The IL1RL1 gene encodes Interleukin-1 Receptor-Like 1 (IL1RL1), also known as ST2 or IL1RL1. This gene is a member of the Interleukin-1 receptor family and serves as the cognate receptor for the alarmin cytokine IL-33[1]. The IL-33/ST2 axis has emerged as a critical signaling pathway in neuroinflammation, immune regulation, and neurodegenerative disease pathogenesis[2]. ST2 exists in multiple isoforms—membrane-bound ST2L and soluble sST2—each with distinct biological functions that modulate cellular responses to tissue injury and stress[3].
IL1RL1/ST2 is expressed across diverse cell types including immune cells (T cells, mast cells, basophils), structural cells (fibroblasts, epithelial cells), and resident brain cells (astrocytes, microglia, neurons)[4]. The IL-33/ST2 pathway exerts both protective and pathogenic effects depending on context, making it a complex therapeutic target in neurodegenerative diseases where neuroinflammation plays a central role[5].
IL1RL1 is located on chromosome 2q12 and encodes a type I transmembrane protein belonging to the Interleukin-1 receptor family. The gene spans approximately 42 kb and contains 11 exons that undergo alternative splicing to produce multiple transcript variants[6]. The ST2 protein was originally discovered as a glucocorticoid-induced gene in fibroblasts and subsequently characterized as the IL-33 receptor essential for Th2-type immune responses[7].
The biological significance of IL1RL1 extends beyond classical immunology into neurobiology. Within the central nervous system, IL-33 is expressed by astrocytes, oligodendrocytes, and certain neuronal populations, while ST2 is expressed by microglia and infiltrating immune cells[8]. This spatial segregation enables paracrine signaling where IL-33 released from damaged neurons activates ST2-expressing immune cells, triggering neuroinflammatory cascades that contribute to neurodegenerative disease progression[9].
| Gene Information | |
|---|---|
| Gene Symbol | IL1RL1 |
| Full Name | Interleukin-1 Receptor-Like 1 (ST2) |
| Chromosomal Location | 2q12.1 |
| NCBI Gene ID | 9173 |
| OMIM | 601203 |
| Ensembl ID | ENSG00000115607 |
| UniProt ID | Q9INT6 |
| Gene Family | IL-1 receptor family |
| Protein Length | 556 amino acids (ST2L) |
| Associated Diseases | Alzheimer Disease, Parkinson Disease, Asthma, Cardiovascular Disease, Autoimmune Disorders |
The IL1RL1 gene exhibits complex genomic organization with multiple alternative splicing events:
IL1RL1 produces multiple protein isoforms through alternative splicing:
| Isoform | Type | Length | Expression | Function |
|---|---|---|---|---|
| ST2L | Membrane-bound | 556 aa | Immune cells, brain | IL-33 receptor |
| sST2 | Soluble | 310 aa | Multiple tissues | Decoy receptor |
| ST2V | Variant | 399 aa | Testis, lung | Unknown |
| ST2LV | Long variant | 597 aa | Rare | Extended signaling |
ST2L (Membrane-bound):
sST2 (Soluble):
The ST2 protein exhibits characteristic IL-1 receptor family architecture:
Extracellular Domain (1-337 aa):
Transmembrane Domain (338-360 aa):
Cytoplasmic Domain (361-556 aa):
The IL-33/ST2 axis represents a crucial alarmin signaling system:
MyD88-Dependent Pathway:
MyD88-Independent (TRIF) Pathway:
Alternative Pathways:
Immune Regulation:
Tissue Homeostasis:
| Cell Type | ST2 Expression | Functional Significance |
|---|---|---|
| Th2 Cells | High | IL-33 responsiveness |
| Mast Cells | High | Activation, degranulation |
| Basophils | High | Allergic responses |
| Eosinophils | Moderate | Migration, activation |
| Macrophages | Moderate | M2 polarization |
| Dendritic Cells | Low-Moderate | Antigen presentation |
| NK Cells | Low | Cytotoxic function |
| Treg Cells | High | Immunosuppression |
| Cell Type | Expression Level | Notes |
|---|---|---|
| Microglia | Moderate-High | Primary ST2+ immune cell in brain |
| Astrocytes | Low-Moderate | IL-33 source |
| Oligodendrocytes | Low | IL-33 source |
| Neurons | Very Low | Some regional expression |
| Endothelial Cells | Moderate | BBB function |
IL1RL1/ST2 has been implicated in Alzheimer's disease pathogenesis through multiple mechanisms:
Neuroinflammation:
Molecular Mechanisms:
Genetic Associations:
Therapeutic Implications:
The IL-33/ST2 axis contributes to Parkinson's disease through neuroinflammatory mechanisms:
Dopaminergic Neuron Vulnerability:
Molecular Pathology:
Clinical Correlations:
Therapeutic Targeting:
ST2 plays complex roles in MS pathophysiology:
Autoimmune Demyelination:
Remyelination:
Clinical Evidence:
The IL-33/ST2 axis participates in stroke pathophysiology:
Acute Phase:
Subacute Phase:
Chronic Phase:
IL1RL1 was originally characterized in cardiac contexts:
| Approach | Agent Type | Mechanism | Development Stage |
|---|---|---|---|
| Anti-ST2 Antibodies | Monoclonal antibody | Block ST2L signaling | Preclinical |
| sST2-Fc Fusion | Soluble receptor | Decoy for IL-33 | Preclinical |
| Anti-IL-33 Antibodies | Monoclonal antibody | Neutralize IL-33 | Phase I/II |
| IL-33 Mutant Proteins | Engineered cytokine | Antagonist activity | Research |
| ST2 Small Molecule Inhibitors | Chemical compounds | TIR domain blockade | Research |
Inflammatory Diseases:
Neurodegenerative Diseases:
Cardiovascular Disease:
Schmitz J, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23(5):479-490. DOI:10.1016/j.immuni.2005.09.015 ↩︎
Gadani SP, et al. IL-33 modulates inflammatory signaling in the brain. J Neuroimmune Pharmacol. 2015;10(4):582-588. DOI:10.1007/s11481-015-9612-7 ↩︎
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