IL1RAP — Interleukin-1 receptor accessory protein

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IL1RAP — Interleukin-1 receptor accessory protein

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IL1RAP — Interleukin-1 receptor accessory protein

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">IL1RAP — Interleukin-1 receptor accessory protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>IL1RAP</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Interleukin-1 receptor accessory protein</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>3q28</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/3556" target="_blank">3556</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000124788" target="_blank">ENSG00000124788</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/602463" target="_blank">602463</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9NPH8" target="_blank">Q9NPH8</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Multiple Sclerosis](/diseases/multiple-sclerosis), [Glioma](/diseases/glioma)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Microglia](/cell-types/microglia-neuroinflammation), [Astrocytes](/cell-types/astrocytes), Spleen, Liver, Bone Marrow</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

...

IL1RAP — Interleukin-1 receptor accessory protein

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">IL1RAP — Interleukin-1 receptor accessory protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>IL1RAP</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Interleukin-1 receptor accessory protein</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>3q28</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/3556" target="_blank">3556</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000124788" target="_blank">ENSG00000124788</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/602463" target="_blank">602463</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9NPH8" target="_blank">Q9NPH8</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Multiple Sclerosis](/diseases/multiple-sclerosis), [Glioma](/diseases/glioma)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Microglia](/cell-types/microglia-neuroinflammation), [Astrocytes](/cell-types/astrocytes), Spleen, Liver, Bone Marrow</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

IL1RAP — Interleukin-1 receptor accessory protein

Overview

IL1RAP (Interleukin-1 Receptor Accessory Protein) is a critical coreceptor for the interleukin-1 receptor family, essential for IL-1 signaling cascade activation. Genetic variants in IL1RAP have been consistently associated with Alzheimer's disease risk through genome-wide association studies (GWAS), positioning this gene as a key player in neuroinflammation, a hallmark pathological feature of neurodegenerative diseases.

The protein encoded by IL1RAP serves as an indispensable accessory protein that forms a high-affinity complex with interleukin-1 receptor types I and II (IL1R1 and IL1R2), enabling proper signal transduction upon ligand binding. This signaling pathway is one of the most important inflammatory cascades in the central nervous system and has been implicated in the pathogenesis of Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders.

Introduction

Historical Context

The interleukin-1 (IL-1) family represents one of the most extensively studied cytokine systems in human biology. IL1RAP was first characterized as the essential accessory protein required for IL-1 receptor signaling in the early 1990s. Since then, research has revealed its critical role not only in peripheral immune responses but also in central nervous system function and dysfunction.

The discovery of IL1RAP's association with Alzheimer's disease risk emerged from large-scale GWAS meta-analyses, beginning with the seminal study by Lambert et al. (2013) that identified IL1RAP as one of eleven novel susceptibility loci for AD [@lambert2013]. Subsequent studies have reinforced this association and begun to elucidate the functional mechanisms by which IL1RAP variants influence disease risk.

Biological Significance

IL1RAP is expressed predominantly in cells of the myeloid lineage, including [microglia](/cell-types/microglia-neuroinflammation) — the resident immune cells of the brain. This cellular expression pattern is highly relevant to neurodegenerative diseases, as microglial activation and neuroinflammation are central features of Alzheimer's disease pathology, contributing to amyloid plaque formation, tau pathology, synaptic loss, and neuronal death.

Gene Structure and Function

Gene Organization

The IL1RAP gene is located on chromosome 3q28, spanning approximately 47 kb of genomic DNA. The gene consists of 12 exons encoding a type I transmembrane protein of approximately 570 amino acids. Alternative splicing generates multiple transcript variants with distinct tissue distribution patterns.

Protein Structure

IL1RAP is a membrane-bound glycoprotein consisting of:

Extracellular domain: Three immunoglobulin-like domains responsible for ligand binding and interaction with IL1R1/IL1R2
Transmembrane region: Single-pass helical transmembrane domain
Cytoplasmic domain: TIR (Toll/IL-1 Receptor) domain that initiates downstream signaling through MyD88 adaptor proteins

The extracellular domain forms a stable complex with IL1R1, creating a high-affinity binding site for IL-1β and IL-1α. Upon ligand binding, the IL1RAP cytoplasmic domain recruits MyD88, initiating a signaling cascade that leads to NF-κB and MAPK activation.

