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Blood. 2008 Dec 15;112(13):5193-201. doi: 10.1182/blood-2008-02-139535. Epub 2008 Sep 29.

A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis.

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1
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Abstract

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.

PMID:
18824600
DOI:
10.1182/blood-2008-02-139535
[Indexed for MEDLINE]
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