title: Disruption of the complement anaphylatoxin receptor C5L2 exacerbates inflammation in allergic contact dermatitis.
abstract: The complement anaphylatoxin C5a is a critical mediator of allergic contact dermatitis, bridging essential aspects of innate and adaptive immunity. This anaphylatoxin functions by interacting with two 7-transmembrane segment receptors, the C5aR and C5L2. The C5aR is a classical G protein coupled receptor, whereas C5L2 is deficient in coupling to G proteins because of variations in the sequence. Our previous work in human neutrophils revealed a unique role for C5L2 in negatively modulating anaphylatoxin receptor mediated cellular activation through interactions with β-arrestin. When C5L2 is deficient, C5aR-mediated β-arrestin signaling is greatly enhanced. The work described in this study was undertaken first to determine the effect of C5L2 deficiency in a murine model of contact sensitivity, and second to determine whether the resultant exacerbation of inflammatory parameters reflects a negative modulatory function of C5L2 on the C5aR. First, we find dramatic increases in inflammation in C5L2(-/-) animals compared with wild type mice. Second, these increases are completely reversed following administration of mAb against the C5aR. Thus, in allergic contact sensitivity, as in isolated human neutrophils, C5L2 functions to suppress C5a-C5aR-mediated responses, further underscoring its role as a negative regulator of anaphylatoxin activity.
authors.affiliation: Ina Sue Perlmutter Laboratory, Division of Respiratory Diseases, Department of Pediatrics, Children's Hospital, Boston, MA 02115;
authors.forename: Ruobing
authors.initials: R
authors.lastname: Wang
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Norma P
authors.initials: NP
authors.lastname: Gerard
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D019390:Arrestins / Q000276:immunology / Q000378:metabolism; D015936:Complement C5a / Q000276:immunology*; D017449:Dermatitis, Allergic Contact / Q000276:immunology*; D005260:Female; D007249:Inflammation / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000276:immunology*; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D000911:Antibodies, Monoclonal; D019390:Arrestins; C000594938:C5ar2 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D000071557:beta-Arrestins; D015936:Complement C5a
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