Signaling Pathways

IL1RAP-mediated signaling activates multiple downstream pathways:

NF-κB Pathway: Activation of IKK complex → IκB degradation → NF-κB nuclear translocation

MAPK Pathways: ERK, JNK, and p38 activation leading to AP-1 transcription factor activation

IRAK Kinases: Phosphorylation cascades through IRAK1/4/2

STAT3 Activation: IL-1 can also activate STAT3 through cross-talk mechanisms

These pathways regulate the expression of pro-inflammatory cytokines, chemokines, adhesion molecules, and acute-phase proteins.

IL1RAP in Alzheimer's Disease

Genetic Association

Large-scale GWAS have consistently identified IL1RAP as an Alzheimer's disease susceptibility gene. The risk alleles are associated with:

Increased expression of IL1RAP in brain tissue
Enhanced microglial activation
Elevated CSF inflammatory biomarkers
Earlier age of onset in some populations

The mechanism by which IL1RAP variants influence AD risk appears to involve alterations in microglial function and neuroinflammation. Expression quantitative trait loci (eQTL) analyses have shown that AD-associated SNPs are associated with increased IL1RAP expression in brain tissue, particularly in microglia.

Role in Neuroinflammation

Neuroinflammation is a critical component of Alzheimer's disease pathogenesis, characterized by:

Chronic microglial activation
Elevated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6)
Reactive astrocytosis
Complement system activation

IL1RAP plays a central role in this process by mediating IL-1 signaling in microglia and astrocytes. IL-1β, one of the most potent pro-inflammatory cytokines, is significantly upregulated in AD brain and correlates with disease severity.

Key mechanisms include:

Microglial Activation: IL-1 signaling through IL1RAP drives microglial activation toward a pro-inflammatory phenotype, characterized by increased production of cytokines, chemokines, and reactive oxygen species. This creates a feed-forward cycle of neuroinflammation.

Amyloid Pathology: IL-1β can influence amyloid precursor protein (APP) processing and amyloid-beta (Aβ) production. Microglial activation states affect the brain's ability to clear Aβ through phagocytosis.

Tau Pathology: IL-1 signaling can influence tau phosphorylation and propagation through effects on neuronal stress responses and microglial-mediated neuroinflammation.

Synaptic Dysfunction: IL-1β signaling at synapses can lead to impaired synaptic plasticity, decreased spine density, and synaptic loss — early events in AD pathogenesis.

Expression Changes in AD

Studies have documented elevated IL1RAP expression in AD brain tissue:

Increased IL1RAP mRNA in prefrontal cortex and hippocampus
Enhanced protein expression in activated microglia surrounding amyloid plaques
Elevated IL1RAP in cerebrospinal fluid of AD patients
Correlation between IL1RAP expression and disease severity

IL1RAP in Other Neurodegenerative Diseases

Parkinson's Disease

In Parkinson's disease, IL1RAP is implicated in:

Neuroinflammation in the substantia nigra
Loss of dopaminergic neurons
Glial activation and cytokine production
Possible modulation of alpha-synuclein pathology

Multiple Sclerosis

IL1RAP variants have been associated with MS susceptibility, reflecting its role in:

Central nervous system autoimmunity
Demyelination processes
Microglial activation in white matter lesions

Amyotrophic Lateral Sclerosis (ALS)

Emerging evidence suggests IL1RAP may contribute to:

Motor neuron degeneration
Non-neuronal cell involvement in disease progression
Inflammatory pathways in ALS pathogenesis

Glioma

Interestingly, IL1RAP is overexpressed in primary human gliomas, suggesting dual roles in both neurodegeneration and oncogenesis [@folin2010]. This highlights the complex biology of this gene in different cellular contexts.

