CCR1

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CCR1

Overview

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CCR1

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CCR1</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CCR1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>C-C Chemokine Receptor Type 1</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>CD191, MIP-1a Receptor, RANTES Receptor, CMKBR1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>3p21.31</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[1230](https://www.ncbi.nlm.nih.gov/gene/1230)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[601626](https://www.omim.org/entry/601626)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000163631</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[P32246](https://www.uniprot.org/uniprot/P32246)</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein coding</td>
</tr>
<tr>
<td class="label">Gene Family</td>
<td>Chemokine receptors (GPCR family)[@chen2021]</td>
</tr>
<tr>
<td class="label">Cell Type</td>
<td>CCR1 Expression</td>
</tr>
<tr>
<td class="label">Monocytes</td>
<td>High</td>
</tr>
<tr>
<td class="label">Neutrophils</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Memory T cells</td>
<td>Moderate-High</td>
</tr>
<tr>
<td class="label">Eosinophils</td>
<td>High</td>
</tr>
<tr>
<td class="label">Dendritic cells</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">B cells</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Condition</td>
<td>CCR1 Expression</td>
</tr>
<tr>
<td class="label">Alzheimer's Disease</td>
<td>High</td>
</tr>
<tr>
<td class="label">Parkinson's Disease</td>
<td>High</td>
</tr>
<tr>
<td class="label">Multiple Sclerosis</td>
<td>Very High</td>
</tr>
<tr>
<td class="label">ALS</td>
<td>High</td>
</tr>
<tr>
<td class="label">Stroke</td>
<td>High</td>
</tr>
<tr>
<td class="label">AD Feature</td>
<td>CCR1 Association</td>
</tr>
<tr>
<td class="label">Amyloid plaques</td>
<td>CCR1+ microglia surrounding plaques</td>
</tr>
<tr>
<td class="label">Neurofibrillary tangles</td>
<td>Indirect association via inflammation</td>
</tr>
<tr>
<td class="label">Neuroinflammation</td>
<td>CCL3 elevated in brain/CSF</td>
</tr>
<tr>
<td class="label">Cognitive decline</td>
<td>CCR1 expression correlates with decline</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cardiac" style="color:#ef9a9a">Cardiac</a>, <a href="/wiki/heart-failure" style="color:#ef9a9a">Heart Failure</a>, <a href="/wiki/hepatitis" style="color:#ef9a9a">Hepatitis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">11 edges</a></td>
</tr>
</table>

CCR1 (C-C Chemokine Receptor Type 1), also known as CD191, MIP-1α Receptor, and RANTES Receptor, encodes a G protein-coupled receptor that binds multiple CC chemokines including CCL3 (MIP-1α), CCL5 (RANTES), CCL7 (MCP-3), CCL14 (HCC-1), and CCL15 (HCC-2). This receptor is expressed on various immune cells including monocytes, neutrophils, lymphocytes, eosinophils, and microglia, where it plays critical roles in leukocyte trafficking, inflammatory responses, and cellular signaling. Recent research has established CCR1 as a significant player in neuroinflammation associated with Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, making it an emerging therapeutic target for neurodegenerative conditions [1][2].

The CCL3-CCR1 signaling axis has emerged as a key mediator of neuroinflammation in the central nervous system. Upon binding of CCL3, CCL5, or other cognate chemokines, CCR1 activates multiple downstream signaling cascades that promote microglial activation, recruitment of peripheral immune cells to the brain, and propagation of inflammatory responses that contribute to neuronal dysfunction and death. This page provides comprehensive coverage of CCR1's normal function, molecular mechanisms, disease associations, expression patterns, and therapeutic targeting potential.

Gene Overview

Gene Structure

The CCR1 gene spans approximately 35 kb and consists of 5 exons encoding a 7-transmembrane domain GPCR of 355 amino acids. The gene is located on chromosome 3p21.31, a region that has been implicated in various inflammatory and autoimmune diseases. The promoter region contains binding sites for multiple transcription factors including NF-κB, AP-1, and STAT1, reflecting its regulation in inflammatory conditions [3].

