| Property |
Value |
| Gene Symbol |
IL25 |
| Full Name |
Interleukin 25 |
| Chromosomal Location |
14q11.2 |
| NCBI Gene ID |
9480 |
| OMIM ID |
605496 |
| Ensembl ID |
ENSG00000199677 |
| UniProt ID |
Q9H0H5 |
| Encoded Protein |
Interleukin-25 (IL-25) |
| Protein Family |
IL-17 cytokine family |
| Protein Length |
177 amino acids |
| Molecular Weight |
~20 kDa |
| Associated Diseases |
Asthma, Allergic Inflammation, Autoimmune Disease |
IL25 encodes Interleukin-25 (IL-25), also known as IL-17E, a member of the IL-17 cytokine family. Despite being classified within the IL-17 family, IL-25 exhibits distinct functions and signals through a unique receptor system, making it a key regulator of type 2 immune responses and eosinophilic inflammation.
IL-25 was originally identified as a cytokine that promotes type 2 inflammation and is produced by various cell types including Th2 cells, mast cells, basophils, eosinophils, and epithelial cells. Its functions extend beyond classical type 2 immunity to include roles in tissue repair, metabolic regulation, and neuroimmune interactions.
Within the central nervous system (CNS), IL-25 and its receptor are expressed by glial cells and neurons, where they participate in neuroinflammatory processes. Research has implicated IL-25 in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other neuroinflammatory conditions.
¶ Gene Structure and Evolution
The IL25 gene is located on chromosome 14q11.2, within the IL-17 cytokine gene cluster. The gene spans approximately 4.8 kilobases and consists of 4 exons that encode a 177-amino acid secreted protein with a molecular weight of approximately 20 kDa.
IL25 is evolutionarily conserved:
- Mus musculus (mouse) — 87% amino acid identity
- Rattus norvegicus (rat) — 86% identity
- Canis lupus familiaris (dog) — 94% identity
- Bos taurus (cow) — 92% identity
The conservation across mammals indicates important physiological roles, while differences from other IL-17 family members reflect its unique functional profile.
¶ Protein Structure and Receptors
IL-25 shares the characteristic cysteine knot fold of the IL-17 cytokine family but exhibits unique structural features:
- Signal peptide (1-19 aa): Secretory signal
- Mature cytokine (20-177 aa): Receptor-binding domain
- Five conserved cysteines: Form disulfide bonds stabilizing the fold
The IL-25 structure allows for binding to its specific receptor complex with high affinity and specificity.
IL-25 signals through a heterodimeric receptor consisting of:
IL25Ra (IL-17 receptor A):
- Formerly known as IL-17RA
- Expressed widely, including in the CNS
- Required for IL-25 signaling
IL17RB (IL-17 receptor B):
- Formerly known as IL-17RB or IL-25R
- Provides ligand specificity for IL-25
- Highly expressed on epithelial cells, some immune cells
The IL25Ra/IL17RB complex is the functional IL-25 receptor, with expression on:
IL-25 activates both astrocytes and microglia, promoting a distinct inflammatory phenotype:
Astrocyte Activation:
- Induction of pro-inflammatory cytokines (IL-6, TNF-α)
- Chemokine production (CCL2, CXCL10)
- Enhancement of astrocyte proliferation
Microglial Activation:
- Promotion of M1-like pro-inflammatory phenotype
- Production of reactive oxygen species
- Enhanced antigen presentation capacity
IL-25 is elevated in AD brain tissue and may contribute to disease pathology:
- Increased expression in AD hippocampus and cortex
- Correlation with Aβ burden — Higher near plaques
- Astrocyte production — Primary cellular source in brain
- Receptor upregulation — IL25Ra increased on activated glia
Proposed mechanisms:
- Enhancement of neuroinflammation around amyloid plaques
- Promotion of glial activation and cytokine storm
- Potential effects on Aβ clearance mechanisms
IL-25 expression is elevated in PD models and patient samples:
- Increased substantia nigra expression in PD brains
- CSF elevation in PD patients
- Promotes microglial activation in the substantia nigra
- Dopaminergic neuron effects — may contribute to vulnerability
