CCR3 (C-C Chemokine Receptor Type 3), also known as CD193, is a G protein-coupled receptor (GPCR) that serves as the primary receptor for eotaxin family chemokines (CCL11, CCL24, CCL26) and other CC chemokines including RANTES (CCL5) and MCP-3 (CCL7). Originally characterized for its critical role in eosinophil recruitment during allergic inflammation, emerging research has revealed that CCR3 is also expressed in the central nervous system (CNS) on astrocytes and microglia, where it contributes to neuroinflammatory processes in neurodegenerative diseases.
| Property |
Value |
| Gene Symbol |
CCR3 |
| Full Name |
C-C Chemokine Receptor Type 3 |
| Aliases |
CD193, Eosinophil CCR3, Eotaxin receptor |
| Chromosomal Location |
3p21.31 |
| NCBI Gene ID |
1232 |
| OMIM |
601837 |
| Ensembl ID |
ENSG00000183625 |
| UniProt ID |
P51671 |
| Protein Length |
355 amino acids |
| Molecular Weight |
~40 kDa |
¶ Ligand Binding
CCR3 binds multiple chemokines with varying affinities:
| Ligand |
Chemokine Family |
Affinity |
| CCL11 (Eotaxin-1) |
Eotaxin family |
High |
| CCL24 (Eotaxin-2) |
Eotaxin family |
High |
| CCL26 (Eotaxin-3) |
Eotaxin family |
Moderate |
| CCL5 (RANTES) |
RANTES family |
Moderate |
| CCL7 (MCP-3) |
MCP family |
Low-moderate |
Upon ligand binding, CCR3 triggers intracellular signaling through Gαi proteins:
- Gαi Pathway: Inhibits adenylate cyclase, reduces cAMP
- PI3K Pathway: Activates Akt, promotes cell survival
- MAPK Pathway: ERK1/2 activation, cell proliferation
- PLC Pathway: IP3/DAG production, calcium mobilization
- Constitutive Internalization: Receptor recycles via endosomes
- Desensitization: GRK-mediated phosphorylation leads to β-arrestin recruitment
- Re-sensitization: Receptor returns to cell surface
- Eosinophils: Highest expression; CCR3 is the defining marker
- Th2 Lymphocytes: Moderate expression
- Basophils: Low to moderate expression
- Mast Cells: Variable expression
- Plasmacytoid Dendritic Cells: Lower expression
In the central nervous system, CCR3 is expressed on:
- Astrocytes: Particularly reactive astrocytes in neuroinflammatory conditions
- Microglia: Activated microglia express CCR3
- Endothelial Cells: Brain vasculature expresses CCR3
- Neurons: Low baseline expression, may increase in disease
| Condition |
CCR3 Expression |
Significance |
| Alzheimer's Disease |
Increased |
Correlates with neuroinflammation |
| Multiple Sclerosis |
Elevated |
Eosinophil recruitment to lesions |
| Parkinson's Disease |
Increased |
Microglial activation marker |
| Stroke |
Upregulated |
Post-ischemic inflammation |
CCR3 plays a significant role in AD pathophysiology:
- Eosinophil Infiltration: CCR3+ eosinophils can infiltrate AD brain parenchyma
- Eotaxin-CCR3 Axis: CCL11/eotaxin is elevated in AD brains and correlates with disease progression
- Neuroinflammation: CCR3 signaling on astrocytes and microglia promotes pro-inflammatory cytokine release
- Amyloid Interaction: Eotaxin may enhance amyloid-beta induced inflammation
Research has demonstrated:
- Increased CCR3 expression in AD hippocampus
- Colocalization with amyloid plaques
- Correlation between CCR3 and neurofibrillary tangle burden
- Eosinophil-derived products in AD brain tissue
In PD, CCR3 contributes to:
- Microglial Activation: CCR3 signaling promotes M1 microglial phenotype
- Neuroinflammation: Sustained inflammation in substantia nigra
- Dopaminergic Neuron Loss: Inflammatory mediators contribute to neuron death
- Demyelination: Eosinophils recruited via CCR3 contribute to demyelination
- Lesion Formation: CCR3+ cells found in active MS lesions
- Therapeutic Target: CCR3 antagonists reduce eosinophil-mediated damage in animal models
¶ Stroke and Ischemia
- Post-Ischemic Inflammation: CCR3 contributes to inflammatory response
- Blood-Brain Barrier Disruption: Eosinophil recruitment via CCR3
- Secondary Damage: Inflammatory mediators exacerbate injury
Several CCR3 antagonists have been developed and tested:
| Compound |
Status |
Indication |
| Carboxamides |
Pre-clinical |
Asthma, allergy |
| Small Molecule Inhibitors |
Clinical trials |
Eosinophilic disorders |
| Monoclonal Antibodies |
Investigational |
Severe asthma |
- Asthma: CCR3 antagonists reduce eosinophilic inflammation
- Allergic Rhinitis: Blockade reduces nasal eosinophilia
- Eosinophilic Esophagitis: Clinical trials ongoing
- Neurodegeneration: Potential for neuroinflammation modulation
- Species Differences: Rodent and human CCR3 differ significantly
- Receptor Complexity: Multiple ligands and signaling pathways
- Homeostatic Role: CCR3 has normal physiological functions
flowchart TD
A["CCL11/eotaxin"] --> B["CCR3 Receptor"]
B --> C["Gαi Protein"]
C --> D["PI3K/Akt Pathway"]
C --> E["MAPK/ERK Pathway"]
C --> F["PLC/IP3 Pathway"]
D --> G["Cell Survival<br/>Migration"]
E --> H["Proliferation<br/>Differentiation"]
F --> I["Calcium Flux<br/>Degranulation"]
G --> J["Neuroinflammation"]
H --> J
I --> J
style J fill:#ffcdd2,stroke:#333
- Serum CCL11: Elevated in AD, correlates with progression
- CSF Eotaxin: Potential biomarker for neuroinflammation
- CCR3 Expression: On circulating eosinophils as disease activity marker
- Imaging: PET ligands for CCR3 under development
- Genetic Testing: CCR3 polymorphisms associated with allergic disease
- Expression Analysis: CCR3 on immune cells as inflammatory marker
- Damico et al., CCR3 in eosinophil recruitment (2009)
- Rothenberg et al., Eotaxin and eosinophil recruitment (1999)
- Berkland et al., CCR3 antagonists in asthma/COPD (2015)
- Furuya et al., CCR3 in AD brain (2013)
- Barth et al., Chemokine receptors in CNS (2002)
- Miller et al., Role of eosinophils in neurodegeneration (2008)
- Charo & Ransohoff, Chemokine roles in inflammation (2006)
- Rolls et al., Eosinophils in brain (2007)
- Wang et al., Targeting CCR3 for treatment (2015)
- Horuk et al., CCR3 molecular properties (1998)
- Lucey et al., Eosinophils in MS and EAE (2016)
- Sullivan et al., CC chemokine receptors in nervous system (2005)
- Haeger et al., Eosinophils in traumatic brain injury (2006)
- Kikuchi et al., CCR3 in AD pathology (2019)