Interleukin-1 Receptor Type 1 Protein

Interleukin-1 Receptor Type 1 (IL-1R1) Protein

Introduction

Interleukin 1 Receptor Type 1 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Interleukin-1 Receptor Type 1 (IL-1R1) Protein

Introduction

Interleukin 1 Receptor Type 1 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

The Interleukin-1 Receptor Type 1 (IL-1R1) is a critical membrane receptor that mediates pro-inflammatory signaling in the brain and peripheral tissues. It is the primary signaling receptor for interleukin-1 (IL-1) cytokines, including IL-1alpha and IL-1beta, and plays a central role in neuroinflammation, a hallmark of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). [@dinarello2018]

<div class="infobox infobox-protein"> [@liu2014]
<table> [@shaftel2008]
<tr><th colspan="2" style="background:#f0f0f0;">Interleukin-1 Receptor Type 1 Protein</th></tr> [@griffin2006]
<tr><td><b>Gene</b></td><td>[IL1R1](/genes/il1r1)</td></tr> [@pinteaux2002]
<tr><td><b>UniProt ID</b></td><td>[P01589](https://www.uniprot.org/uniprot/P01589)</td></tr> [@basu2012]
<tr><td><b>PDB IDs</b></td><td>1G0R, 1IRA, 2NVW</td></tr> [@drouinouellet2015]
<tr><td><b>Molecular Weight</b></td><td>~80 kDa (glycosylated)</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cell membrane (type I transmembrane)</td></tr>
<tr><td><b>Protein Family</b></td><td>IL-1 receptor family (TIR domain superfamily)</td></tr>
<tr><td><b>Expression</b></td><td>Ubiquitous (neurons, [astrocytes](/entities/astrocytes), [microglia](/cell-types/microglia-neuroinflammation), endothelial cells)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/neuroinflammation" style="color:#ef9a9a">Neuroinflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">18 edges</a></td>
</tr>
</table>
</div>

IL-1R1 is essential for the brain's innate immune response and mediates both physiological processes (fever, sleep regulation, memory formation) and pathological chronic inflammation in neurodegenerative conditions.

Structure

IL-1R1 is a type I transmembrane receptor with distinct structural domains:

Extracellular Domain (1-319 amino acids)

• Three immunoglobulin-like (Ig-like) domains
• Ligand-binding site for IL-1α, IL-1β, and IL-1Ra
• Disulfide bonds (Cys residues) for structural stability
• Contains the IL-1 receptor accessory protein (IL-1R3) binding interface

Transmembrane Domain (320-340 amino acids)

• Single α-helical transmembrane segment
• Anchors receptor in the plasma membrane
• Connects extracellular sensing to intracellular signaling

Cytoplasmic Domain (341-569 amino acids)

• Toll/IL-1 Receptor (TIR) domain (~180 amino acids)
• Critical for downstream signal transduction
• Contains conserved BB loop motif essential for MyD88 recruitment

Co-receptor Requirement

• IL-1R3 (IL-1RAcP - IL-1 Receptor Accessory Protein) is required for signal transduction
• Forms heterodimeric complex with IL-1R1 upon ligand binding
• Co-receptor binding induces conformational change enabling signaling

Normal Function

IL-1R1 mediates the potent pro-inflammatory effects of IL-1 cytokines in the central nervous system:

Ligand Binding and Specificity

• IL-1β: Highest affinity (Kd ~ 10⁻¹¹ M), primary pro-inflammatory ligand
• IL-1α: Lower affinity, acts locally in tissues
• IL-1 Receptor Antagonist (IL-1Ra): Binds without signaling, endogenous antagonist

MyD88-Dependent Signaling Cascade

• [NF-κB](/entities/nf-kb) (Nuclear Factor kappa-B) - primary pathway
• MAPK (Mitogen-Activated Protein Kinases) - JNK, p38, ERK
• AP-1 transcription factor

Biological Effects in the Brain

• Fever generation: Acts on hypothalamic thermoregulatory centers
• Sleep regulation: Promotes slow-wave sleep
• Memory and synaptic plasticity: IL-1 modulates hippocampal synaptic transmission
• Acute phase response: Hepatic production of inflammatory proteins
• Leukocyte recruitment: Up-regulation of adhesion molecules
• Cytokine storm: Amplification of inflammatory signaling

Physiological Roles

• Normal synaptic plasticity and memory formation (at low levels)
• Response to infection and tissue injury
• Regulation of neurogenesis
• Modulation of neurotransmitter systems

Role in Neurodegenerative Diseases

Alzheimer's Disease (AD)

IL-1R1 overexpression is a hallmark of neuroinflammation in AD:

• Elevated expression: IL-1R1 is significantly upregulated in AD brain ([hippocampus](/brain-regions/hippocampus), cortex)
• Amyloid interaction: IL-1β promotes [amyloid-beta](/proteins/amyloid-beta) (Aβ) production via [BACE1](/entities/bace1) upregulation
• [Tau](/proteins/tau) pathology: Enhances [tau](/proteins/tau) phosphorylation and aggregation
• Synaptic dysfunction: IL-1 signaling disrupts synaptic plasticity
• Glial activation: Perpetuates microglial and astrocyte activation
• Therapeutic implication: IL-1R1 antagonist anakinra shows promise in preclinical studies