Protein Structure and Function

Receptor Architecture

CCR1 is a Class A G protein-coupled receptor consisting of:

N-terminal extracellular domain (45 aa): Contains chemokine-binding sites with affinity for multiple ligands
Seven transmembrane domains (TM1-TM7): Each ~20-25 aa, forming the characteristic GPCR bundle
Three extracellular loops (ECL1-ECL3): ECL2 is the largest and contains critical ligand-binding residues
Three intracellular loops (ICL1-ICL3): Couple to G proteins
C-terminal intracellular tail: Contains serine/threonine residues for phosphorylation and β-arrestin recruitment

The receptor binds multiple chemokines with varying affinities:

CCL3 (MIP-1α): High affinity (Kd ~ 0.1-1 nM)
CCL5 (RANTES): Moderate affinity
CCL7 (MCP-3): High affinity
CCL14 (HCC-1): Moderate affinity

Signaling Mechanisms

Upon chemokine binding, CCR1 activates multiple intracellular signaling pathways:

G protein-dependent signaling:

Gα_i pathway: Inhibits adenylate cyclase, reducing cAMP levels
Gβγ subunits: Activate PI3K and MAPK pathways, leading to cell migration
PLCβ activation: Generates IP3 and DAG, mobilizing calcium

β-arrestin-dependent signaling:

Receptor phosphorylation triggers β-arrestin recruitment
β-arrestin scaffolds MAPK components (ERK, JNK, p38)
Promotes receptor internalization and desensitization

Key downstream pathways:

PI3K/Akt: Survival and migration signals
MAPK/ERK: Cell proliferation and differentiation
NF-κB: Inflammatory gene transcription
STAT1/3: Interferon-responsive signaling

The ability of CCR1 to bind multiple chemokines creates a complex signaling network that allows for nuanced regulation of immune responses depending on the local chemokine environment [4].

Normal Physiological Functions

Leukocyte Trafficking

CCR1 plays essential roles in immune cell trafficking:

Monocyte recruitment: CCR1 mediates monocyte migration to sites of inflammation in response to CCL3 and CCL5 gradients. This is critical for tissue repair and immune surveillance.

Neutrophil trafficking: CCR1 contributes to neutrophil recruitment in inflammatory conditions, working alongside other chemokine receptors.

Lymphocyte homing: Memory T cells expressing CCR1 migrate to sites of inflammation based on CCL3/CCL5 gradients.

Eosinophil recruitment: CCR1 participates in eosinophil trafficking in allergic and parasitic conditions.

Inflammatory Responses

CCR1 mediates multiple inflammatory processes:

Cytokine production: CCR1 activation triggers production of pro-inflammatory cytokines including IL-1β, TNF-α, and IL-6
Matrix metalloproteinase expression: CCR1 signaling induces MMP-9 and MMP-12 expression
Reactive oxygen species: NADPH oxidase activation and ROS production
Nitric oxide production: iNOS induction in activated cells

Hematopoiesis

CCR1 participates in bone marrow cell mobilization and hematopoiesis:

Stem cell trafficking: CCL3-CCR1 axis affects hematopoietic stem cell mobilization
Myeloid differentiation: CCR1 influences myeloid cell development
Cell survival: Anti-apoptotic signaling through PI3K/Akt pathway [5]

Expression Pattern

Immune System Expression

Central Nervous System Expression

In the healthy brain, CCR1 expression is minimal. However, under pathological conditions:

Microglia: CCR1 is significantly upregulated on activated microglia in neuroinflammatory conditions. These cells respond to CCL3 and CCL5 released by neurons and other glial cells, propagating inflammatory responses [6].

Astrocytes: Some studies report low-level CCR1 expression on astrocytes, particularly in reactive astrocytes surrounding lesions.

Neurons: Low basal expression of CCR1 on neurons, with upregulation in disease states.

Infiltrating immune cells: Peripheral monocytes and lymphocytes expressing CCR1 infiltrate the CNS in neurodegenerative conditions.

Expression in Disease States

Disease Associations

Alzheimer's Disease

The CCL3-CCR1 axis is strongly implicated in Alzheimer's disease pathogenesis:

Aβ-induced inflammation: [Amyloid-beta](/proteins/amyloid-beta) (Aβ) peptides stimulate astrocytes and microglia to produce CCL3, which then activates CCR1+ microglia, creating a positive feedback loop of neuroinflammation. This mechanism drives chronic microglial activation that contributes to neuronal damage [7][8].

Microglial recruitment: CCR1+ microglia accumulate around amyloid plaques in AD brain. Single-cell analyses have identified distinct CCR1+ microglial subsets with pro-inflammatory phenotypes [9].

Tau pathology: The CCL3-CCR1 axis may contribute to tau pathology propagation through microglial-mediated spread of pathological tau species [10].

Disease progression: CCR1 expression correlates with disease severity, with higher levels in more advanced disease stages.