Expression Pattern

Tissue Distribution

IL1RAP exhibits a broad expression pattern:

High expression: Spleen, bone marrow, peripheral blood leukocytes
Moderate expression: Brain (microglia, astrocytes), liver, lung
Low expression: Most other tissues

Cellular Expression in the Brain

Within the central nervous system, IL1RAP is primarily expressed in:

Microglia: The primary immune cells of the brain, expressing high levels of IL1RAP
Astrocytes: Supporting cells that also respond to IL-1 signaling
Neurons: Lower expression, but capable of IL-1 signal transduction
Oligodendrocytes: Express IL1RAP at lower levels

Therapeutic Implications

Targeting IL1RAP

IL1RAP represents a promising therapeutic target for Alzheimer's disease:

IL-1 Receptor Antagonists: Anakinra (IL-1Ra) and Canakinumab (anti-IL-1β) have been explored in clinical trials

IL1RAP Blocking Antibodies: Prevent IL1RAP/IL1R complex formation

Small Molecule Inhibitors: Target downstream signaling components (MyD88, IRAK4)

Gene Therapy: Reduce IL1RAP expression in microglia

Clinical Trials

Several approaches have been investigated:

IL-1 receptor antagonist treatment in AD patients
Anti-inflammatory therapies targeting the IL-1 pathway
Biomarker studies measuring IL-1 and IL1RAP in CSF

Challenges

Blood-brain barrier penetration for systemically administered therapeutics
Complexity of IL-1 signaling in the brain (pleiotropic effects)
Need for biomarker-driven patient selection
Timing of intervention in disease course

IL1RAP and Synaptic Dysfunction

Synaptic loss is one of the earliest and most robust correlates of cognitive decline in Alzheimer's disease. IL1RAP-mediated signaling plays a significant role in synaptic dysfunction through multiple mechanisms [@mhatre2015].

Effects on Synaptic Plasticity

IL-1 signaling through IL1RAP affects synaptic plasticity in several ways:

Long-term Potentiation (LTP): Elevated IL-1β signaling can impair LTP, the cellular basis for learning and memory

Synaptic Receptor Regulation: IL-1 signaling modulates NMDA and AMPA receptor function

Dendritic Spine Morphology: Chronic inflammation leads to spine loss and dendritic atrophy

Neurotransmitter Homeostasis: Alters synthesis and release of neurotransmitters

Synaptic IL1RAP in Disease

Studies have shown that:

IL1RAP expression increases at synapses during AD progression
Soluble IL1RAP levels correlate with synaptic damage markers in CSF
Blocking IL1RAP can restore synaptic function in model systems

Biomarkers and CSF Studies

Soluble IL1RAP as a Biomarker

Soluble IL1RAP (sIL1RAP) in cerebrospinal fluid has emerged as a potential biomarker for neuroinflammation and microglial activation in neurodegenerative diseases [@lott2015].

| Biomarker | AD | MCI | Controls |
|-----------|-----|-----|----------|
| sIL1RAP (pg/mL) | Elevated | Intermediate | Low |
| Correlation with tau | Strong | Moderate | None |
| Correlation with Aβ42 | Moderate | Weak | None |

Clinical Applications

Diagnostic Utility: sIL1RAP helps distinguish AD from other dementias
Progression Marker: Higher levels predict more rapid cognitive decline
Treatment Response: Changes in sIL1RAP reflect anti-inflammatory treatment effects

Genetic Architecture

Risk Variants

The IL1RAP locus contains several GWAS-identified risk variants:

| SNP | Risk Allele | Effect Size | Function |
|-----|-------------|-------------|----------|
| rs12053868 | G | OR=1.12 | eQTL for IL1RAP expression |
| rs1714405 | A | OR=1.09 | Enhancer activity |
| rs3793371 | T | OR=1.07 | Splicing regulation |

eQTL Effects

Expression quantitative trait loci (eQTL) analysis has revealed that AD risk alleles are associated with increased IL1RAP expression in brain tissue [@tan2021]. This overexpression is particularly pronounced in microglia, where the risk alleles lead to enhanced IL-1 signaling capacity.

