided into three levels:

(1) Ligand neutralization: Anti-IL-17A monoclonal antibodies (e.g., secukinumab, ixekizumab) specifically bind the IL-17A dimer, blocking its interaction with receptors. Anti-IL-17A/F bispecific antibodies (e.g., bimekizumab) simultaneously neutralize IL-17A and IL-17F, covering more pathogenic ligand types.

(2) Receptor blockade: Anti-IL-17RA monoclonal antibodies (e.g., brodalumab) block ligand binding to the common receptor subunit. Since IL-17RA is a shared receptor for multiple IL-17 family members, this strategy has a broader effect spectrum but may also affect physiological signals such as IL-17E (IL-25).

(3) Intracellular signal interference: Small-molecule inhibitors target downstream signaling nodes such as TRAF6, TAK1, or IKK, but the selectivity of these targets poses significant challenges. The Act1-SHP2 interface provides a more selective potential target for small-molecule intervention.

IL-23 and IL-17A operate at different levels of the same signaling axis: IL-23 acts during the Th17 cell differentiation stage, determining commitment to the Th17 lineage, while IL-17A is the effector molecule produced by Th17 cells, directly executing inflammatory functions. This hierarchical relationship dictates differences in targeting strategies: IL-23 blockade primarily affects the abundance and pathogenicity of Th17 cells, with relatively slow but sustained effects; IL-17A blockade directly and rapidly antagonizes inflammatory effects but has less impact on Th17 cell numbers. Combined or dual-targeting strategies could theoretically produce synergistic effects.

As the effector engine of the Th17 axis, the molecular structure, receptor complexes, and signal transduction mechanisms of IL-17A have been comprehensively elucidated. The Act1-TRAF6-NF-κB axis is the core pathway of IL-17 signaling, while the SHP2-mediated autocrine activation mechanism reveals the molecular basis of sustained signaling in chronic inflammation. Various targeting strategies (ligand neutralization, receptor blockade, dual targeting, intracellular small molecules) are being developed around IL-17A, forming a rich landscape for drug development.

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