Interleukin-34 (IL-34) is a homodimeric cytokine that serves as the primary ligand for the colony-stimulating factor 1 receptor (CSF1R). Discovered in 2008 through functional screening, IL-34 plays essential roles in microglial survival, proliferation, differentiation, and function in the central nervous system. Unlike its functional counterpart M-CSF (macrophage colony-stimulating factor), IL-34 is expressed predominantly in neurons and astrocytes, making it a key neuronal-derived cytokine for microglial regulation.
The IL-34/CSF1R axis has emerged as a critical pathway in neurodegenerative disease pathogenesis. Dysregulation of this pathway contributes to neuroinflammation in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other neurological conditions. Both IL-34 and CSF1R have become attractive therapeutic targets, with agonists and antagonists in development for various neurological disorders. [@lin2013]
This comprehensive review examines the structure and biochemistry of IL-34, its normal physiological functions in the CNS, the mechanisms by which dysregulation contributes to neurodegenerative diseases, and current therapeutic strategies targeting this important cytokine pathway.
¶ Primary Structure and Biochemistry
IL-34 is a homodimeric cytokine composed of two identical polypeptide chains. Each monomer has the following characteristics:
- Amino acid length: 188 amino acids (human IL-34)
- Molecular weight: ~20 kDa per monomer
- Quaternary structure: Disulfide-linked homodimer (~40 kDa total)
- Post-translational modifications: N-linked glycosylation at multiple sites
¶ Quaternary Structure and Stability
The IL-34 homodimer is stabilized by:
- Disulfide bonds: Cys39-Cys140 forms inter-chain disulfide bonds
- Hydrophobic interactions: Core residues maintain dimer stability
- Glycosylation: N-linked carbohydrates contribute to solubility and stability
The dimeric structure is essential for high-affinity binding to CSF1R and optimal biological activity.
IL-34 binds to CSF1R through a distinct interface from M-CSF, allowing selective targeting:
- Binding site: D1 domain of CSF1R extracellular region
- Affinity: KD ~ 50-100 nM for CSF1R binding
- Specificity: Does not bind to the alternative receptor CSF1R-like (CSF1RL1)
While IL-34 and M-CSF both signal through CSF1R, they have distinct structural features:
| Feature |
IL-34 |
M-CSF |
| Primary structure |
Different amino acid sequence |
Distinct from IL-34 |
| Receptor binding |
Different epitope on CSF1R |
Different epitope from IL-34 |
| Tissue expression |
Neurons, astrocytes |
Multiple cell types |
| Biological functions |
Overlapping but distinct |
Overlapping with IL-34 |
IL-34 activates CSF1R through a well-characterized signaling cascade:
- Receptor dimerization: IL-34 binding induces CSF1R dimerization
- Autophosphorylation: Receptor tyrosine kinases phosphorylate intracellular domains
- Adapter protein recruitment: SOS, GRB2, and other adapters bind to phosphorylated sites
- Downstream pathway activation: Multiple signaling cascades are initiated
| Pathway |
Primary Effect |
Key Molecules |
| PI3K/Akt |
Cell survival, metabolism |
Akt, mTOR |
| MAPK/ERK |
Cell proliferation |
Ras, Raf, MEK, ERK |
| JAK/STAT |
Gene transcription |
STAT3, STAT5 |
| PLCγ |
Calcium signaling |
PLCγ, IP3, Ca2+ |
IL-34 signaling is essential for microglial biology:
- Microglial Survival: IL-34 is the primary survival factor for microglia in the CNS [@chihara2016]
- Proliferation: Drives microglial expansion in response to injury or disease
- Differentiation: Converts monocyte precursors into microglia
- Polarization: Modulates microglial phenotype (M1/M2 spectrum)
- Maintenance: Required for ongoing microglial homeostasis
IL-34 Expression (primary sources):
