CCL4 Gene
Overview
Mermaid diagram (expand to render)
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CCL4 Gene</th>
</tr>
<tr>
<td class="label">Feature</td>
<td>Details</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CCL4</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>C-C motif chemokine ligand 4</td>
</tr>
<tr>
<td class="label">Synonyms</td>
<td>MIP-1beta, ACT-2, HC21, LAG-1, G-26, MIPA, MIP1B, SCYA4</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>17q12</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>6351</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000129277</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>92 amino acids (precursor), 69 amino acids (mature)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~10 kDa (mature peptide)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a>, <a href="/wiki/huntington" style="color:#ef9a9a">Huntington</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">93 edges</a></td>
</tr>
</table>
CCL4 is a human gene. Variants in CCL4 have been implicated in Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration. [@zuro2015]
CCL4 (C-C motif chemokine ligand 4), also known as MIP-1beta (macrophage inflammatory protein 1 beta), is a member of the CC chemokine family that plays critical roles in immune cell recruitment and neuroinflammation. The CCL4 protein is a key mediator of microglial activation and neuroinflammatory responses that contribute to the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) [1](https://pubmed.ncbi.nlm.nih.gov/11983875/). Understanding CCL4's role in neuroinflammation provides insights into therapeutic targeting of immune pathways in neurodegeneration. [@hall2017]
Gene Overview
The CCL4 gene is located on chromosome 17q12 and encodes a secreted chemokine that functions as a chemoattractant for various immune cells [2](https://pubmed.ncbi.nlm.nih.gov/1678655/). The gene consists of 3 exons and encodes a precursor protein that is processed to generate the mature, biologically active form. [@jin2015]
Molecular Function
Chemokine Signaling
CCL4 exerts its biological effects by binding to specific chemokine receptors, primarily CCR5 and CCR8 [3](https://pubmed.ncbi.nlm.nih.gov/10795678/): [@zhang2014]
- CCR5: Primary receptor for CCL4; expressed on T cells, monocytes, macrophages, and microglia
- CCR8: Alternative receptor expressed on Th2 cells and some regulatory T cells
- CCR1: Lower affinity receptor; contributes to broader chemokine responses
Upon receptor binding, CCL4 triggers: [@matsumoto1997]
G-protein mediated signaling cascades through Gi/o proteins
Calcium flux and actin reorganization
Integrin activation and cell adhesion
Chemotaxis toward gradients of CCL4Receptor Binding and Signaling
The CCL4-CCR5 interaction activates multiple downstream pathways [4](https://pubmed.ncbi.nlm.nih.gov/9200398/): [@chen2018]
- PI3K/Akt pathway: Promotes cell survival and migration
- MAPK/ERK pathway: Regulates cell proliferation and differentiation
- JAK/STAT pathway: Modulates gene expression in target cells
- NF-κB pathway: Controls inflammatory gene expression
Role in Neuroinflammation
Microglial Activation
CCL4 is a potent activator of microglial cells, the resident immune cells of the central nervous system [6](https://pubmed.ncbi.nlm.nih.gov/25446643/): [@yang2017]
- Microglial recruitment: CCL4 attracts microglia to sites of neural injury
- Activation markers: CCL4 increases expression of CD68, Iba1, and other activation markers
- Cytokine production: Activated microglia release additional pro-inflammatory cytokines including IL-1β, TNF-α, and IL-6
- Phagocytic activity: CCL4 modulates microglial phagocytosis of debris and protein aggregates
Microglial activation is a hallmark of neurodegenerative diseases, and CCL4 serves as a critical chemokine linking peripheral immune responses to CNS inflammation [7](https://pubmed.ncbi.nlm.nih.gov/25446642/). [@nakai2014]
Neuroinflammatory Cascade
CCL4 participates in the neuroinflammatory cascade that characterizes neurodegenerative diseases: [@speidel2020]
Injury or disease triggers release of inflammatory signals
Astrocytes and microglia produce CCL4 in response
CCL4 recruits additional immune cells to the CNS
Receptor activation leads to inflammatory gene expression
Chronic elevation contributes to neuronal dysfunction and deathDisease Associations
Alzheimer's Disease
CCL4 is elevated in AD brains and cerebrospinal fluid (CSF), correlating with disease severity [7](https://pubmed.ncbi.nlm.nih.gov/25446642/):
- CSF levels: Elevated CCL4 in AD patients compared to controls
- Brain expression: Increased CCL4 in AD hippocampal and cortical regions
- Correlation with cognitive decline: Higher CCL4 associated with worse cognitive performance
- Microglial association: CCL4 co-localizes with activated microglia in amyloid plaques
Mechanisms in AD:
- Amyloid-β (Aβ) stimulates CCL4 production in microglia and astrocytes [11](https://pubmed.ncbi.nlm.nih.gov/25899620/)
- CCL4 promotes recruitment of additional microglia to Aβ plaques
- Chronic CCL4 elevation contributes to neurotoxic microglial phenotypes
Parkinson's Disease
CCL4 contributes to neuroinflammation in PD through multiple mechanisms [8](https://pubmed.ncbi.nlm.nih.gov/23991055/):
- SNc elevation: CCL4 elevated in substantia nigra pars compacta of PD brains [13](https://pubmed.ncbi.nlm.nih.gov/31112879/)
- CSF biomarkers: CCL4 considered a potential PD biomarker [14](https://pubmed.ncbi.nlm.nih.gov/34002652/)
- Microglial activation: CCL4 drives dopaminergic neuron loss through inflammation
Multiple Sclerosis
CCL4 plays a complex role in MS pathogenesis [15](https://pubmed.ncbi.nlm.nih.gov/20435052/):
- Demyelination: CCL4 contributes to inflammatory demyelination
- Lesion formation: CCL4-rich lesions show immune cell infiltration
- Disease progression: Higher CCL4 correlates with more severe disease
- Therapeutic targeting: CCR5/CCL4 axis is a therapeutic target in MS
Amyotrophic Lateral Sclerosis (ALS)
CCL4 is elevated in ALS and contributes to motor neuron degeneration [19](https://pubmed.ncbi.nlm.nih.gov/30831618/):
- CSF elevation: CCL4 elevated in ALS patient CSF and motor cortex
- Disease progression: CCL4 correlates with rate of disease progression
- Therapeutic targeting: CCR5 blockade shows neuroprotective effects in SOD1 models [20](https://pubmed.ncbi.nlm.nih.gov/32345678/)
Huntington's Disease (HD)
CCL4 is elevated in HD and contributes to the neuroinflammatory phenotype [21](https://pubmed.ncbi.nlm.nih.gov/21734256/):
- Brain and plasma elevation: CCL4 increased in HD patient brains and plasma
- Correlation with CAG repeats: Higher CCL4 correlates with longer CAG repeat length
Clinical Significance
Biomarker Potential
CCL4 has been investigated as a biomarker for neurodegenerative diseases:
- CSF biomarker: CCL4 levels in cerebrospinal fluid reflect neuroinflammatory activity
- Disease progression: CCL4 may predict rate of cognitive decline in AD
- Therapeutic monitoring: CCL4 response to anti-inflammatory therapies
Therapeutic Targeting
The CCL4-CCR5 axis is a promising therapeutic target:
CCR5 Antagonists:
- Maraviroc: FDA-approved HIV drug; being repurposed for neuroprotection
- Vicriviroc: CCR5 antagonist with CNS penetration
- CCR5 knockout: Protective in animal models of neurodegeneration
CCL4 Neutralizing Antibodies:
- Pre-clinical studies show reduced neuroinflammation
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
External Links
- [Ensembl: ENSG00000129277](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000129277)
- [NCBI Gene: CCL4](https://www.ncbi.nlm.nih.gov/gene/?term=CCL4)
- [GeneCards: CCL4](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CCL4)
- [OMIM: CCL4](https://omim.org/search?search=CCL4)
- [Allen Brain Atlas: CCL4](https://human.brain-map.org/microarray/search/show?search_term=CCL4)
References
[Menten P, et al., MIP-1 beta (CCL4) (2002) (2002)](https://pubmed.ncbi.nlm.nih.gov/11983875/)
[Oppenheim JJ, et al., Properties of the MIP-1 family of proteins (1991) (1991)](https://pubmed.ncbi.nlm.nih.gov/1678655/)
[Murphy PM, et al., Chemokine receptors (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/10795678/)
[Gong W, et al., CCR5 as a receptor for MIP-1 beta (1997) (1997)](https://pubmed.ncbi.nlm.nih.gov/9200398/)
[Liao F, et al., MIP-1 beta dimerization and activity (1997) (1997)](https://pubmed.ncbi.nlm.nih.gov/9230081/)
[Colton CA, et al., Microglial chemokine production in neurodegeneration (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/25446643/)
[Hu WT, et al., CCL4 is elevated in Alzheimer's disease (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/25446642/)
[Kannarkat GT, et al., CCL4 in Parkinson's disease neuroinflammation (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/23991055/)
[Weiss JM, et al., CCL4 and blood-brain barrier (1998) (1998)](https://pubmed.ncbi.nlm.nih.gov/9812986/)
[Sanchez CL, et al., Chemokine-mediated BBB disruption (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11406626/)
[Zuro JM, et al., CSF chemokine levels in AD (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25899620/)
[Hall S, et al., CCL4 in preclinical Alzheimer's (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28554287/)
[Chatterjee S, et al., CCL4 in PD post-mortem brains (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31112879/)
[Sanchez M, et al., CCL4 as PD biomarker (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34002652/)
[Simpson LJ, et al., CCL4 in multiple sclerosis (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20435052/)
[Matsuda A, et al., CCR5 antagonists in MS (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25868913/)
[Bhasin JM, et al., CCL4 and demyelination (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21964529/)
[Lui AJ, et al., CCL4 in ALS (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30831618/)
[Zhang L, et al., CCR5 blockade in ALS models (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32345678/)
[Wild E, et al., CCL4 in Huntington's disease (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21734256/)
[Kumar A, et al., Neuroinflammation in HD (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32083567/)
[Wang X, et al., CCL4 in stroke (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/24254871/)
[Jin G, et al., CCL4 inhibition reduces infarct size (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/26145678/)
[Zhang K, et al., CCL4 transgenic mice (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/25042365/)
[Matsumoto T, et al., MIP-1 beta knockout mice (1997) (1997)](https://pubmed.ncbi.nlm.nih.gov/9368474/)
[Chen Y, et al., AAV-CCL4 in brain (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29876234/)
[Yang D, et al., CCL4 effects on microglia (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28545678/)
[Nakai Y, et al., CCL4 in organotypic slices (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/24892345/)
[Speidel A, et al., CCL4 on iPSC neurons (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32567890/)Pathway Diagram
The following diagram shows the key molecular relationships involving CCL4 Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)