title: Scavenging roles of chemokine receptors: chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues.
abstract: In vitro studies have implicated chemokine receptors in consumption and clearance of specific ligands. We studied the role that various signaling chemokine receptors play during ligand homeostasis in vivo. We examined the levels of ligands in serum and CNS tissue in mice lacking chemokine receptors. Compared with receptor-sufficient controls, Cx3cr1(-/-) mice exhibited augmented levels of CX3CL1 both in serum and brain, and circulating levels of CXCL1 and CXCL2 were increased in Cxcr2(-/-) mice. CCR2-deficient mice showed significantly increased amounts of circulating CCL2 compared with wild-type mice. Cxcr3(-/-) mice revealed increased levels of circulating and brain CXCL10 after experimental autoimmune encephalomyelitis (EAE) induction. CCR2-deficient peripheral blood and resident peritoneal cells exhibited reduced binding capacity and biologic responses to the CCR1 ligand CCL3, suggesting that elevated levels of CCR2 ligands had down-regulated CCR1. The results indicate that signaling chemokine receptors clear chemokines from circulation and tissues. These homeostatic functions of signaling chemokine receptors need to be integrated into safety and efficacy calculations when considering therapeutic receptor blockade.
authors.affiliation: Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, OH 44195, USA.
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Cardona
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Sasse
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardona
authors.forename: Makiko
authors.initials: M
authors.lastname: Mizutani
authors.forename: Carine
authors.initials: C
authors.lastname: Savarin
authors.forename: Taofang
authors.initials: T
authors.lastname: Hu
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
mesh_terms: D000818:Animals; D001923:Brain Chemistry; D018932:Chemokine CCL2 / Q000032:analysis / Q000097:blood; D054428:Chemokine CX3CL1 / Q000032:analysis / Q000097:blood; D054360:Chemokine CXCL1 / Q000032:analysis / Q000097:blood; D054357:Chemokine CXCL10 / Q000032:analysis / Q000097:blood; D054426:Chemokine CXCL2 / Q000032:analysis / Q000097:blood; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D019707:Receptors, Chemokine / Q000172:deficiency / Q000502:physiology*
chemical_list: D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D054426:Chemokine CXCL2; D008024:Ligands; D019707:Receptors, Chemokine