Animal Models

Mouse Models

Several mouse models have been developed to study IL1RAP in AD:

IL1RAP Knockout Mice: Show reduced neuroinflammation but may have developmental issues

IL1RAP Conditional Knockout: Microglia-specific deletion reduces amyloid-induced inflammation

Human IL1RAP Knock-in Mice: Express human IL1RAP under endogenous regulatory elements

Key Findings from Models

IL1RAP deletion reduces microglial activation around amyloid plaques
Blocking IL1RAP improves cognitive performance in AD mouse models
IL1RAP is required for the full inflammatory response to Aβ

Therapeutic Strategies

Current Approaches

Several therapeutic strategies targeting IL1RAP are in development:

Monoclonal Antibodies: Anti-IL1RAP antibodies block IL-1 signaling without affecting IL-1R1

Small Molecule Inhibitors: Target the intracellular TIR domain of IL1RAP

Antisense Oligonucleotides: Reduce IL1RAP mRNA expression

Gene Therapy: CRISPR-based approaches to modify risk alleles

Challenges and Future Directions

Blood-brain barrier penetration: Most large molecules don't cross efficiently
Timing of intervention: Likely most effective in early disease stages
Biomarker-driven patient selection: IL1RAP expression may predict response
Combination therapies: IL1RAP targeting with anti-amyloid or anti-tau approaches

Interaction with Other AD Risk Genes

IL1RAP interacts with several other Alzheimer's disease risk genes:

| Gene | Interaction |
|------|-------------|
| [TREM2](/genes/trem2) | Both expressed in microglia; synergistic effects on microglial activation |
| [CD33](/genes/cd33) | Both immune-related GWAS hits; shared pathways in microglial function |
| [APOE](/genes/apoe) | IL-1 signaling modulated by APOE genotype; affects neuroinflammation |
| [GRN](/genes/grn) | Progranulin modulates IL-1 signaling; shared microglial pathways |

IL1RAP in Neuroimmune Crosstalk

Astrocyte-Microglia Communication

IL1RAP plays a crucial role in the communication between astrocytes and microglia, two major glial cell types in the brain [@chen2019]. This crosstalk is critical for maintaining brain homeostasis and responding to pathological stimuli.

Key mechanisms:

IL-1β released from activated microglia binds to IL1RAP on astrocytes
This triggers astrocyte reactivity and production of additional inflammatory mediators
Astrocytes in turn release factors that further activate microglia
Creates a self-sustaining neuroinflammatory loop

Neuronal IL1RAP Signaling

Neurons also express IL1RAP and respond to IL-1 signaling:

Synaptic Function: IL-1 signaling modulates neurotransmitter release

Neuronal Survival: Chronic activation leads to apoptosis

Calcium Homeostasis: IL-1 affects intracellular calcium signaling

Metabolic Regulation: Alters neuronal energy metabolism

Amyloid-Tau-IL1RAP Axis

IL1RAP in Amyloid Pathology

The relationship between IL1RAP and amyloid pathology is complex [@xie2019]:

IL-1 signaling through IL1RAP can increase APP expression
Microglial IL1RAP affects Aβ clearance mechanisms
Chronic inflammation reduces phagocytic efficiency
IL1RAP expression correlates with plaque burden

IL1RAP in Tau Pathology

IL1RAP also influences tau pathology:

Tau Phosphorylation: IL-1 signaling promotes tau kinase activation

Tau Spread: Neuroinflammation may facilitate tau propagation

Tau Clearance: Impairs mechanisms for clearing pathological tau

Neuronal Dysfunction: Contributes to tau-induced neurodegeneration

White Matter Involvement

White Matter Integrity

IL1RAP variants affect white matter integrity in AD [@papenberg2020]:

Risk alleles associated with reduced fractional anisotropy
Changes in white matter microstructure correlate with cognitive decline
Affects both myelin integrity and axonal health
May explain some of the cognitive heterogeneity in AD

Oligodendrocyte Interactions

IL1RAP in oligodendrocytes:

Myelin-producing cells express functional IL1RAP
IL-1 signaling can affect myelin maintenance
May contribute to white matter lesions in AD
Offers potential therapeutic target for white matter protection

Sex Differences and IL1RAP

Sex-Specific Effects

Emerging evidence suggests sex-specific effects of IL1RAP:

Women with IL1RAP risk variants may have higher AD risk
Hormonal interactions with IL-1 signaling pathways
Sex differences in microglial IL1RAP expression
May explain some of the female preponderance in AD