• Rubinow KB, et al. (2016). IL-1β in AD pathogenesis. J Neuroinflammation
• Shaftel SS, et al. (2008). Chronic IL-1β expression in AD. Proc Natl Acad Sci

Parkinson's Disease (PD)

IL-1R1 mediates dopaminergic neuron loss:

• Increased expression: Elevated in substantia nigra pars compacta of PD patients
• Dopaminergic vulnerability: IL-1β accelerates [α-synuclein](/proteins/alpha-synuclein) aggregation
• BBB permeability: Increases blood-brain barrier leakiness
• Microglial activation: Creates pro-inflammatory micro-environment
• Therapeutic potential: IL-1R1 blockade protects dopaminergic [neurons](/entities/neurons) in models

• Cao JJ, et al. (2012). IL-1β in PD. Neurosci Lett

Amyotrophic Lateral Sclerosis (ALS)

IL-1R1 contributes to motor neuron injury:

• Microglial activation: Perpetuates inflammatory microenvironment
• Motor neuron toxicity: Direct effects on vulnerable motor neurons
• Disease progression: Correlates with disease severity
• Therapeutic targeting: IL-1R1 antagonists under investigation

• Hoozemans JJ, et al. (2012). IL-1β in ALS. Acta Neuropathol
• Beers DR, et al. (2008). Microglial IL-1β in ALS. J Neurochem

Stroke and Traumatic Brain Injury (TBI)

IL-1R1 mediates secondary brain injury:

• Ischemic damage: Exacerbates neuronal death post-stroke
• Excitotoxicity: Amplifies glutamate-induced toxicity
• BBB disruption: Increases vascular permeability
• Therapeutic window: IL-1R1 blockade beneficial in preclinical models

Multiple Sclerosis (MS)

IL-1R1 drives demyelination:

• Autoimmune pathogenesis: Central to experimental autoimmune encephalomyelitis (EAE)
• Demyelination: Promotes oligodendrocyte death
• Clinical trials: IL-1R1 antagonists being explored

Therapeutic Targeting

IL-1R1 is a validated drug target for inflammatory diseases:

FDA-Approved Antagonists

| Drug | Type | Mechanism | Indications |
|------|------|-----------|-------------|
| Anakinra | Recombinant IL-1Ra | Blocks IL-1R1 | RA, CAPS, Still's disease |
| Canakinumab | Anti-IL-1β monoclonal antibody | Neutralizes IL-1β | CAPS, TRAPS, gout |
| Rilonacept | IL-1R1-Fc fusion | Decoy receptor | CAPS |

Neurodegeneration Clinical Trials

• Anakinra: Phase 2 trial for AD (NCT03269114)
• Canakinumab: Investigated for AD and cardiovascular disease
• Novel small molecules: Brain-penetrant IL-1R1 inhibitors in development

Challenges

• [Blood-brain barrier](/entities/blood-brain-barrier) penetration
• Pleiotropic functions of IL-1
• Safety concerns with immunosuppression

Signaling Pathways

NF-κB Activation (Primary Pathway)

MAPK Pathways

Cross-talk with Other Pathways

• [mTOR](/entities/mtor) pathway: IL-1β activates mTORC1
• JAK/STAT: IL-1 induces STAT3 phosphorylation
• [NLRP3](/entities/nlrp3-inflammasome) inflammasome: IL-1R1 priming and activation

Genetics

• IL1R1 polymorphisms associated with:
• Increased AD risk (rs3917262)
• Altered cytokine responses
• Variable treatment response

Biomarkers

• Soluble IL-1R1 (sIL-1R1): Detectable in cerebrospinal fluid
• Phospho-NF-κB: Downstream marker of IL-1R1 activation
• IL-1β/IL-1Ra ratio: Reflects inflammatory status

See Also

• [Inflammation Pathway](/mechanisms/neuroinflammation-pathway)
• [NLRP3 Inflammasome](/therapeutics/nlrp3-inflammasome-inhibitors)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [CASP1 Gene](/proteins/casp1-protein)
• [IL-1β Protein](/proteins/il1b-protein)
• [MyD88 Signaling](/mechanisms/myd88-signaling-pathway)

External Links

• [UniProt: P01589](https://www.uniprot.org/uniprot/P01589)
• [PDB: 1G0R](https://www.rcsb.org/structure/1G0R)
• [GeneCards: IL1R1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL1R1)
• [IUPHAR/BPS Guide to Pharmacology](https://www.guidetopharmacology.org/record/gto/P0SUB1)

Background

The study of Interleukin 1 Receptor Type 1 Protein 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.

• [Allen Human Brain Atlas - IL1R1](https://human.brain-map.org/microarray/search/show?search_term=IL1R1)
• [Allen Cell Type Atlas - il1r1](https://celltypes.brain-map.org/)
• [Allen Mouse Brain Atlas - il1r1](https://mouse.brain-map.org/)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving Interleukin-1 Receptor Type 1 Protein discovered through SciDEX knowledge graph analysis: