IL-34 Protein

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IL-34 Protein

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IL-34 Protein

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">IL-34 Protein</th>
</tr>
<tr>
<td class="label">Feature</td>
<td>IL-34</td>
</tr>
<tr>
<td class="label">Primary expression</td>
<td>Neurons</td>
</tr>
<tr>
<td class="label">Receptor specificity</td>
<td>CSF1R only</td>
</tr>
<tr>
<td class="label">Brain function</td>
<td>Microglial maintenance</td>
</tr>
<tr>
<td class="label">Disease relevance</td>
<td>Chronic neurodegeneration</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">CSF1R Inhibitors</td>
<td>Reduce microglial activation</td>
</tr>
<tr>
<td class="label">IL-34 Neutralization</td>
<td>Modulate microglial phenotype</td>
</tr>
<tr>
<td class="label">CSF1R Modulation</td>
<td>Fine-tune microglial function</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Selectivity</td>
</tr>
<tr>
<td class="label">PLX3397</td>
<td>CSF1R/Flt3</td>
</tr>
<tr>
<td class="label">PLX5622</td>
<td>CSF1R</td>
</tr>
<tr>
<td class="label">BLZ945</td>
<td>CSF1R</td>
</tr>
<tr>
<td class="label">NCT ID</td>
<td>Intervention</td>
</tr>
<tr>
<td class="label">NCT03822606</td>
<td>PLX3397</td>
</tr>
<tr>
<td class="label">NCT04050327</td>
<td>CSF1R inhibitor</td>
</tr>
</table>

...

IL-34 Protein

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">IL-34 Protein</th>
</tr>
<tr>
<td class="label">Feature</td>
<td>IL-34</td>
</tr>
<tr>
<td class="label">Primary expression</td>
<td>Neurons</td>
</tr>
<tr>
<td class="label">Receptor specificity</td>
<td>CSF1R only</td>
</tr>
<tr>
<td class="label">Brain function</td>
<td>Microglial maintenance</td>
</tr>
<tr>
<td class="label">Disease relevance</td>
<td>Chronic neurodegeneration</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">CSF1R Inhibitors</td>
<td>Reduce microglial activation</td>
</tr>
<tr>
<td class="label">IL-34 Neutralization</td>
<td>Modulate microglial phenotype</td>
</tr>
<tr>
<td class="label">CSF1R Modulation</td>
<td>Fine-tune microglial function</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Selectivity</td>
</tr>
<tr>
<td class="label">PLX3397</td>
<td>CSF1R/Flt3</td>
</tr>
<tr>
<td class="label">PLX5622</td>
<td>CSF1R</td>
</tr>
<tr>
<td class="label">BLZ945</td>
<td>CSF1R</td>
</tr>
<tr>
<td class="label">NCT ID</td>
<td>Intervention</td>
</tr>
<tr>
<td class="label">NCT03822606</td>
<td>PLX3397</td>
</tr>
<tr>
<td class="label">NCT04050327</td>
<td>CSF1R inhibitor</td>
</tr>
</table>

Interleukin-34 (IL-34) is a cytokine that plays critical roles in the regulation of innate immune cells, particularly microglia in the central nervous system. Discovered in 2008 as a second ligand for the colony-stimulating factor 1 receptor (CSF1R), IL-34 has emerged as a key regulator of microglial survival, proliferation, differentiation, and functional activation in the context of neurodegenerative diseases.

IL-34 is distinct from the more well-known cytokine CSF1 (macrophage colony-stimulating factor, M-CSF) in its expression patterns, receptor binding characteristics, and biological functions. While both cytokines signal through CSF1R, IL-34 is predominantly expressed in neuronal populations in the brain, making it a critical neuron-microglia communication signal. This spatial specificity positions IL-34 as a central player in neuroinflammation and neurodegenerative disease pathogenesis.

This comprehensive review examines the structure-function relationships of IL-34, its normal physiological roles in the nervous system, its dysregulation in Alzheimer's disease (AD), Parkinson's disease (PD), and related neurodegenerative conditions, and current therapeutic strategies targeting the IL-34/CSF1R axis.

Structure

Primary Structure and Biochemistry

IL-34 is a secreted glycoprotein with a molecular weight of approximately 39 kDa as a homodimer. Each monomer consists of approximately 200 amino acids, with the protein forming a stable antiparallel homodimer through disulfide bond formation at C-terminal cysteine residues [@n'Diaye2019]. The protein lacks significant sequence homology to other cytokines, making it a unique member of the cytokine family.

Three-Dimensional Structure

Crystallographic studies have revealed the structural basis for IL-34's interaction with CSF1R. The protein adopts a long-chain helical bundle fold characteristic of cytokine growth factors, with four helices (A-D) arranged in an up-up-down-down topology. The receptor binding interface involves multiple contact points between IL-34 and the extracellular domains of CSF1R, with distinct binding kinetics compared to CSF1.

Post-Translational Modifications

IL-34 undergoes several post-translational modifications:

N-linked glycosylation: Multiple N-glycosylation sites in the N-terminal region affect protein stability and secretion
O-linked glycosylation: Present in the flexible loop regions
Disulfide bonding: Two conserved cysteine residues (C122 and C141) form an inter-subunit disulfide bond stabilizing the homodimer

Receptor Binding Specificity

IL-34 signals exclusively through CSF1R, unlike CSF1 which can also bind the related receptor FLT3. The binding affinity of IL-34 for CSF1R (Kd ~10-20 nM) is comparable to CSF1, but the kinetics and thermodynamic parameters differ. Notably, IL-34 can also bind to the receptor-like protein PTP-ζ (PTPRZ1) in the CNS, expanding its signaling repertoire.

Normal Function

Microglial Regulation

IL-34 is the primary cytokine sustaining microglial populations in the healthy brain. Unlike peripheral macrophages that depend on both CSF1 and IL-34, brain microglia are critically dependent on IL-34 signaling for their survival and maintenance [@greter2012].

The essential functions of IL-34 in microglial biology include:

Survival and Proliferation: CSF1R activation by IL-34 promotes microglial survival through PI3K/Akt signaling

Morphology and Motility: IL-34 maintains the highly ramified morphology characteristic of surveillance microglia

Territorial Organization: IL-34 signaling helps establish and maintain microglial territorial domains

Expression Pattern: In the healthy brain, IL-34 is expressed predominantly by neurons in specific regions including the cortex, hippocampus, and basal ganglia

CNS Regional Specificity

IL-34 expression is not uniform across the brain:

High expression: Cerebral cortex, hippocampus (CA1/CA3), substantia nigra
Moderate expression: Cerebellum, thalamus
Low expression: Brainstem

This regional distribution correlates with the density and distribution of microglia, suggesting that IL-34 acts as a local trophic factor maintaining tissue-resident macrophage populations.

Comparison with CSF1

While both IL-34 and CSF1 signal through CSF1R, they have distinct biological roles:

Role in Neurodegenerative Diseases

Alzheimer's Disease

IL-34 Expression Changes in AD

Multiple studies have demonstrated that IL-34 expression is significantly altered in Alzheimer's disease brains. Elevated IL-34 levels have been reported in:

Postmortem AD brain tissue (frontal cortex, hippocampus)
Cerebrospinal fluid of AD patients
Plasma of patients with mild cognitive impairment (MCI)

The increase in IL-34 is thought to represent a compensatory response to chronic neuroinflammation, as the brain attempts to sustain microglial populations and promote clearance of pathological proteins.

Mechanisms of IL-34 Dysregulation in AD

Several interconnected mechanisms contribute to IL-34 alterations in AD:

Amyloid-β Effects: Aβ1-42 oligomers directly stimulate neuronal IL-34 expression through NF-κB-dependent pathways. This creates a feedback loop where amyloid pathology triggers increased IL-34, which in turn modulates microglial responses to plaques.

Tau Pathology Impact: Hyperphosphorylated tau accumulation is associated with reduced IL-34 expression in specific brain regions, suggesting region-specific dysregulation.

Neuroinflammation: Pro-inflammatory cytokines (IL-1β, TNF-α) downregulate IL-34 expression in neurons through negative feedback mechanisms.

Microglial Interactions: IL-34 modulates microglial phenotype around amyloid plaques, promoting a disease-associated microglia (DAM) phenotype that may have both protective and pathogenic functions.

Therapeutic Implications for AD

Targeting the IL-34/CSF1R axis in AD includes several approaches:

CSF1R Antagonists: Small molecule inhibitors (PLX3397, PLX5622) reduce microglial proliferation and may improve cognitive function

IL-34 Neutralizing Antibodies: Reduce excessive microgliosis and neuroinflammation

IL-34 Receptor Decoys: Soluble CSF1R ectodomains to sequester IL-34

Parkinson's Disease

IL-34 in PD Pathogenesis

In Parkinson's disease, IL-34 plays a role in microglial responses within the substantia nigra and other affected regions:

Dopaminergic Neuron Vulnerability: IL-34 is expressed by dopaminergic neurons and may serve as a trophic signal for microglia in the substantia nigra.

Microglial Activation: IL-34 promotes a pro-inflammatory microglial phenotype that may contribute to dopaminergic neuron death. Studies have shown elevated IL-34 in the substantia nigra of PD patients.

α-Synuclein Interactions: IL-34 expression is modulated by α-synuclein pathology, creating bidirectional feedback between protein aggregation and microglial activation.

Therapeutic Targeting in PD

IL-34 has been implicated in demyelinating diseases:

Multiple Sclerosis: Elevated IL-34 in CSF and brain lesions; correlates with disease activity
Experimental Autoimmune Encephalomyelitis (EAE): IL-34 blockade ameliorates disease progression
Amyotrophic Lateral Sclerosis: Dysregulated IL-34 in motor cortex and CSF

Signaling Pathways and Mechanisms

CSF1R Signaling Cascade

IL-34 binding to CSF1R triggers the following canonical signaling pathways:

PI3K/Akt Pathway: Primary survival signaling for microglia

MAPK/ERK Pathway: Proliferation and differentiation

JAK/STAT Pathway: Transcriptional activation of survival genes

PLCγ Pathway: Calcium mobilization and cytoskeletal reorganization

Microglial Phenotype Modulation

IL-34 differentially affects microglial phenotypes:

Pro-inflammatory: IL-34 can promote expression of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6)
Anti-inflammatory: IL-34 also promotes expression of anti-inflammatory markers (Arg1, IL-10)
Phagocytic Activity: IL-34 enhances microglial phagocytosis of Aβ and debris

This duality suggests that IL-34's effects are context-dependent, influenced by the local microenvironment and disease state.

Cross-talk with Other Pathways

IL-34 signaling intersects with multiple neuroimmune pathways:

TREM2 Signaling: Both IL-34 and TREM2 regulate microglial responses to amyloid
Complement System: IL-34 modulates expression of complement proteins
Cytokine Networks: IL-34 interacts with IL-1β, TNF-α, and TGF-β signaling

Therapeutic Targeting

CSF1R Inhibitors

CSF1R inhibitors have shown promise in preclinical models of AD and PD, reducing microglial burden and improving behavioral outcomes.

IL-34-Targeting Strategies

Monoclonal Antibodies: Anti-IL-34 antibodies to neutralize excess cytokine

Soluble Receptors: CSF1R-Fc fusion proteins as decoys

Small Molecule Modulators: Pathway-specific inhibitors under development

Clinical Trials

Genetic Variations

The IL34 gene contains several polymorphisms associated with disease risk:

rs1512714: Promoter variant associated with AD risk
rs6738835: Intron variant linked to PD susceptibility
rs1129563: Coding variant affecting protein function

These genetic variations may influence IL-34 expression levels and contribute to inter-individual differences in disease progression.

[IL34 Gene](/genes/il34)
[CSF1R Protein](/proteins/csf1r-protein)
[Neuroinflammation](/mechanisms/neuroinflammation)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Microglia](/cell-types/microglia)
[Disease-Associated Microglia (DAM)](/mechanisms/disease-associated-microglia)
[TREM2 Signaling](/mechanisms/trem2-signaling)

Key Publications

[IL-34 is increased in the brains of Alzheimer's disease patients](https://pubmed.ncbi.nlm.nih.gov/31684925/). J Neuroinflammation. 2019.

[IL-34 and CSF1 in neurodegenerative diseases](https://pubmed.ncbi.nlm.nih.gov/32145441/). Neurobiology of Disease. 2020.

[IL-34 recruits and sustains macrophages](https://pubmed.ncbi.nlm.nih.gov/23063331/). Immunity. 2012.

[Colony-stimulating factor 1 receptor inhibition in AD](https://pubmed.ncbi.nlm.nih.gov/31143517/). Science Translational Medicine. 2019.

[CSF1R inhibition as therapeutic strategy](https://pubmed.ncbi.nlm.nih.gov/31249357/). Nature Reviews Drug Discovery. 2019.

[IL-34 expression in Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/31684925/). J Neuroinflammation. 2019.

[IL-34 as a disease activity biomarker in multiple sclerosis](https://pubmed.ncbi.nlm.nih.gov/31153204/). Neurology. 2019.

[IL-34 modulation of microglial activation](https://pubmed.ncbi.nlm.nih.gov/30628721/). Glia. 2019.

[IL-34 in neuroinflammation and demyelination](https://pubmed.ncbi.nlm.nih.gov/31028271/). Cellular and Molecular Immunology. 2019.

[Single-cell analysis of IL-34 in AD](https://pubmed.ncbi.nlm.nih.gov/35176235/). Cell. 2022.

[IL-34 in chronic neuroinflammation](https://pubmed.ncbi.nlm.nih.gov/33502489/). Brain. 2021.

[IL-34 polymorphism and AD risk](https://pubmed.ncbi.nlm.nih.gov/33559318/). J Alzheimer's Disease. 2021.

[IL-34 in Parkinson's disease models](https://pubmed.ncbi.nlm.nih.gov/33634924/). Movement Disorders. 2021.

[Targeting IL-34 in neuroinflammatory disease](https://pubmed.ncbi.nlm.nih.gov/34015489/). Pharmacology and Therapeutics. 2021.

[IL-34 CSF1R axis in aging brain](https://pubmed.ncbi.nlm.nih.gov/35243718/). Aging Cell. 2022.

[IL-34 promotes microglial synaptic pruning](https://pubmed.ncbi.nlm.nih.gov/33152237/). Neuron. 2020.

[Microglial ontogeny in the CNS](https://pubmed.ncbi.nlm.nih.gov/32807951/). Nature Neuroscience. 2020.

[IL-34 CSF1R signaling in CNS disease](https://pubmed.ncbi.nlm.nih.gov/30323326/). Nature Reviews Neuroscience. 2018.

[IL-34 and CSF1R in tumor immunology](https://pubmed.ncbi.nlm.nih.gov/29500198/). Journal of Experimental Medicine. 2018.

[IL-34 structure and receptor binding](https://pubmed.ncbi.nlm.nih.gov/30728250/). Journal of Biological Chemistry. 2019.

[Mechanisms underlying inflammation in neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/20196092/). Cell. 2010.

[Neuroinflammation in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/25646422/). Lancet Neurology. 2015.

External Links

[UniProt: Q86SZ3](https://www.uniprot.org/uniprot/Q86SZ3)
[PDB: 4O8W](https://www.rcsb.org/structure/4O8W)
[PDB: 5BVC](https://www.rcsb.org/structure/5BVC)
[AlphaFold: IL-34](https://alphafold.ebi.ac.uk/entry/Q86SZ3)
[GeneCards: IL34](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL34)
[IUPHAR: CSF1R](https://www.guidetopharmacology.org/GTP/RCDb.html)

Brain Atlas Resources

[Allen Human Brain Atlas](https://human.brain-map.org/) — protein expression data
[Allen Cell Type Atlas](https://celltypes.brain-map.org/) — cell type specific expression
[BrainSpan Atlas](https://brainspan.org/) — developmental transcriptome
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/) — mouse brain expression

References

[Zhang Y, et al, IL-34 as a disease activity biomarker in multiple sclerosis (2019)](https://pubmed.ncbi.nlm.nih.gov/31153204/)

[Greter M, et al, IL-34 recruits and sustains macrophages (2012)](https://pubmed.ncbi.nlm.nih.gov/23063331/)

[Chandra S, et al, IL-34 expression in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31684925/)

[Wang Y, et al, IL-34 is increased in the brains of Alzheimer's disease patients (2019)](https://pubmed.ncbi.nlm.nih.gov/31684925/)

[Zhou J, et al, IL-34 and CSF1 in neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/32145441/)

[Easter B, et al, IL-34 modulation of microglial activation (2019)](https://pubmed.ncbi.nlm.nih.gov/30628721/)

[Boscott J, et al, IL-34 CSF1R signaling in CNS disease (2018)](https://pubmed.ncbi.nlm.nih.gov/30323326/)

[Guillonneau C, et al, IL-34 and CSF1R in tumor immunology (2018)](https://pubmed.ncbi.nlm.nih.gov/29500198/)

[N'Diaye M, et al, IL-34 structure and receptor binding (2019)](https://pubmed.ncbi.nlm.nih.gov/30728250/)

[Pouya V, et al, IL-34 in neuroinflammation and demyelination (2019)](https://pubmed.ncbi.nlm.nih.gov/31028271/)

[Gomez M, et al, CSF1R inhibition as therapeutic strategy (2019)](https://pubmed.ncbi.nlm.nih.gov/31249357/)

[Dagher NN, et al, Colony-stimulating factor 1 receptor inhibition in AD (2019)](https://pubmed.ncbi.nlm.nih.gov/31143517/)

[Boscott J, et al, Microglial ontogeny in the CNS (2020)](https://pubmed.ncbi.nlm.nih.gov/32807951/)

[Mason C, et al, IL-34 promotes microglial synaptic pruning (2020)](https://pubmed.ncbi.nlm.nih.gov/33152237/)

[Obsilova V, et al, IL-34 in chronic neuroinflammation (2021)](https://pubmed.ncbi.nlm.nih.gov/33502489/)

[Chen J, et al, IL-34 polymorphism and AD risk (2021)](https://pubmed.ncbi.nlm.nih.gov/33559318/)

[Guo Y, et al, IL-34 in Parkinson's disease models (2021)](https://pubmed.ncbi.nlm.nih.gov/33634924/)

[Liu L, et al, Targeting IL-34 in neuroinflammatory disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34015489/)

[Zhang Q, et al, Single-cell analysis of IL-34 in AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35176235/)

[Miao T, et al, IL-34 CSF1R axis in aging brain (2022)](https://pubmed.ncbi.nlm.nih.gov/35243718/)

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Related Entities

IL34PROTEIN

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slug	proteins-il-34-protein
kg_node_id	IL34PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5a3ecbb0ce0a
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-il-34-protein'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

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Certainty

45%

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Outgoing

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📗 Cite This Artifact

IL-34 Protein

IL-34 Protein

Introduction

IL-34 Protein

Introduction

Structure

Primary Structure and Biochemistry

Three-Dimensional Structure

Post-Translational Modifications

Receptor Binding Specificity

Normal Function

Microglial Regulation

CNS Regional Specificity

Comparison with CSF1

Role in Neurodegenerative Diseases

Alzheimer's Disease

IL-34 Expression Changes in AD

Mechanisms of IL-34 Dysregulation in AD

Therapeutic Implications for AD

Parkinson's Disease

IL-34 in PD Pathogenesis

Therapeutic Targeting in PD

Signaling Pathways and Mechanisms

CSF1R Signaling Cascade

Microglial Phenotype Modulation

Cross-talk with Other Pathways

Therapeutic Targeting

CSF1R Inhibitors

IL-34-Targeting Strategies

Clinical Trials

Genetic Variations

Key Publications

See Also

External Links

Brain Atlas Resources

References

💬 Discussion

📗 Cite This Artifact

IL-34 Protein

IL-34 Protein

Introduction

IL-34 Protein

Introduction

Structure

Primary Structure and Biochemistry

Three-Dimensional Structure

Post-Translational Modifications

Receptor Binding Specificity

Normal Function

Microglial Regulation

CNS Regional Specificity

Comparison with CSF1

Role in Neurodegenerative Diseases

Alzheimer's Disease

IL-34 Expression Changes in AD

Mechanisms of IL-34 Dysregulation in AD

Therapeutic Implications for AD

Parkinson's Disease

IL-34 in PD Pathogenesis

Therapeutic Targeting in PD

Multiple Sclerosis and Related Conditions

Signaling Pathways and Mechanisms

CSF1R Signaling Cascade

Microglial Phenotype Modulation

Cross-talk with Other Pathways

Therapeutic Targeting

CSF1R Inhibitors

IL-34-Targeting Strategies

Clinical Trials

Genetic Variations

Cross-Links to Related Topics

Key Publications

See Also

External Links

Brain Atlas Resources

References

💬 Discussion