CCR3

Official Full Name

C-C motif chemokine receptor 3

Organism

Homo sapiens

GeneID

1232

Background

The protein encoded by this gene is a receptor for C-C type chemokines. It belongs to family 1 of the G protein-coupled receptors. This receptor binds and responds to a variety of chemokines, including eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). It is highly expressed in eosinophils and basophils, and is also detected in TH1 and TH2 cells, as well as in airway epithelial cells. This receptor may contribute to the accumulation and activation of eosinophils and other inflammatory cells in the allergic airway. It is also known to be an entry co-receptor for HIV-1. This gene and seven other chemokine receptor genes form a chemokine receptor gene cluster on the chromosomal region 3p21. Alternatively spliced transcript variants have been described. [provided by RefSeq, Sep 2009]

Synonyms

CKR3; CD193; CKR 3; CMKBR3; C C CKR3; CC-CKR-3;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

MTTSLDTVETFGTTSYYDDVGLLCEKADTRALMAQFVPPLYSLVFTVGLLGNVVVVMILIKYRRLRIMTNIYLLNLAISDLLFLVTLPFWIHYVRGHNWVFGHGMCKLLSGFYHTGLYSEIFFIILLTIDRYLAIVHAVFALRARTVTFGVITSIVTWGLAVLAALPEFIFYETEELFEETLCSALYPEDTVYSWRHFHTLRMTIFCLVLPLLVMAICYTGIIKTLLRCPSKKKYKAIRLIFVIMAVFFIFWTPYNVAILLSSYQSILFGNDCERSKHLDLVMLVTEVIAYSHCCMNPVIYAFVGERFRKYLRHFFHRHLLMHLGRYIPFLPSEKLERTSSVSPSTAEPELSIVF

Open

Disease

Asthma, Parkinsonism, Vasomotor/allergic rhinitis

Approved Drug

Clinical Trial Drug

4 +

Discontinued Drug

3 +

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Detailed Information

CCR3 (C-C Motif Chemokine Receptor 3) is located at chromosome 3p21.31, forming a gene cluster with CCR1, CCR2, and CCR5. The CCR3 protein consists of 355 amino acids and shares 56% sequence homology with CCR1; however, its ligand specificity differs markedly. CCR3 selectively binds eosinophil-attracting chemokines such as CCL11 (eotaxin-1), CCL24 (eotaxin-2), and CCL26 (eotaxin-3). Expression is highest on eosinophils (>50,000 receptors per cell) and is also detected on basophils, Th2 cells, and epithelial cells. Transcriptional regulation involves GATA-1 and STAT6 binding to the CCR3 promoter, with IL-4 and IL-13 upregulating CCR3 expression via STAT6 signaling.

Figure 1. CCL26 binds CCR3 to promote inflammation and blood-brain barrier disruption in EAE, suggesting a pathogenic role in multiple sclerosis. (Shou J, et al., 2019)

Biological Functions and Pathological Mechanisms

CCR3 serves as a central mediator in eosinophilic inflammation:

Eosinophil (EOS) Directed Migration: Activation of CCR3 by ligands CCL11 and CCL26 triggers the Gαi-PLCβ-Ca²⁺ signaling cascade, inducing actin polymerization and promoting eosinophil migration to allergic inflammation sites. Bronchoalveolar lavage fluid from asthmatic patients contains CCL11 at levels three times higher than healthy controls, positively correlating with eosinophil counts.
EOS Maturation and Survival: CCR3 knockout mouse models reveal a 40% reduction in eosinophil proliferation (P < 0.01), a 25% increase in apoptosis, and decreased expression of degranulation proteins such as eosinophil cationic protein (ECP) and major basic protein (MBP), confirming CCR3’s role in maintaining eosinophil activation.
Dual Role in Tumor Biology: CCR3 is upregulated in breast cancer tissues (TCGA data, P < 0.01). Eosinophil recruitment via CCR3 promotes epithelial-mesenchymal transition (EMT) through TGF-β secretion. Paradoxically, patients with high CCR3 expression exhibit better recurrence-free survival, suggesting eosinophils may enhance anti-tumor immunity through antigen presentation.

In allergic diseases, the CCR3-CCL11/CCL26 axis amplifies inflammation: eosinophil infiltration releases MBP, damaging airway epithelium, and upregulates adhesion molecules such as VCAM-1, creating a positive feedback loop exacerbating tissue edema and remodeling.

Clinical Translation and Therapeutic Applications

Therapeutic strategies targeting CCR3 include antagonists and gene modulation:

Small Molecule Antagonists: Emodin, a natural compound, acts as a CCR3 antagonist with an IC₅₀ of 27.28 μM, blocking CCL26-induced calcium influx. Synthetic compound SB297006 (Phase II) significantly reduced pruritus scores in atopic dermatitis patients, achieving a 62% EASI-50 response rate.
Antibodies and Biologics: Bertilimumab, an anti-CCL11 monoclonal antibody, reduced eosinophil infiltration in eosinophilic esophagitis by 50% in Phase II trials. Omalizumab (anti-IgE) indirectly downregulates CCR3 expression; combined with rapid immunotherapy (RIT), it decreases systemic adverse events in allergic patients by 80%.
Gene Therapy: Lentiviral vector-mediated CCR3-shRNA transfection into mast cells reduces receptor expression by 70%, representing a potential intervention for allergic rhinitis.

Challenges and Emerging Directions

CCR3-targeted therapy faces tissue-specific paradoxes: inhibition is required in asthma but preservation of potential anti-tumor effects is desirable in breast cancer. Potential solutions include:

Development of allosteric modulators that selectively block migration pathways while sparing apoptosis induction;
Tissue-targeted delivery systems, such as inhaled antagonists for respiratory diseases.

Moreover, receptor heterodimerization (e.g., CCR3/CCR1) may contribute to drug resistance. Dual receptor antagonists like AZD-2098 are currently under preclinical evaluation.

Reference

Bertrand CP, Ponath PD. CCR3 blockade as a new therapy for asthma. Expert Opin Investig Drugs. 2000 Jan;9(1):43-52.
Gangur V, Birmingham NP, Thanesvorakul S, et al. CCR3 and CXCR3 as drug targets for allergy: principles and potential. Curr Drug Targets Inflamm Allergy. 2003 Mar;2(1):53-62.
Erin EM, Williams TJ, Barnes PJ, et al. Eotaxin receptor (CCR3) antagonism in asthma and allergic disease. Curr Drug Targets Inflamm Allergy. 2002 Jun;1(2):201-14.
Willems LI, Ijzerman AP. Small molecule antagonists for chemokine CCR3 receptors. Med Res Rev. 2010 Sep;30(5):778-817.
Shou J, Peng J, Zhao Z, et al. CCL26 and CCR3 are associated with the acute inflammatory response in the CNS in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2019 Aug 15;333:576967.

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