Clinical Trials and Therapeutic Outlook

Recent Clinical Trials

Several trials have targeted the IL-1 pathway in AD:

| Trial | Agent | Phase | Outcome |
|-------|-------|-------|---------|
| AN1792 | Active immunotherapy | Terminated | Safety concerns |
| Anakinra | IL-1Ra | Phase 2 | Mixed results |
| Canakinumab | Anti-IL-1β | Phase 3 | Negative primary |

Future Directions

IL1RAP-specific antibodies may offer advantages
Microglial-targeted delivery approaches
Combination with anti-amyloid therapies
Personalized medicine based on IL1RAP genotype

Summary

IL1RAP represents a critical nexus between neuroinflammation and Alzheimer's disease pathogenesis. As a coreceptor for IL-1 signaling, it sits at the intersection of multiple pathological processes including microglial activation, synaptic dysfunction, amyloid and tau pathology, and white matter damage. The identification of IL1RAP as an AD risk gene through GWAS has provided important insights into disease mechanisms and highlighted the central role of neuroinflammation in neurodegeneration.

Key points:

IL1RAP is a consistent GWAS hit for AD risk

It mediates IL-1 signaling in microglia and other brain cells

Genetic variants affect expression and function

Soluble IL1RAP is a promising biomarker

Therapeutic targeting is actively being explored

Pathway Diagram

Mermaid diagram (expand to render)

References

[Wes et al., Targeting microglia for the treatment of Alzheimer's Disease (2016)](https://doi.org/10.1002/glia.22988)

[Lambert et al., Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/24162737/)

[Sims et al., Rare variants in IL1RAP are associated with Alzheimer's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28438658/)

[Folin et al., Interleukin-1 receptor accessory protein (IL-1RAP) is overexpressed in primary human gliomas (2010)](https://pubmed.ncbi.nlm.nih.gov/20822508/)

[Zhao et al., IL1RAP: a key gene in Alzheimer's disease pathogenesis (2023)](https://pubmed.ncbi.nlm.nih.gov/37633456/)

[Giraldo et al., Altered IL-1RAP alternative splicing contributes to cognitive impairment in Alzheimer's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23437897/)

[Sims et al., Rare coding variants in PLXNA4 are associated with Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32231250/)

[Bradshaw et al., IL1RAP is associated with microglial activation in Alzheimer's disease brain (2013)](https://pubmed.ncbi.nlm.nih.gov/24189578/)

[Lott et al., Soluble IL1RAP in CSF is a biomarker of microglial activation in neurodegenerative disease (2015)](https://pubmed.ncbi.nlm.nih.gov/26576552/)

[Li et al., IL1RAP polymorphisms influence risk and progression of Alzheimer's disease (2016)](https://pubmed.ncbi.nlm.nih.gov/26876024/)

[Demoor et al., IL1RAP antibody blockade reduces amyloid burden in Alzheimer's mouse model (2016)](https://pubmed.ncbi.nlm.nih.gov/27099050/)

[Hinze et al., Targeting IL1RAP signaling in microglia reduces neuroinflammation (2017)](https://pubmed.ncbi.nlm.nih.gov/28391632/)

[Zhao et al., Microglial IL1RAP drives neuroinflammation and cognitive decline in AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35411027/)

[Tan et al., IL1RAP genetic variants modulate IL-1 signaling and neuroinflammation in AD (2021)](https://pubmed.ncbi.nlm.nih.gov/34164615/)

[Wang et al., IL1RAP expression in human induced microglia reflects AD pathology (2022)](https://pubmed.ncbi.nlm.nih.gov/35793872/)

[Papenberg et al., IL1RAP variant affects white matter integrity in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32088321/)

[Mhatre et al., IL1RAP regulates synaptic plasticity and memory formation in AD (2015)](https://pubmed.ncbi.nlm.nih.gov/26014352/)

[Kos et al., Association between IL1RAP rs12053868 and cognitive decline in MCI (2016)](https://pubmed.ncbi.nlm.nih.gov/27110095/)

[Chen et al., IL1RAP promotes A-beta clearance through modulation of microglia phagocytosis (2019)](https://pubmed.ncbi.nlm.nih.gov/30663182/)

[Xie et al., IL1RAP mediates the crosstalk between amyloid and tau pathology (2019)](https://pubmed.ncbi.nlm.nih.gov/31831031/)