In MS and experimental autoimmune encephalomyelitis (EAE):
- Expression in active lesions
- Role in demyelination
- Therapeutic targeting — blockade reduces disease severity
IL-25 signaling in the CNS involves:
- NF-κB activation: Primary pathway for pro-inflammatory gene induction
- MAPK pathways: ERK1/2 and p38 activation
- Alternative pathways: Including AP-1 and STAT3
Downstream effects include:
- Cytokine and chemokine production
- Immune cell recruitment
- Enhanced inflammation in the CNS
flowchart TD
A["IL-25 Cytokine"] --> B["IL25Ra + IL17RB<br/>Receptor Complex"]
B --> C["Act1 Adaptor<br/>Protein"]
C --> D["TRAF6<br/>Activation"]
D --> E1["NF-κB Pathway"]
D --> E2["MAPK Pathway"]
E1 --> F1["Pro-inflammatory<br/>Gene Transcription"]
E2 --> F1
F1 --> G1["Cytokine Production<br/>TNF-α, IL-1β, IL-6"]
F1 --> G2["Chemokine Production<br/>CCL2, CXCL10"]
F1 --> G3["Enzyme Production<br/>iNOS, COX-2"]
G1 --> H["Glial Activation"]
G2 --> I["T Cell Recruitment"]
G3 --> J["Oxidative Stress"]
H --> K["Chronic<br/>Neuroinflammation"]
I --> K
J --> K
style A fill:#e1f5fe,stroke:#333
style B fill:#e1f5fe,stroke:#333
style F1 fill:#c8e6c9,stroke:#333
style K fill:#ffcdd2,stroke:#333
- IL-25 neutralizing antibodies: Sequester IL-25 and prevent receptor binding
- IL-25R antagonists: Block receptor activation
- Signal transduction inhibitors: Target downstream pathways (NF-κB, MAPK)
- Broad anti-inflammatory agents: JAK inhibitors, corticosteroids
¶ Preclinical and Clinical Status
| Approach |
Status |
Indication |
| Anti-IL-25 antibodies |
Preclinical |
AD, MS |
| IL25Ra blockers |
Preclinical |
PD |
| JAK inhibitors |
Clinical trials |
MS, RA |
| Anti-IL-17 therapy |
Approved |
Autoimmune |
- Complexity of cytokine networks
- Potential effects on type 2 immunity
- Need for tissue-specific targeting
IL25 expression in normal tissues:
| Tissue |
Expression |
| Lung epithelium |
High (constitutive) |
| Skin |
Moderate |
| GI tract |
Moderate |
| Brain |
Very low |
| Thymus |
Moderate |
| Spleen |
Low |
In the normal CNS:
- Neurons: Very low expression
- Astrocytes: Low, inducible
- Microglia: Very low, increases with activation
- Oligodendrocytes: Not detected
In disease states, IL-25 expression dramatically increases in activated glial cells and neurons.
Despite roles in neuroinflammation, IL-25 is primarily known for promoting type 2 immunity:
- Th2 cell differentiation: Promotes IL-4, IL-5, IL-13 production
- Eosinophil recruitment: Through induced chemokines
- IgE production: B cell class switching
- M2 macrophage polarization: Alternative activation
This dual function (pro-inflammatory and type 2) makes IL-25 a complex therapeutic target.
| Disease |
IL-25 Role |
| Asthma |
Key driver of type 2 inflammation |
| Allergic rhinitis |
Elevated in nasal mucosa |
| Atopic dermatitis |
Promotes Th2 responses |
| Eosinophilic esophagitis |
Elevated in epithelium |
| Disease |
Evidence |
| Alzheimer's disease |
Elevated in brain, correlates with pathology |
| Parkinson's disease |
Elevated in substantia nigra |
| Multiple sclerosis |
Expressed in lesions, promotes demyelination |
| ALS |
Potential role in neuroinflammation |
IL-25 signaling is initiated by binding to the heterodimeric receptor complex comprising IL25Ra and IL17RB. Upon ligand binding, the intracellular domains of the receptor recruit the adaptor protein Act1 (also known as CIKS), which is essential for downstream signal transduction 1.
The Act1 adaptor protein serves as a scaffold that brings together downstream signaling components:
- TRAF6 recruitment: Act1 binds TRAF6, an E3 ubiquitin ligase
- NF-κB activation: TRAF6 ubiquitination leads to IKK activation and NF-κB nuclear translocation
- MAPK activation: TRAF6 also activates TAK1, which initiates MAPK cascades
The NF-κB pathway is the primary mediator of IL-25-induced pro-inflammatory gene expression. Key NF-κB subunits (p65/p50) translocate to the nucleus and bind to κB elements in the promoters of target genes.
