Submitted February 25, 2008
Accepted September 1, 2008
A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis
Jo L. Eyles, Michael J. Hickey, M. Ursula Norman, Ben A. Croker, Andrew W. Roberts, Sarah F. Drake, Will G. James, Donald Metcalf, Ian K. Campbell, and Ian P. Wicks*
University of Melbourne, Parkville, Victoria, Australia
Centre for Inflammatory Diseases, Monash University, Melbourne, Victoria, Australia
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
* Corresponding author; email: wicks{at}wehi.edu.au.
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 non-hemopoietic cells as the major producers of G-CSF and hemopoietic cells as the major responders to G-CSF during CIA. In each chimera pair, protection against CIA was associated with relative neutropenia. Depletion of neutrophils or blockade of the key 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 upregulated CD11b expression on neutrophils. Multi-photon microscopy of synovial vessels in the knee joint during CIA revealed significantly less adherent Gr-1+ neutrophils in G-CSF-/- mice compared to WT mice. These data confirm a central pro-inflammatory 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.
