Molecular mechanism and therapeutic progress of IL-1 receptor family and inflammatory diseases

Introduction
The interleukin-1 (IL-1) family represents a pivotal group of cytokines that regulate innate immune responses and inflammatory processes. Based on receptor binding characteristics, this family is classified into three subfamilies: IL-1, IL-18, and IL-36. Notably, the IL-18 subfamily's coreceptor IL-1R5 (also designated IL-18Rα) plays critical roles in infections, autoimmune disorders, and metabolic diseases. This review systematically examines IL-1R5-mediated signaling pathways, their involvement in disease pathogenesis, and current therapeutic developments.

I. Structural Organization and Classification of the IL-1 Receptor Family

1. Structural Features
   All IL-1 family members contain a conserved AXD motif (A: aliphatic amino acid; X: any amino acid; D: aspartate), essential for receptor recognition. IL-1 receptors are Type I transmembrane proteins featuring extracellular immunoglobulin-like domains and intracellular Toll/IL-1 receptor (TIR) domains responsible for signal transduction.

2. Subfamily Classification Criteria

• IL-1 subfamily: Includes IL-1α, IL-1β, and IL-33, requiring IL-1R3 (IL-1RAcP) as a coreceptor.

• IL-18 subfamily: Comprises IL-18 and IL-37, dependent on IL-1R5 (IL-18Rα) for signaling.

• IL-36 subfamily: Members (e.g., IL-36α/β/γ) bind to IL-1R6 (IL-1RL2).

II. Biological Properties of IL-1R5/IL-18Rα

1. Molecular Structure and Function
   IL-1R5, encoded on human chromosome 2q12, requires dimerization with accessory receptors (e.g., IL-1R7/IL-18Rβ) for signal initiation. Soluble IL-1R5 (sIL-1R5), generated via proteolytic shedding or alternative splicing, exhibits IL-18-neutralizing activity.

2. Signaling Mechanisms
   IL-18 binding to IL-1R5 recruits IL-1R7, inducing TIR domain oligomerization and MyD88-dependent activation of NF-κB and MAPK pathways, thereby promoting proinflammatory cytokine release (e.g., IFN-γ, TNF-α). In contrast, IL-37 engagement of IL-1R5 suppresses MyD88 phosphorylation, exerting anti-inflammatory effects (Figure 1).

III. Pathogenic Roles of IL-1R5 in Inflammatory Diseases

1. Autoimmune Disorders

• Rheumatoid arthritis (RA): While meta-analyses show inconsistent genetic associations, elevated synovial IL-18 activates fibroblasts to secrete matrix metalloproteinases (MMPs), exacerbating joint destruction.

• Systemic lupus erythematosus (SLE): IL-18 promotes Th1 responses and B-cell activation, driving anti-dsDNA antibody production. Clinical studies correlate serum IL-18 levels with SLE Disease Activity Index (SLEDAI) scores.

2. Metabolic Diseases

• Gouty arthritis: Urate crystals activate NLRP3 inflammasomes, catalyzing pro-IL-18 cleavage to recruit neutrophils. IL-1R5-knockout mice show attenuated inflammation.

• Type 2 diabetes: IL-18 induces β-cell apoptosis, whereas IL-37 improves insulin resistance via IL-1R5 signaling modulation.

3. Allergic Conditions
   IL-18 synergizes with IL-33 to drive Th2 responses. In allergic asthma, IL-1R5+ mast cells release histamine and leukotrienes, contributing to airway hyperreactivity. Clinical trials (e.g., NCT03469934) are evaluating anti-IL-1R5 antibodies for severe asthma.

IV. Therapeutic Strategies Targeting IL-1R5

1. Neutralizing Antibodies and Receptor Antagonists

• Tadekinig alfa (recombinant IL-18BP): Demonstrated efficacy in adult-onset Still's disease (AoSD) Phase II trials before discontinuation for commercial reasons.

• GSK1070806 (anti-IL-18 mAb): Under investigation for Crohn’s disease and diabetes (NCT03681067).

2. Gene Therapy and Small-Molecule Inhibitors

• IL-1R5-targeted siRNA: Reduces epidermal hyperplasia and inflammation in psoriasis models.

• NLRP3 inhibitors (e.g., MCC950): Indirectly modulate IL-1R5 signaling by blocking IL-18 maturation.

3. Combination Therapy Potential
   Co-administration with JAK inhibitors (e.g., tofacitinib) may synergistically suppress Th1/Th17 pathways, as evidenced in RA animal models.

V. Challenges and Future Perspectives
Key unresolved issues include:

1. Signaling complexity: Opposing effects of IL-18 (proinflammatory) and IL-37 (anti-inflammatory) through IL-1R5 demand precise targeting strategies.

2. Biomarker gaps: Predictive biomarkers for IL-1R5 activation are needed to guide personalized therapy.

3. Long-term safety: Chronic IL-1R5 inhibition may impair antimicrobial immunity.

Future research should focus on conformational modulation, tissue-specific drug delivery, and bispecific antibody design to optimize outcomes.

Conclusion
As the central receptor for IL-18 signaling, IL-1R5 exhibits dual roles across inflammatory diseases. Deciphering its structural dynamics and regulatory networks will accelerate the development of next-generation therapeutics. With advancing biotechnologies, IL-1R5-targeted precision medicine holds transformative potential.