| IL1RN |
|---|
| Full Name | Interleukin 1 Receptor Antagonist |
| Symbol | IL1RN |
| Chromosome | 2q14.1 |
| NCBI Gene ID | [3557](https://www.ncbi.nlm.nih.gov/gene/3557) |
| Ensembl ID | ENSG00000136689 |
| OMIM ID | 147679 |
| UniProt ID | [P18510](https://www.uniprot.org/uniprot/P18510) |
| Protein Size | 152 amino acids (secreted) |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Stroke, TBI |
IL1RN (Interleukin-1 Receptor Antagonist) encodes the IL-1 receptor antagonist (IL-1Ra), a naturally occurring 152-amino acid secreted glycoprotein. IL-1Ra competitively binds to the IL-1 receptor type I (IL-1R1) without triggering signal transduction, thereby blocking the pro-inflammatory actions of IL-1α and IL-1β. This makes IL-1Ra a crucial endogenous anti-inflammatory protein that regulates the magnitude and duration of IL-1-mediated inflammatory responses. Therapeutic recombinant IL-1Ra (Anakinra) is FDA-approved for rheumatoid arthritis and cryopyrin-associated periodic syndromes (CAPS) and is under investigation for neurodegenerative diseases [@arend1998][@basu2007].
IL-1Ra functions as a competitive antagonist at the IL-1 receptor:
- Receptor binding: IL-1Ra binds IL-1R1 with similar affinity to IL-1α and IL-1β, but without activating downstream signaling
- No signaling: The IL-1Ra/IL-1R1 complex cannot recruit the IL-1 receptor accessory protein (IL-1RAP), blocking signal transduction
- Four isoforms: Generated by alternative splicing — a secreted form (sIL-1Ra) and three intracellular forms (icIL-1Ra1, icIL-1Ra2, icIL-1Ra3)
- Expression regulation: Low basal expression in most tissues; strongly upregulated by IL-1β, TNF-α, and TLR ligands
| Mechanism |
Effect |
| IL-1 blockade |
Prevents IL-1R1 signaling by IL-1α and IL-1β |
| NF-κB inhibition |
Reduces downstream pro-inflammatory gene expression |
| Glucocorticoid synergy |
Enhances anti-inflammatory effects of glucocorticoids |
| Microglial modulation |
Shifts microglia from pro-inflammatory (M1) to anti-inflammatory (M2) phenotype |
IL-1Ra is neuroprotective in Alzheimer's Disease through several mechanisms:
- Blocks IL-1β-induced inflammation: Prevents the pro-inflammatory cascade that accelerates amyloid pathology and tau hyperphosphorylation
- Modulates microglial activation: Reduces M1-type microglial activation and promotes neuroprotective M2 phenotype
- Reduces neuronal death: In mouse models of AD, IL-1Ra administration reduces hippocampal neuron loss and improves cognitive performance
- Genetic evidence: IL1RN polymorphisms have been associated with AD risk in some populations [@wu2018][@andrer2005]
In Parkinson's Disease, IL-1Ra provides neuroprotection to dopaminergic neurons:
- Nigral protection: IL-1Ra administration in the 6-OHDA and MPTP models protects substantia nigra dopaminergic neurons from degeneration
- Microglial suppression: Reduces IL-1β-mediated microglial activation and oxidative stress in the nigrostriatal pathway
- Motor improvement: IL-1Ra treatment improves behavioral outcomes in PD animal models [@depino2015][@mccoy2012]
¶ Stroke and Ischemia
IL-1Ra has been extensively studied in cerebral ischemia:
- Neuroprotection: IL-1Ra reduces infarct volume and improves functional outcomes in transient and permanent middle cerebral artery occlusion (MCAO) models
- Anti-inflammatory: Blocks IL-1β-mediated recruitment of leukocytes to ischemic brain tissue
- Clinical translation: A Phase II trial of intravenous IL-1Ra in acute ischemic stroke showed good safety and promising efficacy signals
- BBB penetration: IL-1Ra crosses the blood-brain barrier in sufficient quantities to exert CNS effects [@clarke2018]
- Secondary damage reduction: IL-1Ra reduces inflammation-driven secondary injury following TBI
- Motor recovery: Improves motor function recovery in TBI models
- Clinical trial: Ongoing Phase II studies with Anakinra in moderate-severe TBI
| Drug |
Type |
Indication |
Notes |
| Anakinra |
Recombinant human IL-1Ra |
Rheumatoid Arthritis, CAPS, gout |
Subcutaneous injection |
| Rilonacept |
IL-1 Trap (fusion protein) |
CAPS |
Weekly subcutaneous |
| Canakinumab |
Anti-IL-1β monoclonal antibody |
CAPS, JIA, gout |
Subcutaneous |
- Anakinra in PD: Phase II trials investigating neuroprotective effects (NCT05633777)
- Anakinra in AD: Phase I/II trials (NCT02078795)
- Anakinra in Stroke: Phase II completed, Phase III planned
- Anakinra in TBI: Phase II ongoing (NCT04156148)
¶ Challenges and Limitations
- BBB permeability: While IL-1Ra does cross the BBB, CNS concentrations may be suboptimal; modified versions or intranasal delivery are being explored
- Dosing: High doses may be needed for CNS effects; subcutaneous Anakinra achieves limited brain penetration
- Immunogenicity: Recombinant protein carries low risk of anti-drug antibodies