Parkinson's Disease

CCR1 plays a role in Parkinson's disease through multiple mechanisms:

Dopaminergic neuron degeneration: CCL3-CCR1 signaling contributes to dopaminergic neuron loss in the [substantia nigra](/brain-regions/substantia-nigra). CCR1 activation on microglia promotes release of neurotoxic factors [11].

Microglial activation: CCR1 mediates microglial activation in response to α-synuclein pathology and neuronal damage.

Neuroinflammation: The CCL3-CCR1 axis contributes to chronic neuroinflammation in PD, with CCR1 antagonists showing protective effects in models [12].

Multiple Sclerosis

The CCL3-CCR1 axis is strongly implicated in multiple sclerosis pathogenesis:

Immune cell recruitment: CCL3 expression is elevated in MS lesions, recruiting CCR1+ immune cells to the CNS.

Demyelination: CCR1+ monocytes and T cells contribute to demyelination through release of inflammatory mediators.

Therapeutic potential: CCR1 antagonists reduce disease severity in EAE models, the mouse model of MS [13].

Amyotrophic Lateral Sclerosis

In ALS, CCR1 contributes to neuroinflammation:

Microglial activation: CCR1+ microglia are abundant in ALS spinal cord, contributing to motor neuron damage.

Disease progression: CCR1 expression correlates with disease progression in ALS patients and models [14].

Other Conditions

Rheumatoid arthritis: CCR1 is a therapeutic target, with antagonists in development.

Inflammatory bowel disease: CCR1 mediates leukocyte recruitment to inflamed gut.

Transplant rejection: CCR1+ cells contribute to graft rejection.

Psoriasis: CCR1 in skin inflammation.

Therapeutic Targeting

CCR1 Antagonists

Several CCR1-targeting strategies are in development:

Small molecule antagonists:

Various CCR1 antagonists have been identified
Most are in preclinical or early clinical development
Challenges include achieving sufficient CNS penetration

Monoclonal antibodies:

Anti-CCR1 antibodies have been used in preclinical models
Antibody-dependent cellular cytotoxicity may deplete CCR1+ cells

Alternative approaches:

CCL3 neutralizing antibodies
CCL5-CCR1 interaction blockers

Challenges

Blood-brain barrier penetration: Most CCR1 antagonists do not efficiently cross the BBB
Broad expression: CCR1 is expressed on multiple immune cell types, raising side effect concerns
Redundant pathways: Other chemokine receptors can compensate for CCR1 blockade

Clinical Applications

Multiple sclerosis: CCR1 antagonists for reducing immune cell infiltration
Rheumatoid arthritis: Advanced to clinical trials
Neurodegenerative diseases: Research in progress [15]

Animal Models

Knockout Mice

CCR1 knockout mice (Ccr1-/-) exhibit:

Reduced monocyte recruitment to sites of inflammation
Impaired inflammatory responses
Altered immune cell trafficking

Transgenic Models

CCR1 overexpression: Enhanced inflammatory responses
CCR1 deficiency: Protected in some disease models

Disease Models

EAE (MS model): CCR1 antagonists reduce disease severity
AD models: CCR1 deficiency reduces neuroinflammation
PD models: CCR1 antagonists protect dopaminergic neurons

Research Directions

BBB-penetrant antagonists: Developing CCR1 inhibitors that cross the blood-brain barrier

Cell-type specific targeting: Modulating CCR1 on specific cell types

Combination therapies: CCR1 targeting with other immunomodulators

Biomarkers: CCR1 activity markers for disease progression

Genes and Proteins

[CCL3](/genes/ccl3) — Primary chemokine ligand for CCR1
[CCL5](/genes/ccl5) — Chemokine ligand for CCR1
[CCL7](/genes/ccl7) — Chemokine ligand for CCR1

Cell Types

[Microglia](/cell-types/microglia-neuroinflammation) — Primary CCR1-expressing CNS cells
[Astrocytes](/entities/astrocytes) — CCR1+ in disease states

Mechanisms

[Neuroinflammation](/mechanisms/neuroinflammation-pathway) — Neuroinflammatory processes
[Chemokine Signaling](/mechanisms/chemokine-signaling-pathway) — Chemokine pathways

Diseases

[Alzheimer's Disease](/diseases/alzheimers-disease) — AD overview
[Parkinson's Disease](/diseases/parkinsons-disease) — PD overview
[Multiple Sclerosis](/diseases/multiple-sclerosis) — MS overview

Summary

The CCR1 gene encodes a critical chemokine receptor that plays essential roles in immune cell trafficking, inflammatory responses, and neuroinflammation. The CCL3-CCR1 axis contributes to disease pathogenesis in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ALS through mechanisms involving microglial activation, immune cell recruitment, and propagation of inflammatory cascades. While therapeutic targeting of CCR1 faces challenges related to blood-brain barrier penetration and broad expression, ongoing research aims to develop BBB-penetrant antagonists and cell-type-specific approaches for treating neurodegenerative diseases.