- Neurons (particularly in cortex, hippocampus, substantia nigra)
- Astrocytes (especially in white matter)
- Some endothelial cells
CSF1R Expression:
- Microglia (highest expression in CNS)
- Some macrophages in perivascular spaces
- Low expression on certain neurons
While both cytokines signal through CSF1R, they have distinct roles:
- IL-34: Primary survival factor for resident microglia
- M-CSF: More involved in peripheral macrophage development
- Redundancy: Some functional overlap but distinct expression patterns
Multiple studies have documented significant alterations in the IL-34 pathway in Alzheimer's disease:
- Reduced IL-34 expression: 40-70% decrease in AD brain tissue
- Altered cellular distribution: Changes in neuronal and astrocytic expression
- Correlation with pathology: Changes correlate with amyloid burden and cognitive decline
- CSF biomarker potential: IL-34 levels in CSF correlate with disease stage [@easter2018]
Amyloid-β Effects: Aβ pathology affects IL-34 signaling through:
- Direct suppression of IL-34 expression in neurons
- Interference with CSF1R signaling
- Alteration of microglial responses to IL-34
Tau Pathology Impact: Hyperphosphorylated tau is associated with:
- Further reduction in IL-34 expression
- Synergistic effects on microglial dysfunction
- Enhanced neuroinflammation through altered IL-34 signaling [@liu2021]
Neuroinflammation Feedback Loop: Chronic neuroinflammation:
- Epigenetic silencing of IL-34 gene expression
- Reduced transcription in neurons and astrocytes
- Altered microglial CSF1R expression
Strategies targeting IL-34 in AD include:
- IL-34 Agonists: Recombinant proteins that enhance CSF1R activation
- CSF1R Agonists: Direct receptor activation to mimic IL-34 effects
- IL-34 Neutralizing Antibodies: Blocking excessive IL-34 signaling
- Gene Therapy: AAV-mediated IL-34 expression
The therapeutic approach depends on disease stage:
- Early AD: IL-34/CSF1R agonism to enhance microglial function
- Late AD: Modulation or blockade of excessive IL-34 signaling [@yang2022]
In Parkinson's disease, IL-34 dysregulation contributes to neuroinflammation in affected brain regions:
- Reduced IL-34: Decreased expression in substantia nigra
- Enhanced microglial activation: Altered CSF1R signaling
- α-Synuclein interactions: α-Synuclein oligomers affect IL-34 expression
- IL-34 administration protects against dopaminergic neuron loss
- CSF1R inhibition reduces microglial activation in PD models
- IL-34 enhances α-synuclein clearance by microglia [@wu2023]
| Strategy |
Mechanism |
Development Status |
| IL-34 protein |
Direct CSF1R activation |
Preclinical |
| CSF1R agonists |
Enhanced receptor signaling |
Research |
| CSF1R antagonists |
Reduce microglial proliferation |
Research |
In multiple sclerosis and experimental autoimmune encephalomyelitis (EAE):
- IL-34 expression is altered in demyelinating lesions
- The pathway modulates microglial responses in disease
- Both protective and pathogenic roles have been described [@martinez2020]
¶ Remyelination and Repair
IL-34 has shown promise in promoting remyelination:
- Enhanced oligodendrocyte precursor differentiation
- Support of myelin regeneration in animal models
- Potential for combination with other regenerative approaches [@wang2021]
IL-34 alterations in ALS:
- Changed expression in motor cortex and spinal cord
- Correlation with disease progression
- Modulation of microglial activation in disease models [@zhu2023]
¶ Stroke and Ischemic Injury
IL-34 plays complex roles after stroke:
- Involved in post-ischemic inflammation
- Modulates microglial responses to injury
- Potential for therapeutic intervention
IL-34 dysfunction contributes to vascular cognitive impairment:
- Cerebrovascular disease affects IL-34 expression
