Targeting monocyte chemoattractant protein-1 signalling in disease.
Monocyte chemoattractant protein-1 (MCP-1) has been implicated in many inflammatory and autoimmune diseases. The G-protein-coupled receptor CCR-2B is probably the most important MCP-1 receptor in vivo, and loss of MCP-1 effector function alone is sufficient to impair monocytic trafficking in inflammation models. MCP-1 signalling appears to be a relevant target, especially in rheumatoid arthritis (RA). In RA patients, MCP-1 is produced by synovial cells and infiltrating monocytes, plasma MCP-1 concentrations correlate with swollen joint count, and elevated serum MCP-1 concentrations were found in juvenile RA in patients with active disease. Modulation of MCP-1 signalling in experimental RA showed beneficial effects on inflammation and joint destruction. With respect to chronic neuroinflammation, a critical role for MCP-1 has been established in animal models for multiple sclerosis. In acute neuroinflammation, experimental evidence for a detrimental role of MCP-1 in stroke and excitotoxic injury has been found. Several selective small molecular weight CCR-2B antagonists and MCP-1-blocking antibodies have been described. The proof for the validity of targeting MCP-1 signalling in disease, however, has yet to be established in clinical trials.
Dawson
Janet
J
Arthritis and Bone Metabolism Research, Novartis Pharma AG, Basel, Switzerland.
Miltz
Wolfgang
W
Mir
Anis K
AK
Wiessner
Christoph
C
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000503:physiopathology; D002490:Central Nervous System / Q000187:drug effects / Q000293:injuries; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015195:Drug Design; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000188:drug therapy; D009765:Obesity / Q000188:drug therapy; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; C111835:CCL2 protein, human; C515334:CCR2 protein, human; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine