Disease relevance of C5ar1

• Macrophages induce the inflammatory response in the pulmonary Arthus reaction through G alpha i2 activation that controls C5aR and Fc receptor cooperation [1].
• AM lacking either C5aR or FcgammaRIII do not possess any such inducibility of immune complex disease, whereas reconstitution with FcgammaRIIB-negative AM results in an enhanced pathology [1].
• These C5a-receptor-deficient mice challenged with sublethal inocula of Pseudomonas become superinfected with secondary bacterial strains [2].
• In the reverse passive Arthus reaction in the skin the C5aR was also required for the full expression of neutrophil influx and edema formation; C5aR-deficient mice showed reduced neutrophil migration and microvascular permeability changes [3].
• These data indicate a dominant role for the C5aR and its ligand in the reverse passive Arthus reaction in the lung and a synergistic role together with other inflammatory mediators in immune complex-mediated peritonitis and skin injury [3].

Psychiatry related information on C5ar1

• Direct evidence of C5aR involvement in host defense mechanisms was demonstrated recently using C5aR knockout mice [4].

High impact information on C5ar1

• Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection [5].
• Here we show that mice deficient in the chemoattractant C5a receptor, in comparison to their wild-type littermates, were unable to clear intrapulmonary-instilled Pseudomonas aeruginosa, despite a marked increase in neutrophil influx, and succumbed to pneumonia [2].
• C5aR- deficient mice exhibit decreased migration of neutrophils and decreased levels of TNF-alpha and interleukin 6 in the peritoneal reverse passive Arthus reaction compared to their wild-type littermates [3].
• Impaired inflammatory responses in the reverse arthus reaction through genetic deletion of the C5a receptor [3].
• In this study, we compare the effect of C5aR deficiency in immune complex-induced inflammation in the peritoneal cavity and skin with the results derived from our immune complex alveolitis model [3].

Chemical compound and disease context of C5ar1

• Ca(2+) signaling was abolished only in mutant cells pretreated with pertussis toxin, suggesting that the C5a receptor couples to both Galpha15 and Galphai in vivo [6].
• We induced the passive reverse Arthus reaction to IgG immune complexes (IC) at different tissue sites in mice lacking C3 treated or not with a C5aR-specific antagonist, or in mice lacking mast cells (Kit(W)/Kit(W-v) mice), and compared the inflammatory responses with those in the corresponding wild-type mice [7].
• In both strains of genetically altered mice, the severity of pancreatitis and pancreatitis-associated lung injury was greater than that noted in the comparison wild-type strains of C5aR- and C5-sufficient animals [8].

Biological context of C5ar1

• Upon administration of anti-erythrocyte antibodies, upregulation of activating Fcgamma receptors (FcgammaRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcgammaR-mediated in vivo erythrophagocytosis was impaired [9].
• Importantly, C5aR-deficient mice exhibited a similar, increased allergic phenotype [10].
• In contrast, up until now, no specific contribution of C5a and its receptor, C5aR, was recognized in diseases of antibody-dependent type II autoimmunity [9].
• Here we report that local pharmacological targeting of the C5a receptor (C5aR) prior to initial allergen sensitization in murine models of inhalation tolerance or allergic asthma resulted in either induction or marked enhancement of Th2-polarized immune responses, airway inflammation, and AHR [10].
• Furthermore, blocking of the C5aR pathway had no influence on renal apoptosis [11].

Anatomical context of C5ar1

• Pulmonary allergen exposure in C5aR-targeted mice resulted in increased sensitization and accumulation of CD4+ CD69+ T cells associated with a marked increase in pulmonary myeloid, but not plasmacytoid, DC numbers [10].
• We show that ablation of C5a receptor signaling abrogates neutrophil recruitment in wild-type mice and prevents the enhancement of neutrophil migration seen in FcgammaRIIB(-/-) mice, suggesting that C5aR signaling is the crucial initial event upstream of FcgammaR signaling [12].
• Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid [13].
• On the other hand, C5aR deficient mice are either protected from tissue injury induced by ICs, as in the lung, or the degree of the inflammatory response is markedly attenuated, as in peritoneum and skin [14].
• Expression and function of C5a receptor in mouse microvascular endothelial cells [15].

Associations of C5ar1 with chemical compounds

• In addition, AHR was absent in complement C5 and C5a receptor-deficient mice [16].
• A series of studies has been performed in mice with engineered deficiencies of either FcgammaRs, the complement components C3, C4 or the C5a receptor [14].
• Distinct tissue site-specific requirements of mast cells and complement components C3/C5a receptor in IgG immune complex-induced injury of skin and lung [7].
• Generation of an expressible cDNA for the mouse C5a receptor was accomplished using the polymerase chain reaction and a sense oligodeoxynucleotide primer which included an initiation codon just 5' to the sequence encoding the N-linked glycosylation site [17].
• C3a and C5a mediate these effects by binding to their specific receptors, C3aR and C5aR, respectively [18].

Physical interactions of C5ar1

• The inhibition of C5a binding to C5a receptor was studied using a radioligand binding assay [19].

Regulatory relationships of C5ar1

• Furthermore, these data suggest that the C5a anaphylatoxin mediates previously unrecognized functions by binding to tissue cells that express the C5aR [20].
• C5L2 is an enigmatic serpentine receptor that is co-expressed with the C5a receptor on many cells including polymorphonuclear neutrophils [21].
• Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-alpha following closed head injury in mice [22].

Other interactions of C5ar1

• Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade [13].
• In this paper, we demonstrate that, in response to IgG immune complex formation, FcgammaRI/III- and C5aR-mediated pathways are both necessary and only together are they sufficient to trigger the full expression of inflammation in skin and lung [23].
• Enhanced binding of C5a occurred, as well as increased mRNA for C5aR, after in vitro exposure of MDMEC to LPS, IFN-gamma, or IL-6 in a time- and dose-dependent manner [15].
• Blocking the C5aR pathway by a specific C5a receptor antagonist (C5aRA) abrogated up-regulation of CXC chemokines but not of TNF-alpha and reduced neutrophil infiltration by >50% [11].
• We found that renal expression of C5aR mRNA and protein was significantly increased in MRL/lpr mice compared to control MRL/+ mice [24].

Analytical, diagnostic and therapeutic context of C5ar1

• Using the cecal ligation/puncture (CLP) model in mice, we show here that C5aR immunoreactivity was strikingly increased in lung, liver, kidney, and heart early in sepsis in both control and neutrophil-depleted mice [25].
• Northern blot analysis of murine and baboon organs shows that, in addition to the liver, other tissues express C5aR mRNA in significant quantities, including the spleen, lung, heart, kidney, and intestine [20].
• In vivo expression of C5aR in human liver cells was demonstrated by in situ hybridization and immunohistochemistry analyses [20].
• HepG2 cells were demonstrated to express the C5aR on their cell surface by flow cytometric and immunofluorescence analyses as well as by 125I-C5a binding assays [20].
• By confocal microscopy, C5aR could be detected on surfaces of MDMEC using anti-C5aR Ab [15].

References