Details for: C5AR2

Gene ID: 27202

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: C5AR2

Ensembl ID: ENSG00000134830

Description: complement C5a receptor 2

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • elicited macrophage CL0000861
    CSI 2.87
    rCSI 2.63%
    PRS 97.38
  • endothelial cell of pericentral hepatic sinusoid CL0019022
    CSI 2.65
    rCSI 8.18%
    PRS 95.27
  • Kupffer cell CL0000091
    CSI 2.44
    rCSI 5.57%
    PRS 95.42
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 2.42
    rCSI 1.86%
    PRS 96.7
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI 2.24
    rCSI 2.93%
    PRS 98.1
  • mononuclear phagocyte CL0000113
    CSI 1.95
    rCSI 4.29%
    PRS 96.34
  • intermediate monocyte CL0002393
    CSI 1.67
    rCSI 2.52%
    PRS 97.22
  • lung macrophage CL1001603
    CSI 1.44
    rCSI 3.22%
    PRS 97.56
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 1.43
    rCSI 1.73%
    PRS 97.4
  • colon macrophage CL0009038
    CSI 1.4
    rCSI 6.46%
    PRS 98.26
  • alveolar macrophage CL0000583
    CSI 1.37
    rCSI 2.26%
    PRS 95.6

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
    • Medium
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    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [C5AR2](/details-gene/27202), or Complement C5a Receptor 2, is a G protein-coupled receptor that functions as a key component of the innate immune system. While it binds the potent anaphylatoxin C5a, its signaling capacity and precise function have been a subject of investigation, with some evidence suggesting it acts as a modulator or decoy receptor for C5a signaling through the canonical C5aR1 receptor ([Link](https://doi.org/10.1074/jbc.c100714200)). It has also been identified as a functional receptor for acylation-stimulating protein (ASP), implicating it in lipid metabolism ([Link](https://doi.org/10.1074/jbc.m406921200)). **Overall**, expression data reveals that [C5AR2](/details-gene/27202) is predominantly expressed in cells of the mononuclear phagocyte system, including various populations of [macrophages](/details-cell/CL0000861) and [monocytes](/details-cell/CL0002396), positioning it as a critical regulator of inflammatory and chemotactic responses in these sentinel immune cells. ## Cellular Roles and Expression Landscape The expression profile of [C5AR2](/details-gene/27202) strongly associates it with the myeloid lineage, particularly professional phagocytes. **Overall**, the gene shows the highest significance in [elicited macrophage](/details-cell/CL0000861) (CSI: 2.87), liver-resident [Kupffer cell](/details-cell/CL0000091) (CSI: 2.44), and both non-classical [CD14-low, CD16-positive monocyte](/details-cell/CL0002396) (CSI: 2.42) and intermediate [CD14-positive, CD16-positive monocyte](/details-cell/CL0002397) (CSI: 2.24). This pattern is extended to other macrophage populations, including [lung macrophage](/details-cell/CL1001603) and [alveolar macrophage](/details-cell/CL0000583), as well as [CD1c-positive myeloid dendritic cell](/details-cell/CL0002399). This widespread expression across key phagocytic cell types underscores its integral role in sensing and responding to complement activation throughout the body. Interestingly, [C5AR2](/details-gene/27202) also shows high significance in [endothelial cell of pericentral hepatic sinusoid](/details-cell/CL0019022) (CSI: 2.65), suggesting a potential function in modulating liver-specific immune surveillance and inflammation at the interface between blood and hepatic tissue. Early studies also reported its expression in immature but not mature dendritic cells, suggesting a role in dendritic cell development or initial antigen presentation events ([Link](https://doi.org/10.1016/s0161-5890(00)00067-5)). ## Pathways and Molecular Function Functionally, [C5AR2](/details-gene/27202) is annotated with `[Complement component c5a receptor activity](/details-go/GO:0004878)`, placing it directly within the `[Complement cascade](/details-reactome/R-HSA-166658)` and the broader `[Innate immune system](/details-reactome/R-HSA-168249)` pathways. Its involvement in the `[Complement receptor mediated signaling pathway](/details-go/GO:0002430)` is consistent with its high expression in myeloid cells, which utilize these pathways for `[Chemotaxis](/details-go/GO:0006935)` and mounting an `[Inflammatory response](/details-go/GO:0006954)`. However, the functional annotations suggest a nuanced, and potentially regulatory, role. [C5AR2](/details-gene/27202) is implicated in the `[Negative regulation of neutrophil chemotaxis](/details-go/GO:0090024)` as well as the negative regulation of key pro-inflammatory cytokines, including `[interleukin-6](/details-go/GO:0032715)` and `[tumor necrosis factor](/details-go/GO:0032720)`. This dual capacity to bind C5a while also dampening certain inflammatory outputs suggests that [C5AR2](/details-gene/27202) may act as a critical checkpoint to prevent excessive inflammation driven by complement activation. ## Research Directions The dual role of [C5AR2](/details-gene/27202) as a receptor for both the inflammatory mediator C5a and the metabolic regulator ASP, combined with its association with cardiovascular and metabolic diseases ([Link](https://doi.org/10.1371/journal.pone.0020984), [Link](https://doi.org/10.1161/01.atv.0000222907.72985.0b)), presents several compelling avenues for future research. **Proposed Hypotheses:** 1. Given its high expression in [Kupffer cell](/details-cell/CL0000091) and sinusoidal endothelial cells, [C5AR2](/details-gene/27202) acts as a metabolic sensor in the liver. Its signaling through the ASP-binding pathway may regulate lipid uptake and inflammatory tone in these cells, and its dysregulation could be a contributing factor to the progression of metabolic-associated fatty liver disease (MAFLD). 2. The negative regulatory functions associated with [C5AR2](/details-gene/27202) suggest it functions as a "braking" mechanism on macrophages during acute inflammation. In chronic inflammatory diseases, reduced [C5AR2](/details-gene/27202) expression or signaling on tissue-resident macrophages may lead to unresolved inflammation and persistent tissue damage. **Experimental Approach:** To test the first hypothesis regarding its role in MAFLD, a conditional knockout mouse model would be highly informative. *C5ar2* could be selectively deleted in myeloid cells (using Lyz2-Cre) or liver sinusoidal endothelial cells (using Stab2-Cre). These mice, along with wild-type controls, would be subjected to a diet-induced MAFLD model (e.g., a high-fat, high-fructose diet). The development of steatosis, inflammation (lobular inflammation, ballooning), and fibrosis would be assessed by histology and serum markers (e.g., ALT, AST). Furthermore, single-cell RNA sequencing of liver non-parenchymal cells from these models would allow for detailed characterization of the transcriptional changes in [Kupffer cells](/details-cell/CL0000091) and endothelial cells, specifically examining pathways related to lipid metabolism and inflammatory signaling. **Therapeutic Potential:** As a cell-surface G protein-coupled receptor, [C5AR2](/details-gene/27202) is an accessible and attractive therapeutic target. Its potential, however, is complex. In conditions characterized by excessive complement-driven inflammation, a small molecule agonist that enhances its negative regulatory functions could serve as a novel anti-inflammatory therapy. Conversely, in metabolic diseases where ASP-mediated signaling via [C5AR2](/details-gene/27202) may be pathogenic, a specific antagonist could be beneficial. The development of biased agonists or antagonists that selectively trigger either the anti-inflammatory or metabolic pathways could offer a sophisticated approach to treating a range of diseases from sepsis to coronary artery disease.

