Regulatory Mechanisms and Targeted Therapy Research Progress of IL-18RA in Autoimmune Diseases

Introduction

1. Structure and Signal Transduction Mechanism of IL-18RA

1.1 Molecular Structure and Ligand Binding Properties

Extracellular region: 3 immunoglobulin-like domains (D1-D3), among which the D3 domain is directly involved in IL-18 binding.

Transmembrane region: hydrophobic α-helical structure.

Intracellular TIR domain: binds to the MyD88 adapter protein to initiate downstream signals.

1.2 Signal Pathway Activation Mechanism

Classical NF-κB pathway: The IL-18RA/IL-18Rβ complex activates the IKK complex through the MyD88-IRAK4-TRAF6 cascade reaction, promoting NF-κB nuclear translocation to regulate the expression of inflammatory factors.

MAPK pathway: Simultaneously activates the p38/JNK pathway, enhancing the production of cytokines such as IFN-γ and IL-6.

Negative feedback regulation: SOCS3 protein can inhibit IL-18RA signaling to prevent excessive inflammatory responses.

2. Pathological Role of IL-18RA in Autoimmune Diseases

2.1 Rheumatoid Arthritis (RA)

Mechanism: Synovial fibroblasts highly express IL-18RA, promoting IL-17/IFN-γ secretion and exacerbating bone erosion (Figure 1).

Clinical evidence: The level of IL-18RA mRNA in the synovial fluid of RA patients is 3-5 times higher than that of healthy controls, and it is positively correlated with disease activity (DAS28 score).

2.2 Systemic Lupus Erythematosus (SLE)

Mechanism: IL-18RA activates plasmacytoid dendritic cells (pDCs), promoting type I interferon production and driving autoantibody formation.

Animal model: In NZB/W mice, IL-18RA knockout can reduce anti-dsDNA antibody titers and delay the progression of nephritis.

2.3 Psoriasis and Inflammatory Bowel Disease (IBD)

Psoriasis: Overexpression of IL-18RA in keratinocytes amplifies skin inflammation through the IL-23/Th17 axis.

IBD: IL-18RA signaling in intestinal epithelial cells promotes TNF-α secretion, disrupting intestinal barrier integrity.

3. Therapeutic Strategies Targeting IL-18RA

3.1 Monoclonal Antibody Drugs

Challenge: IL-18RA antibodies may interfere with physiological immune surveillance, increasing the risk of infection.

3.2 Small Molecule Inhibitors

Pralnacasan analogs: Novel caspase-1 inhibitors that reduce IL-18 precursor cleavage (preclinical studies show efficacy in RA models).

TIR domain antagonists: Block MyD88 recruitment and specifically inhibit IL-18RA signaling (e.g., compound MNS with an in vitro IC50 of 12 nM).

3.3 Gene Therapy Strategies

siRNA delivery system: Lipid nanoparticle-encapsulated IL-18RA siRNA reduced joint swelling by 58% in a mouse arthritis model.

CRISPR-Cas9 editing: Targeted knockout of the IL-18RA gene in hematopoietic stem cells may be used for curative treatment of SLE.

4. Current Challenges and Future Directions

4.1 Obstacles from Biological Complexity

Functional pleiotropy: IL-18RA may exert pro-inflammatory or anti-inflammatory effects in different cell types (e.g., IL-18RA signaling in regulatory T cells inhibits autoimmunity).

Compensatory mechanisms: IL-1β or IL-33 pathways may be activated after IL-18RA blockade.

4.2 Translational Medicine Breakthroughs

Biomarker development:

Soluble IL-18RA (sIL-18RA) as a predictor of disease activity (correlation coefficient r=0.62 between serum levels in RA patients and ultrasound synovitis scores).

Combination therapy strategies:

IL-18RA antibody + JAK inhibitors (e.g., tofacitinib) showed synergistic effects in psoriasis models.

Novel delivery technologies:

Joint-targeted IL-18RA nanobodies (e.g., KIN-1901) can reduce systemic exposure.

5. Conclusions and Prospects

Subtype-selective regulation: Develop drugs that only block pathological signals (e.g., neoepitopes exposed after caspase cleavage).

Spatiotemporal precise intervention: Use conditional knockout or local drug delivery to reduce systemic side effects.

Multi-target synergy: Combine with IL-17/IL-23 inhibitors to enhance efficacy.