Scavenging roles of chemokine receptors: chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues
Scavenging roles of chemokine receptors: chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues
Astrid E. Cardona, et al. 2008. Blood. 112: 256-263
Speaker: Wen-Ling Yeh (葉玟伶) Time: 14:00~15:00, Dec. 17, 2008
Commentator: Dr. Bei-Chang Yang (楊倍昌老師) Place: Room 601
Abstract:
The interactions between chemokines and their receptors exhibit roles during inflammation, atherosclerosis, autoimmunity, viral pathogenesis, cancer, and neurodegeneration such as experimental autoimmune encephalomyelitis (EAE)[1]. The excess chemokines can be cleared by non-signaling chemokine receptors such as D6, DARC and CCX-CKR[2]. However, whether signaling chemokine receptors also have scavenging roles was poorly understood. In this paper, the authors found those chemokine ligands were increased obviously in the sera and brains of the Cx3cr1-/-, Cxcr2-/-, CCR2-/-, Cxcr3-/- mice. In addition, they detected much higher CXCL10, the ligand of CXCR3, in brain tissues of the Cxcr3-/- mice than that of wild-type mice after EAE induction. However, there was no significant difference of chemokine mRNA between wild-type and receptor-deficient mice suggesting that the elevated chemokines might result from the fail of clearance by their receptors. Subsequently, they transfered wild-type bone marrow to Ccr2-/- or Cx3cr1-/-Ccr2-/- mice, and found that CCL2 and CX3CL1 in sera were reduced to basal levels, showing that the chemokine receptor+/+ cells can clear excess chemokine molecules. In Ccr2-/- resident peritoneal cells, the binding ability of CCR5 was decreased showing that excess Ccr2 ligands could down-regulated other receptors. Thus, chemokine receptors have scavenging role to clear excess chemokines from the circulation and tissues. These findings suggest that the homeostatic functions of signal chemokine receptors need to be integrated into safety and efficacy calculations when considering therapeutic receptor blockade.
References:
1. Marcus Müller, et al. 2007. CXCR3 signaling reduces the severity of Experimental Autoimmune Encephalomyelitis by controlling the parenchymal distribution of effector and regulatory T cells in the central nervous system. The Journal of Immunology. 179: 2774–2786.
2. Iain Comerford et al, 2007. Regulation of chemotactic networks by ‘atypical’ receptors. BioEssays. 29:237–247.