Genular Protein ID: 624307845

Symbol: C5AR2_HUMAN

Name: C5a anaphylatoxin chemotactic receptor 2

UniProtKB Accession Codes:

Q9P296 B2RA09

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 7 Ensembl 2 GO 14 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRINTS 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 4 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 11090875

Title: A putative chemoattractant receptor, C5L2, is expressed in granulocyte and immature dendritic cells, but not in mature dendritic cells.

PubMed ID: 11090875

DOI: 10.1016/s0161-5890(00)00067-5

PubMed ID: 11165367

Title: Identification of four novel human G protein-coupled receptors expressed in the brain.

PubMed ID: 11165367

DOI: 10.1016/s0169-328x(00)00242-4

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 11773063

Title: The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des Arg(74).

PubMed ID: 11773063

DOI: 10.1074/jbc.c100714200

PubMed ID: 12540846

Title: The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg77/acylation-stimulating protein.

PubMed ID: 12540846

DOI: 10.1074/jbc.m206169200

PubMed ID: 15833747

Title: C5L2 is a functional receptor for acylation-stimulating protein.

PubMed ID: 15833747

DOI: 10.1074/jbc.m406921200

PubMed ID: 19615750

Title: C5a- and ASP-mediated C5L2 activation, endocytosis and recycling are lost in S323I-C5L2 mutation.

PubMed ID: 19615750

DOI: 10.1016/j.molimm.2009.06.007

PubMed ID: 16627811

Title: Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia.

PubMed ID: 16627811

DOI: 10.1161/01.atv.0000222907.72985.0b

PubMed ID: 21698200

Title: Relationship between a novel polymorphism of the C5L2 gene and coronary artery disease.

PubMed ID: 21698200

DOI: 10.1371/journal.pone.0020984

Sequence Information:

  • Length: 337
  • Mass: 36080
  • Checksum: 53AF41B129FE8FE6
  • Sequence:
    • MGNDSVSYEY GDYSDLSDRP VDCLDGACLA IDPLRVAPLP LYAAIFLVGV PGNAMVAWVA 
GKVARRRVGA TWLLHLAVAD LLCCLSLPIL AVPIARGGHW PYGAVGCRAL PSIILLTMYA 
SVLLLAALSA DLCFLALGPA WWSTVQRACG VQVACGAAWT LALLLTVPSA IYRRLHQEHF 
PARLQCVVDY GGSSSTENAV TAIRFLFGFL GPLVAVASCH SALLCWAARR CRPLGTAIVV 
GFFVCWAPYH LLGLVLTVAA PNSALLARAL RAEPLIVGLA LAHSCLNPML FLYFGRAQLR 
RSLPAACHWA LRESQGQDES VDSKKSTSHD LVSEMEV