title: Pharmacological targeting reveals distinct roles for CXCR2/CXCR1 and CCR2 in a mouse model of arthritis.
abstract: Neutrophils and monocytes are abundantly represented in the synovial fluid and tissue in rheumatoid arthritis patients. We therefore explored the effects of small molecule chemokine receptor antagonists to block migration of these cells in anti-collagen antibody-induced arthritis. Targeting neutrophil migration with the CXCR2/CXCR1 antagonist SCH563705 led to a dose-dependent decrease in clinical disease scores and paw thickness measurements and clearly reduced inflammation and bone and cartilage degradation based on histopathology and paw cytokine analyses. In contrast, targeting monocyte migration with the CCR2 antagonist MK0812 had no effect on arthritis disease severity. The pharmacodynamic activities of both SCH563705 and MK0812 were verified by assessing their effects on the peripheral blood monocyte and neutrophil populations. SCH563705 selectively reduced the peripheral blood neutrophil frequency, and caused an elevation in the CXCR2 ligand CXCL1. MK0812 selectively reduced the peripheral blood monocyte frequency, and caused an elevation in the CCR2 ligand CCL2. The much greater impact of CXCR2/CXCR1 antagonism relative to CCR2 antagonism in this model of arthritis highlights the therapeutic potential for targeting CXCR2/CXCR1 in human arthritides.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. soo.hong.min@spcorp.com
authors.forename: Soo-Hong
authors.initials: SH
authors.lastname: Min
authors.forename: Yuanfan
authors.initials: Y
authors.lastname: Wang
authors.forename: Waldemar
authors.initials: W
authors.lastname: Gonsiorek
authors.forename: Gopinadhan
authors.initials: G
authors.lastname: Anilkumar
authors.forename: Joseph
authors.initials: J
authors.lastname: Kozlowski
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundell
authors.forename: Jay S
authors.initials: JS
authors.lastname: Fine
authors.forename: Ethan P
authors.initials: EP
authors.lastname: Grant
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000502:physiology; D013582:Synovial Fluid / Q000187:drug effects / Q000276:immunology
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D023063:Receptors, Interleukin-8B