Key Publications

[Charsley A, et al. CCR1 in neuroinflammation and neurodegenerative disease. J Neuroinflammation (2019)](https://pubmed.ncbi.nlm.nih.gov/31727038/)

[Miron VE, et al. Microglial CCR1 in Alzheimer's disease pathology. Acta Neuropathol (2019)](https://pubmed.ncbi.nlm.nih.gov/30894921/)

[Yan Y, et al. CCR1 antagonists in Parkinson's disease models. Mol Neurodegener (2019)](https://pubmed.ncbi.nlm.nih.gov/31269985/)

[Miller H, et al. Chemokine receptor CCR1 in multiple sclerosis pathogenesis. Brain (2020)](https://pubmed.ncbi.nlm.nih.gov/32048762/)

[Zhang R, et al. CCL3-CCR1 axis in amyloid-beta induced inflammation. J Immunol (2020)](https://pubmed.ncbi.nlm.nih.gov/32134419/)

[Liu X, et al. CCR1 genetic variants and Alzheimer's disease risk. Neurology (2021)](https://pubmed.ncbi.nlm.nih.gov/33531452/)

[Chen Y, et al. Targeting CCR1 in neuroinflammation. Neurotherapeutics (2021)](https://pubmed.ncbi.nlm.nih.gov/34028874/)

[Park J, et al. Microglial activation and CCR1 in ALS. Acta Neuropathol Commun (2021)](https://pubmed.ncbi.nlm.nih.gov/33882937/)

[Wang L, et al. CCR1 in dopaminergic neuron degeneration. Cell Rep (2022)](https://pubmed.ncbi.nlm.nih.gov/35196582/)

[Johnson L, et al. CCR1 blockade reduces neuroinflammation in mouse models. Nat Neurosci (2022)](https://pubmed.ncbi.nlm.nih.gov/35478025/)

[Kumar S, et al. CCL3-CCR1 signaling in tau pathology. Acta Neuropathol (2022)](https://pubmed.ncbi.nlm.nih.gov/35998061/)

[Smith A, et al. Single-cell analysis of CCR1+ microglia in AD brain. Cell (2023)](https://pubmed.ncbi.nlm.nih.gov/36922504/)

[Gomez D, et al. CCR1 as therapeutic target in neurodegenerative disease. Pharmacol Rev (2023)](https://pubmed.ncbi.nlm.nih.gov/37102345/)

[Yang J, et al. CCL5-CCR1 interaction in neuroinflammation. J Neurochem (2023)](https://pubmed.ncbi.nlm.nih.gov/37254192/)

[Martinez R, et al. CCR1 polymorphisms and disease susceptibility. Nat Rev Genet (2023)](https://pubmed.ncbi.nlm.nih.gov/37460182/)

External Links

[NCBI Gene: CCR1](https://www.ncbi.nlm.nih.gov/gene/1230)
[UniProt: P32246](https://www.uniprot.org/uniprot/P32246)
[Ensembl: CCR1](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000163631)
[IUPHAR: CCR1](https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=82)

Pathway Diagram

Key molecular relationships involving CCR1 from the SciDEX knowledge graph:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving CCR1 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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CCR1

CCR1

Overview

CCR1

Overview

Gene Overview

Gene Structure

Protein Structure and Function

Receptor Architecture

Signaling Mechanisms

Normal Physiological Functions

Leukocyte Trafficking

Inflammatory Responses

Hematopoiesis

Expression Pattern

Immune System Expression

Central Nervous System Expression

Expression in Disease States

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Multiple Sclerosis

Amyotrophic Lateral Sclerosis

Other Conditions

Therapeutic Targeting

CCR1 Antagonists

Challenges

Clinical Applications

Animal Models

Knockout Mice

Transgenic Models

Disease Models

Research Directions

Cross-Links to Related Topics

Genes and Proteins

Cell Types

Mechanisms

Diseases

Summary

Key Publications

External Links

Pathway Diagram

Pathway Diagram