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.
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.
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.
IL-34 undergoes several post-translational modifications:
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.
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 [1].
The essential functions of IL-34 in microglial biology include:
IL-34 expression is not uniform across the brain:
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.
While both IL-34 and CSF1 signal through CSF1R, they have distinct biological roles:
| Feature | IL-34 | CSF1 |
|---|---|---|
| Primary expression | Neurons | Various cell types |
| Receptor specificity | CSF1R only | CSF1R, FLT3 |
| Brain function | Microglial maintenance | Inflammatory responses |
| Disease relevance | Chronic neurodegeneration | Acute inflammation |
Multiple studies have demonstrated that IL-34 expression is significantly altered in Alzheimer's disease brains. Elevated IL-34 levels have been reported in:
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.
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.
Targeting the IL-34/CSF1R axis in AD includes several approaches:
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.
| Strategy | Mechanism | Development Status |
|---|---|---|
| CSF1R Inhibitors | Reduce microglial activation | Phase I completed |
| IL-34 Neutralization | Modulate microglial phenotype | Preclinical |
| CSF1R Modulation | Fine-tune microglial function | Discovery |
IL-34 has been implicated in demyelinating diseases:
IL-34 binding to CSF1R triggers the following canonical signaling pathways:
IL-34 differentially affects microglial phenotypes:
This duality suggests that IL-34's effects are context-dependent, influenced by the local microenvironment and disease state.
IL-34 signaling intersects with multiple neuroimmune pathways:
| Compound | Selectivity | Clinical Status | Indication |
|---|---|---|---|
| PLX3397 | CSF1R/Flt3 | Phase I/II | AD, oncology |
| PLX5622 | CSF1R | Preclinical | AD, PD |
| BLZ945 | CSF1R | Preclinical | Neuroinflammation |
CSF1R inhibitors have shown promise in preclinical models of AD and PD, reducing microglial burden and improving behavioral outcomes.
| NCT ID | Intervention | Phase | Indication | Status |
|---|---|---|---|---|
| NCT03822606 | PLX3397 | Phase I | AD | Completed |
| NCT04050327 | CSF1R inhibitor | Phase I | PD | Recruiting |
The IL34 gene contains several polymorphisms associated with disease risk:
These genetic variations may influence IL-34 expression levels and contribute to inter-individual differences in disease progression.
Greter M, et al. IL-34 recruits and sustains macrophages. Immunity. 2012. ↩︎