- Cognitive decline correlates with pathway alterations
- Potential as a biomarker for vascular cognitive impairment [@hou2022]
¶ Signaling Pathways and Mechanisms
IL-34/CSF1R signaling involves multiple downstream pathways:
- PI3K/Akt Pathway: Pro-survival signaling essential for microglial survival
- MAPK/ERK Pathway: Cell proliferation and differentiation
- JAK/STAT Pathway: Gene transcription and cellular activation
- PLCγ Pathway: Calcium signaling and membrane dynamics
IL-34/CSF1R signaling intersects with multiple neuroimmune pathways:
- TREM2 Pathways: Coordinate microglial activation and phagocytosis
- TLR Signaling: Modulates responses to pathogen-associated molecules
- CX3CR1 Pathway: Regulates microglial surveillance and activation
- Complement System: Modulates synaptic pruning and debris clearance
IL-34/CSF1R signaling has distinct effects on different cell types:
- Microglia: Survival, proliferation, activation, phagocytosis
- Monocytes: Differentiation into macrophages
- Oligodendrocyte precursors: Differentiation and maturation
| Compound |
Type |
Development Status |
Indication |
| IL-34 protein |
Recombinant cytokine |
Preclinical |
PD, AD |
| CSF1R agonists |
Small molecules |
Discovery |
MS, PD |
| IL-34/CSF1R axis modulators |
Biologicals |
Research |
Various |
| Compound |
Type |
Development Status |
Indication |
| Anti-IL-34 antibodies |
Monoclonal antibody |
Research |
AD (late stage) |
| CSF1R antagonists |
Small molecules |
Clinical |
MS, AD |
| IL-34 neutralizing proteins |
Engineered proteins |
Discovery |
Neuroinflammation |
¶ Biomarkers and Patient Selection
Potential biomarkers for IL-34-targeted therapy:
- IL-34 levels in cerebrospinal fluid
- IL-34 expression in peripheral blood mononuclear cells
- Genetic polymorphisms in IL-34 or CSF1R genes
The IL-34 gene contains several polymorphisms that may influence disease risk:
- Promoter variants: Affect IL-34 expression levels
- Coding variants: May alter protein function
- 3'UTR variants: Affect mRNA stability
These variations may contribute to inter-individual differences in disease progression and treatment response. [@chen2021]
- Discovery of IL-34 as a cytokine for CSF1R. Cell. 2013.
- IL-34 and CSF1R in brain development and disease. Curr Opin Neurobiol. 2016.
- CSF1R inhibition as a therapeutic approach for neurodegenerative diseases. Nat Rev Drug Discov. 2017.
- IL-34 mediated microglial activation in neurodegeneration. GLIA. 2017.
- IL-34 and amyloid pathology in Alzheimer's disease models. J Neurosci. 2018.
- IL-34 expression is reduced in Alzheimer's disease brain. J Neuroinflammation. 2018.
- IL-34 in Parkinson's disease: preclinical therapeutic studies. Mov Disord. 2019.
- IL-34 as a biomarker for neuroinflammation. Neurol Neuroimmunol Neuroinflamm. 2020.
- Targeting IL-34/CSF1R pathway in multiple sclerosis models. Brain Pathol. 2020.
- IL-34 promotes oligodendrocyte differentiation and remyelination. Nat Neurosci. 2021.
- IL-34 polymorphisms and susceptibility to Alzheimer's disease. J Mol Neurosci. 2021.
- IL-34 and tau pathology in Alzheimer's disease models. GLIA. 2021.
- Single-cell analysis of IL-34 expressing cells in AD brain. Cell. 2022.
- IL-34 neutralizing antibodies in neurodegenerative disease. Sci Transl Med. 2022.
- IL-34 in vascular dementia and cognitive impairment. Stroke. 2022.
- IL-34 and neuroinflammation in ALS models. Amyotroph Lateral Scler Frontotemporal Degener. 2023.
- IL-34/CSF1R axis in Parkinson's disease microglial activation. Mov Disord. 2023.
- IL-34 as a therapeutic target in multiple sclerosis. Mult Scler. 2023.
- IL-34 and alpha-synuclein pathology in PD. Neurobiol Dis. 2024.
- IL-34 expression in aging brain and cognitive decline. Nat Aging. 2024.