Disease relevance of C3ar1

• These data illustrate that C3aR is relevant in experimental lupus nephritis and may be a target for therapeutic intervention in the human disease [1].
• These results confirm that the cloned gene encodes a functional C3aR capable of coupling to a pertussis toxin-sensitive G protein [2].
• These results suggest that C3a-C3aR interactions inhibit the ability of APCs to drive Th2 cell differentiation in response to epicutaneously introduced antigen and may have important implications for allergic skin diseases [3].
• Deletion of the complement anaphylatoxin C3a receptor attenuates, whereas ectopic expression of C3a in the brain exacerbates, experimental autoimmune encephalomyelitis [4].
• Treatment of C5-deficient mice with a C3aR antagonist significantly attenuated airway reactivity, eosinophilia, and mucus production [5].

High impact information on C3ar1

• Here we show that in a murine model of allergic airway disease, genetic deletion of the C3a receptor protects against the changes in lung physiology seen after allergen challenge [6].
• Presentation of OVA peptide by C3aR(-/-) APCs caused significantly more IL-4 and IL-5 secretion by T cells from OVA-T cell receptor (OVA-TCR) transgenic mice compared with presentation by WT APCs [3].
• We used C3aR(-/-) mice to examine the role of C3a in a mouse model of allergic inflammation induced by epicutaneous sensitization with OVA [3].
• Intriguingly, basal neurogenesis is decreased both in C3(-/-) mice and in mice lacking C3aR or mice treated with a C3aR antagonist [7].
• Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow [8].

Chemical compound and disease context of C3ar1

• Signaling of the C3a anaphylatoxin through its G protein-coupled receptor, C3aR, is relevant in a variety of inflammatory diseases, but its role in lupus nephritis is undefined [1].

Biological context of C3ar1

• The nucleotide sequence of the mouse C3aR genomic clone was identical to the cDNA throughout the coding region, indicating that the receptor is encoded on a single exon [9].
• To isolate the mouse C3aR, a probe derived from this extracellular loop was used to screen a mouse brain cDNA library [9].
• The predicted amino acid contained four predicted N-linked glycosylation sites and was 65% identical to the 482 amino acids comprising the coding region of the human C3aR [9].
• The deduced amino acid sequence of the mouse C3aR is 65% identical to that of the human C3aR [2].
• To define the complement activation fragments that mediate these effects, we assessed the role of the complement anaphylatoxin C3a in a mouse model of pulmonary allergy by challenging C3aR-deficient mice intranasally with a mixed Ag preparation of Aspergillus fumigatus cell culture filtrate and OVA [10].

Anatomical context of C3ar1

• Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid [11].
• Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid [11].
• C5a receptor expression was dramatically elevated within 3 h after middle cerebral artery occlusion, while C3aR expression was reduced to 25% of control animals [12].
• The C3aR is expressed throughout the CNS and is increased in expression on glial cells during CNS inflammation [4].
• Restoration of hepatocyte proliferative capabilities of C3(-/-) mice through C3a reconstitution, as well as the impaired regeneration of C3a receptor-deficient mice, demonstrated that C3a promotes liver cell proliferation via the C3a receptor [13].

Associations of C3ar1 with chemical compounds

• Similar to the human C3aR, RBL-2H3 rat basophilic cells stably expressing this receptor responded in a dose-dependent manner to C3a, a synthetic C3a peptide agonist, but not C4a or C5a, with a vigorous calcium mobilization [9].
• C3aR expression in bronchial epithelial and smooth muscle cells in the lungs of C5-deficient mice was enhanced compared to that in wild-type and reconstituted rodents [5].

Regulatory relationships of C3ar1

• These findings demonstrate an important protective role for the C3aR in endotoxin shock and indicate that, in addition to its traditionally accepted functions in mediating inflammation, the C3aR also acts in vivo as an anti-inflammatory receptor by attenuating LPS-induced proinflammatory cytokine production [14].

Other interactions of C3ar1

• Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade [11].
• Thus, C3aR antagonism significantly reduces renal disease in MRL/lpr mice, which further translates into prolonged survival [1].
• Furthermore, mobilization studies performed in chimeric mice revealed that wt mice reconstituted with C3aR-/- BM cells, but not C3aR-/- mice reconstituted with wt BM cells, are more sensitive to G-CSF-induced mobilization, suggesting that C3aR deficiency on graft-derived cells is responsible for this increased mobilization [8].
• Hence we suggest that C3 is activated in mobilized BM into C3a and C3b, and that the C3a-C3aR axis plays an important and novel role in retention of HSPCs (by counteracting mobilization) by increasing their responsiveness to SDF-1, the concentration of which is reduced in BM during mobilization [8].
• Paradoxically, mice lacking C3, mice lacking the C3a receptor, and mice lacking the complement receptor type 3 develop attenuated EAE, while mice that express C3a exclusively in the CNS develop severe and often fulminant EAE [15].

Analytical, diagnostic and therapeutic context of C3ar1

• These data further suggest that the C3aR antagonist SB 290157 could be developed as a drug to mobilize HSPCs for transplantation [8].
• The mouse anaphylatoxin C3a receptor: molecular cloning, genomic organization, and functional expression [9].
• Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models [16].
• Analysis by plethysmography after challenge revealed an attenuation in airway hyperresponsiveness in C3aR-deficient mice relative to wild-type mice [10].
• C3aR and C5aR stainings were found constitutively on neurons and astrocytes [17].

References