Disease relevance of C3AR1

• Expression of C3aR and C5aR could also be demonstrated on pDC in lesions of cutaneous lupus erythematosus and allergic contact dermatitis [1].
• Site-directed C3a receptor antibodies from phage display libraries [2].
• However, a strong C3aR staining was evident in areas of inflammation in multiple sclerosis and bacterial meningitis [3].
• In meningitis, C3aR was abundantly expressed by reactive astrocytes, microglia, and infiltrating cells (macrophages and neutrophils) [3].
• A functional response with the anaphylatoxin C3a receptor in oocytes was dependent on co-injection of a pertussis toxin sensitive complementary human factor which could be supplied by co-injection of total RNA isolated from U937 cells [4].

High impact information on C3AR1

• The functions of glial-cell C3a and C5a receptors (C3aR and C5aR) appear to be similar to immune-cell C3aRs and C5aRs [5].
• It is unclear whether neutrophils also express the C3aR, but need a costimulus provided by eosinophils for certain biological responses, or whether neutrophils lack the C3aR and respond to C3a via a secondary stimulus generated by eosinophils, i.e., by an indirect mode [6].
• Flow cytometric analyses, functional assays, and binding assays on highly purified neutrophils confirmed C3aR expression and coupling [6].
• The expression of the C3aR on eosinophils could be confirmed [6].
• The human C3a receptor is expressed on neutrophils and monocytes, but not on B or T lymphocytes [6].

Chemical compound and disease context of C3AR1

• To determine if C3a is an essential mediator of systemic anaphylaxis, the anaphylactic response to ovalbumin (OA) was assessed in guinea pigs genetically deficient in the C3a receptor (C3aR-) compared to their control strain of animals which were C3a receptor positive (C3aR+) [7].

Biological context of C3AR1

• Third, enhancement of chemotaxis of hemopoietic cells is also mediated by C3a-desArg, which does not bind to C3aR [8].
• During complement activation the pro-inflammatory anaphylatoxins C3a and C5a are generated, which interact with the C3a receptor and C5a receptor (CD88), respectively [9].
• A panel of anti-C3aR single chain Fv fragments (scFvs) was selected after four rounds of panning using the second extracellular loop of the C3aR, fused to the maltose binding protein as Ag [2].
• When expressed in rat basophilic leukemia cells and exposed to C3a, the C3aR underwent rapid (t(1/2) approximately 15 s), dose-dependent (EC50 approximately 10 nM) and reversible phosphorylation by a kinase refractory to the effects of PKC inhibitors [10].
• A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells which had been differentiated with dibutyryl cAMP to a macrophage-like phenotype [11].

Anatomical context of C3AR1

• C3aR internalization could also be induced by PMA, an activator of protein kinase C. Similarly, monocytes, the human mast cell line HMC-1, and differentiated monocyte/macrophage-like U937-cells exhibited rapid agonist-dependent receptor internalization [12].
• Within minutes of C3a addition to human granulocytes, C3aR almost completely disappeared from the cell surface [12].
• The C3a receptor (C3aR) is expressed on most human peripheral blood leukocytes with the exception of resting lymphocytes, implying a much higher pathophysiological relevance of the anaphylatoxin C3a as a proinflammatory mediator than previously thought [12].
• Complement C3a enhances CXCL12 (SDF-1)-mediated chemotaxis of bone marrow hematopoietic cells independently of C3a receptor [8].
• Thus, immature pDC represent another type of antigen-presenting cell that express C3aR and C5aR, and respond to anaphylatoxins with chemotaxis [1].

Associations of C3AR1 with chemical compounds

• We report that normal human CD34(+) cells and lineage-differentiated hematopoietic progenitors express the complement anaphylatoxin C3a receptor (C3aR) and respond to C3a [13].
• Second, the competitive C3aR inhibitor SB290157 does not affect C3a-mediated enhancement of CXCL12-induced chemotaxis [8].
• Recent studies have provided evidence that C3, C3a receptor, and C5 are linked to airway hyperresponsiveness [14].
• Sulfation of tyrosine 174 in the human C3a receptor is essential for binding of C3a anaphylatoxin [15].
• SB 290157 was a functional antagonist, blocking C3a-induced C3aR internalization in a concentration-dependent manner and C3a-induced Ca(2+) mobilization in RBL-C3aR cells and human neutrophils with IC(50)s of 27.7 and 28 nM, respectively [16].

Physical interactions of C3AR1

• Freshly isolated or cultured dermal CD1a+ and CD83+ DC bound anti-C5aR and anti-C3aR monoclonal antibodies (mAbs), as detected by flow cytometry [17].
• Identification of ligand effector binding sites in transmembrane regions of the human G protein-coupled C3a receptor [18].

Regulatory relationships of C3AR1

• C3aR internalization is a rapid negative control mechanism and is influenced by the C5aR pathway [12].
• Neither C5a nor FMLP stimulated any cross-internalization of the C3aR [12].
• For U937 cells, IFN-gamma and Bt2cAMP up-regulated the C3aR to the same extent, whereas Bt2cAMP was 20-fold more effective in C5aR induction [19].

Other interactions of C3AR1

• Chimeras were generated between the human anaphylatoxin C3a and C5a receptors (C3aR and C5aR, respectively) to define the structural requirements for ligand binding and discrimination [20].
• On the contrary, costimulation of granulocytes with C5a, but not FMLP, drastically decreased C3aR internalization [12].
• A novel computational method for predicting the transmembrane structure of G-protein coupled receptors: application to human C5aR and C3aR [21].
• Unlike CD88 and C3a receptor, C5L2 transfected into RBL-2H3 cells does not support degranulation or increases in intracellular [Ca(2+)] and is not rapidly internalized in response to ligand binding [22].
• Some of them (CTCE, C3a receptor agonist and GrobetaT) are still subject of pre-clinical development, others, such as chemokine receptor ligand AMD3100, have recently been introduced in clinical trials and already deliver promising results [23].

Analytical, diagnostic and therapeutic context of C3AR1

• First, human BM CD34(+) and B lineage cells do not express C3aR by flow cytometry [8].
• Molecular cloning and characterization of the human anaphylatoxin C3a receptor [24].
• Flow cytometrical analysis and RT-PCR revealed that the C3a receptor is constitutively expressed on human eosinophils [25].
• C3aR is highly expressed in normal human and murine kidney, as demonstrated by immunohistochemistry and in situ hybridization [26].
• Immunofluorescence studies showed C3aR expression on polymorphonuclear granulocytes and monocytes, but not on lymphocytes [2].

References