Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in experimental arthritis.
A characteristic feature of rheumatoid arthritis is the abundance of inflammatory cells in the diseased joint. Two major components of this infiltrate are neutrophils in the synovial fluid and macrophages in the synovial tissue. These cells produce cytokines including tumor necrosis factor alpha and other proinflammatory mediators that likely drive the disease through its effector phases. To investigate what mechanisms underlie the recruitment of these cells into the synovial fluid and tissue, we performed expression analyses of chemoattractant receptors in a related family that includes the anaphylatoxin receptors and the formyl-MetLeuPhe receptor. We then examined the effect of targeted disruption of two abundantly expressed chemoattractant receptors, the receptors for C3a and C5a, on arthritogenesis in a mouse model of disease. We report that genetic ablation of C5a receptor expression completely protects mice from arthritis.
Grant
Ethan P
EP
Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139, USA. egrant@mpi.com
Picarella
Dominic
D
Burwell
Timothy
T
Delaney
Tracy
T
Croci
Alisa
A
Avitahl
Nicole
N
Humbles
Alison A
AA
Gutierrez-Ramos
Jose-Carlos
JC
Briskin
Michael
M
Gerard
Craig
C
Coyle
Anthony J
AJ
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D001168:Arthritis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen / Q000276:immunology; D003167:Complement Activation; D003182:Complement C5 / Q000502:physiology; D019040:E-Selectin / Q000096:biosynthesis; D015870:Gene Expression; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007596:Joints / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017463:Receptors, Complement 3b / Q000032:analysis / Q000502:physiology; D013583:Synovial Membrane / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D015703:Antigens, CD; D003182:Complement C5; D019040:E-Selectin; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen