A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis
A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis
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DOI：
10.1182/blood-2008-02-139535
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发表时间：
2008-12-15
期刊：
影响因子：
20.3
通讯作者：
Wicks, Ian P.
中科院分区：
文献类型：
--
作者：
Eyles, Jo L.;Hickey, Michael J.;Wicks, Ian P.
我们先前已经证明，G-CSF缺陷(G-CSF-/-)小鼠对胶原诱导性关节炎(CIA)具有明显的保护作用，而CIA是类风湿关节炎的主要小鼠模型，现在我们正在研究G-CSF促进炎症性疾病的机制。血清G-CSF水平在CIA期间显著升高。使用G-CSF-/-、G-CSFR-/-和野生型(WT)小鼠的相互骨髓嵌合体发现，在CIA期间，非造血细胞是G-CSF的主要产生者，造血细胞是G-CSF的主要反应者。对CIA的保护与相对的中性粒细胞减少有关。中性粒细胞的耗尽或中性粒细胞黏附分子Mac-1的阻断，极大地减弱了WT小鼠已建立的CIA的进展。活体微循环显微镜显示，局部和全身应用G-CSF显著增加了白细胞在体内组织中的转运。G-CSF诱导的转运依赖于Mac-1，G-CSF上调中性粒细胞表面CD11b的表达。CIA期间膝关节滑膜血管的多光子显微镜显示，与WT鼠相比，G-CSF-/-鼠的Gr-1(+)中性粒细胞显著减少。这些数据证实了G-CSF在炎性关节炎发病机制中的中心促炎作用，这可能是由于除了G-CSF诱导的中性粒细胞产生外，还促进了中性粒细胞向炎症关节的运输。(血。2008年；112：5193-5201)
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. (Blood. 2008; 112: 5193-5201)