A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis.
We have previously shown that G-CSF-deficient (G-CSF(-/-)) mice are markedly protected from collagen-induced arthritis (CIA), which is the major murine model of rheumatoid arthritis, and now investigate the mechanisms by which G-CSF can promote inflammatory disease. Serum G-CSF levels were significantly elevated during CIA. Reciprocal bone marrow chimeras using G-CSF(-/-), G-CSFR(-/-), and wild-type (WT) mice identified nonhematopoietic cells as the major producers of G-CSF and hematopoietic cells as the major responders to G-CSF during CIA. Protection against CIA was associated with relative neutropenia. Depletion of neutrophils or blockade of the neutrophil adhesion molecule, Mac-1, dramatically attenuated the progression of established CIA in WT mice. Intravital microscopy of the microcirculation showed that both local and systemic administration of G-CSF significantly increased leukocyte trafficking into tissues in vivo. G-CSF-induced trafficking was Mac-1 dependent, and G-CSF up-regulated CD11b expression on neutrophils. Multiphoton microscopy of synovial vessels in the knee joint during CIA revealed significantly fewer adherent Gr-1(+) neutrophils in G-CSF(-/-) mice compared with WT mice. These data confirm a central proinflammatory role for G-CSF in the pathogenesis of inflammatory arthritis, which may be due to the promotion of neutrophil trafficking into inflamed joints, in addition to G-CSF-induced neutrophil production.
Eyles
Jo L
JL
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Hickey
Michael J
MJ
Norman
M Ursula
MU
Croker
Ben A
BA
Roberts
Andrew W
AW
Drake
Sarah F
SF
James
Will G
WG
Metcalf
Donald
D
Campbell
Ian K
IK
Wicks
Ian P
IP
D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000473:pathology; D039481:CD11b Antigen; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D007719:Knee Joint / Q000473:pathology; D019891:Leukopoiesis / Q000187:drug effects; D016177:Macrophage-1 Antigen; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects*; D013582:Synovial Fluid
D039481:CD11b Antigen; D016177:Macrophage-1 Antigen; D016179:Granulocyte Colony-Stimulating Factor