Pharmacological targeting reveals distinct roles for CXCR2/CXCR1 and CCR2 in a mouse model of arthritis

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 neutroph...

Full description

Saved in:
Bibliographic Details
Published in:Biochemical and biophysical research communications 2010-01, Vol.391 (1), p.1080-1086
Main Authors: Min, Soo-Hong, Wang, Yuanfan, Gonsiorek, Waldemar, Anilkumar, Gopinadhan, Kozlowski, Joseph, Lundell, Daniel, Fine, Jay S., Grant, Ethan P.
Format: Article
Language:English
Subjects:
Animals
Arthritis
Arthritis, Rheumatoid - immunology
CCR2
Cell Movement - drug effects
CXCR2
Disease Models, Animal
Female
Mice
Mice, Inbred BALB C
Migration
Neutrophils - drug effects
Neutrophils - immunology
Pharmacodynamics
Pharmacology
Receptors, CCR2 - antagonists & inhibitors
Receptors, CCR2 - physiology
Receptors, Interleukin-8B - antagonists & inhibitors
Receptors, Interleukin-8B - physiology
Synovial Fluid - drug effects
Synovial Fluid - immunology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2009.12.025