Santos Leilani L, Fan Huapeng, Hall Pam, Ngo Devi, Mackay Charles R, Fingerle-Rowson Gunter, Bucala Richard, Hickey Michael J, Morand Eric F
Monash Medical Centre, Clayton, Victoria, Australia.
Arthritis Rheum. 2011 Apr;63(4):960-70. doi: 10.1002/art.30203.
Macrophage migration inhibitory factor (MIF) facilitates multiple aspects of inflammatory arthritis, the pathogenesis of which has been significantly linked to the activity of neutrophils. The effects of MIF on neutrophil recruitment are unknown. This study was undertaken to investigate the contribution of MIF to the regulation of neutrophil chemotactic responses.
K/BxN serum-transfer arthritis was induced in wild-type (WT), MIF(-/-) , and monocyte chemotactic protein 1 (MCP-1; CCL2)-deficient mice as well as in WT mice treated with monoclonal antibodies to cytokine-induced neutrophil chemoattractant (anti-KC). Leukocyte trafficking in vivo was examined using intravital microscopy, and neutrophil function in vitro was examined using migration chambers and assessment of MAP kinase activation.
K/BxN serum-transfer arthritis was markedly attenuated in MIF(-/-) mice, with reductions in the clinical and histologic severity of arthritis and the synovial expression of KC and interleukin-1. Arthritis was also reduced by anti-KC antibody treatment, but not in MCP-1-deficient mice. In vivo, neutrophil recruitment responses to KC were reduced in MIF(-/-) mice. Similarly, MIF(-/-) mouse neutrophils exhibited reduced chemotactic responses to KC in vitro, despite displaying unaltered chemokine receptor expression. Reduced chemotactic responses of MIF(-/-) mouse neutrophils were associated with reduced phosphorylation of p38 and ERK MAP kinases.
These findings suggest that MIF promotes neutrophil trafficking in inflammatory arthritis via facilitation of chemokine-induced migratory responses and MAP kinase activation. Therapeutic MIF inhibition could limit synovial neutrophil recruitment.
巨噬细胞移动抑制因子（MIF）促进炎性关节炎的多个方面，其发病机制与中性粒细胞的活性显著相关。MIF对中性粒细胞募集的影响尚不清楚。本研究旨在探讨MIF在调节中性粒细胞趋化反应中的作用。
在野生型（WT）、MIF基因敲除（MIF(-/-)）、单核细胞趋化蛋白1（MCP-1；CCL2）缺陷小鼠以及用细胞因子诱导的中性粒细胞趋化因子单克隆抗体（抗KC）处理的WT小鼠中诱导K/BxN血清转移关节炎。使用活体显微镜检查体内白细胞运输，并使用迁移小室和评估丝裂原活化蛋白激酶（MAP激酶）激活来检查体外中性粒细胞功能。
在MIF(-/-)小鼠中，K/BxN血清转移关节炎明显减轻，关节炎的临床和组织学严重程度以及KC和白细胞介素-1的滑膜表达均降低。抗KC抗体治疗也可减轻关节炎，但在MCP-1缺陷小鼠中则不然。在体内，MIF(-/-)小鼠对KC的中性粒细胞募集反应降低。同样，MIF(-/-)小鼠中性粒细胞在体外对KC的趋化反应降低，尽管其趋化因子受体表达未改变。MIF(-/-)小鼠中性粒细胞趋化反应降低与p38和ERK MAP激酶的磷酸化减少有关。
这些发现表明，MIF通过促进趋化因子诱导的迁移反应和MAP激酶激活来促进炎性关节炎中的中性粒细胞运输。抑制MIF的治疗方法可能会限制滑膜中性粒细胞的募集。
