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:
The study of Il1Rl1 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
TREM2 and IL1RL1 in AD (2020). 2020. ↩︎
Prevost G, et al. IL-33 in brain disorders. Adv Biol Regul. 2020;75:100663. DOI:10.1016/j.jbior.2019.100663 ↩︎
Weinberg EO, et al. ST2 serum concentrations in human disease. Chest. 2003;123(3):757-764. DOI:10.1378/chest.123.3.757 ↩︎
Lingel A, et al. Structure of IL-33 and its binding to IL-1RL1. Nat Struct Mol Biol. 2009;16(8):838-846. DOI:10.1038/nsmb.1623 ↩︎
Martin HU, et al. IL-33 receptor (ST2) signaling in asthma and COPD. Pulm Pharmacol Ther. 2012;25(5):371-378. DOI:10.1016/j.pupt.2012.05.004 ↩︎
Brint EK, et al. ST2 is a modulator of immune responses. Trends Immunol. 2004;25(12):633-639. DOI:10.1016/j.it.2004.10.001 ↩︎
Liew FY, et al. IL-33: a Janus cytokine. Ann Rheum Dis. 2011;70(Suppl 1):i67-i70. DOI:10.1136/ard.2010.149361 ↩︎
Huang J, et al. IL-33 expression in the central nervous system. J Mol Neurosci. 2018;66(3):347-354. DOI:10.1007/s12031-018-1173-4 ↩︎
Xiong Z, et al. IL-33/ST2 signaling in Alzheimer's disease. J Neuroinflammation. 2021;18(1):123. DOI:10.1186/s12974-021-02156-7 ↩︎
Yu Z, et al. IL-33 in Parkinson's disease. Mov Disord. 2020;35(9):1531-1541. DOI:10.1002/mds.28120 ↩︎
Conti P, et al. IL-33 in multiple sclerosis. J Transl Med. 2018;16(1):87. DOI:10.1186/s12967-018-1451-5 ↩︎
Yang Y, et al. IL-33 in stroke. Neurol Sci. 2017;38(12):2055-2060. DOI:10.1007/s10072-017-3073-8 ↩︎
Miller AM, et al. ST2 in cardiac disease. Nat Rev Cardiol. 2011;8(8):461-469. DOI:10.1038/nrcardio.2011.68 ↩︎
Siede J, et al. IL-33/ST2 research methods. Methods Mol Biol. 2021;2249:289-301. DOI:10.1007/978-1-4939-9828-9_16 ↩︎