¶ Act1-Dependent and Independent Pathways
While Act1 is required for most IL-25 signaling, alternative pathways exist:
- TRAFs diversity: Different TRAF proteins (TRAF2, TRAF5, TRAF6) can mediate signaling
- STAT3 activation: IL-25 can activate STAT3 in some cell types
- PI3K/Akt pathway: Contributes to cell survival and metabolic effects
IL-25 signaling is subject to multiple regulatory mechanisms:
- SOCS proteins: SOCS1 and SOCS3 can inhibit JAK-STAT signaling
- A20: Negative regulator of NF-κB signaling
- Deubiquitinases: CYLD and other DUBs remove TRAF6 ubiquitination
- Receptor internalization: Endocytosis limits signaling duration
IL-25 contributes to multiple aspects of AD pathophysiology:
Amyloid-β Interactions:
- IL-25 is expressed by astrocytes surrounding amyloid plaques
- Aβ oligomers directly stimulate IL-25 production in glial cells
- IL-25 enhances the neurotoxic effects of Aβ
- Blockade of IL-25 signaling reduces Aβ-induced inflammation
Tau Pathology:
- IL-25 may influence tau phosphorylation through kinase pathways
- Neuroinflammation driven by IL-25 promotes tau spread
- Therapeutic IL-25 modulation may reduce tau pathology
Synaptic Dysfunction:
- IL-25-induced inflammation contributes to synaptic loss
- Pro-inflammatory cytokines from IL-25-activated glia impair synaptic plasticity
- Memory deficits correlate with IL-25 levels in animal models
In PD, IL-25 plays several roles:
Dopaminergic Neuron Vulnerability:
- IL-25 promotes microglial activation in the substantia nigra
- Enhanced cytokine release contributes to neuron death
- IL-25 may accelerate α-synuclein pathology
Neuroinflammation Loop:
- α-Synuclein aggregates trigger IL-25 production
- IL-25 amplifies the inflammatory response
- This creates a feed-forward loop driving progression
Therapeutic Implications:
- IL-25R blockade protects dopaminergic neurons
- Combination with standard PD therapies shows promise
¶ Multiple Sclerosis and EAE
IL-25 has complex roles in demyelinating disease:
Pro-inflammatory Effects:
- Promotes Th2 and Th17 responses
- Enhances glial activation in lesions
- Contributes to demyelination
Protective Aspects:
- IL-25 can promote remyelination in some contexts
- Type 2 responses may be tissue-protective
The net effect depends on disease stage and cellular context.
¶ Animal Models and Experimental Findings
¶ Knockout and Transgenic Models
| Model |
Phenotype |
Relevance |
| IL25-/- mice |
Reduced neuroinflammation |
Confirms IL-25 role |
| IL25Ra-/- mice |
Protected in EAE |
Receptor requirement |
| IL-25 overexpression |
Spontaneous neuroinflammation |
Sufficient for disease |
| Act1-/- mice |
Reduced inflammatory responses |
Downstream requirements |
- Anti-IL-25 antibodies: Reduce neuroinflammation in AD and PD models
- IL25Ra-Fc decoy receptor: Block IL-25 binding, reduce disease severity
- Act1 inhibitors: Downstream blockade of signaling
- JAK inhibitors: Broader anti-inflammatory effects
Findings from animal models have been partially validated in human studies:
- IL-25 is elevated in AD, PD, and MS patient brains
- IL-25 levels in CSF correlate with disease severity
- Genetic variants in IL25RA may influence disease risk
While both are in the IL-17 family, IL-25 has distinct functions:
| Feature |
IL-17A |
IL-25 |
| Primary receptor |
IL17RA/IL17RC |
IL25Ra/IL17RB |
| Main function |
Pro-inflammatory |
Type 2 immunity |
| CNS expression |
Higher baseline |
Lower, inducible |
| Therapeutic target |
Established |
Developing |
- IL-17F shares some receptors with IL-25
- Both can signal through IL25Ra/IL17RB
- IL-25 is generally more potent in type 2 contexts
- Monoclonal antibodies: Anti-IL-25 antibodies in development
- Receptor constructs: IL25Ra-Fc fusion proteins
- Small molecules: Act1-TRAF6 interaction inhibitors
- JAK inhibitors: Broader anti-cytokine approach
| Approach |
Stage |
Indications |
| Anti-IL-25 mAb |
Preclinical |
AD, PD |
| IL25Ra-Fc |
Preclinical |
MS |
| JAK inhibitors |
Phase 2/3 |
MS, RA |
¶ Challenges and Solutions
Brain Penetration:
- Problem: Most biologics don't cross the blood-brain barrier
- Solutions: Focused ultrasound, intranasal delivery, BBB-modulating agents
Specificity:
- Problem: Cytokine redundancy limits single-target efficacy
- Solutions: Combination approaches, broad-spectrum agents
Timing:
- Problem: Intervention may be too late in disease course
- Solutions: Biomarker-driven early intervention
¶ Biomarker and Diagnostic Potential
Cerebrospinal Fluid:
- Elevated in AD, PD, MS compared to controls
- Correlates with disease severity
- Potential for disease monitoring
Blood:
- More accessible but less specific
- May reflect peripheral inflammation
- Useful for longitudinal monitoring
IL-25 works best in combination with other markers:
- With IL-17 family cytokines
- With neurofilament light chain (NfL)
- With tau and Aβ biomarkers
- Cell-specific roles: Which CNS cell types are most relevant?
- Temporal dynamics: How does IL-25 change across disease stages?
- Therapeutic window: When is intervention most effective?
- Biomarker validation: Can IL-25 be validated for clinical use?
- Single-cell studies of IL-25 responses in the CNS
- Structural studies of IL-25-receptor interactions
- Clinical trials of IL-25-targeted therapies
- Biomarker development for patient selection