Macrophage CD74 contributes to MIF-induced pulmonary inflammation.
Macrophage CD74 contributes to MIF-induced pulmonary inflammation.
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巨噬细胞 CD74 有助于 MIF 诱导的肺部炎症。
DOI：
10.1186/1465-9921-10-33
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发表时间：
2009-05-04
影响因子：
5.8
通讯作者：
Miller EJ
中科院分区：
文献类型：
--
作者：
Takahashi K;Koga K;Linge HM;Zhang Y;Lin X;Metz CN;Al-Abed Y;Ojamaa K;Miller EJ
MIF是宿主防御的关键介质，参与肺的急性和慢性反应。在动物模型中，MIF的中和减少了中性粒细胞在肺中的积聚。我们假设，肺泡腔中的MIF通过激活巨噬细胞上的CD74受体促进中性粒细胞聚集。为了确定巨噬细胞表面CD74的表达是否有助于MIF诱导的中性粒细胞聚集，我们在存在或不存在抗CD74抗体或MIF特异性抑制剂ISO-1的情况下，将重组MIF(r-MIF)注入小鼠的气管。利用巨噬细胞培养，我们研究了MIF诱导的导致中性粒细胞聚集的下游激活途径。气管内滴注r-MIF可增加BAL液中中性粒细胞数量及巨噬细胞炎性蛋白-2(MIP-2)和角质形成细胞源性趋化因子(KC)的浓度。CD74表达于肺泡巨噬细胞表面，MIF诱导的MIP-2聚集依赖于巨噬细胞中的p44/p42 MAPK。抗CD74抗体可抑制MIF诱导的巨噬细胞p44/p42 MAPK磷酸化和MIP-2释放。此外，在我们的小鼠模型中，抗CD74抗体抑制了MIF诱导的肺泡内MIP-2(对照免疫球蛋白和CD74抗体分别为477.1±136.7和242.2±102.2 pg/ml，p<；0.05)，KC(1796.2±436.1和1138.2±310.2 pg/ml，p<；0.05)和中性粒细胞(中性粒细胞总数，3.33±0.93×104和1.90±0.61×104，p<；0.05)。MIF诱导的中性粒细胞在肺泡间隙的聚集是与肺泡巨噬细胞表面表达的CD74相互作用的结果。这种相互作用诱导p44/p42 MAPK激活和趋化因子释放。这些数据表明，MIF及其受体CD74可能是减少中性粒细胞肺部炎症和急性肺损伤的有用靶点。
MIF is a critical mediator of the host defense, and is involved in both acute and chronic responses in the lung. Neutralization of MIF reduces neutrophil accumulation into the lung in animal models. We hypothesized that MIF, in the alveolar space, promotes neutrophil accumulation via activation of the CD74 receptor on macrophages. To determine whether macrophage CD74 surface expression contributes MIF-induced neutrophil accumulation, we instilled recombinant MIF (r-MIF) into the trachea of mice in the presence or absence of anti-CD74 antibody or the MIF specific inhibitor, ISO-1. Using macrophage culture, we examined the downstream pathways of MIF-induced activation that lead to neutrophil accumulation. Intratracheal instillation of r-MIF increased the number of neutrophils as well as the concentration of macrophage inflammatory protein 2 (MIP-2) and keratinocyte-derived chemokine (KC) in BAL fluids. CD74 was found to be expressed on the surface of alveolar macrophages, and MIF-induced MIP-2 accumulation was dependent on p44/p42 MAPK in macrophages. Anti-CD74 antibody inhibited MIF-induced p44/p42 MAPK phosphorylation and MIP-2 release by macrophages. Furthermore, we show that anti-CD74 antibody inhibits MIF-induced alveolar accumulation of MIP-2 (control IgG vs. CD74 Ab; 477.1 ± 136.7 vs. 242.2 ± 102.2 pg/ml, p < 0.05), KC (1796.2 ± 436.1 vs. 1138.2 ± 310.2 pg/ml, p < 0.05) and neutrophils (total number of neutrophils, 3.33 ± 0.93 × 104 vs. 1.90 ± 0.61 × 104, p < 0.05) in our mouse model. MIF-induced neutrophil accumulation in the alveolar space results from interaction with CD74 expressed on the surface of alveolar macrophage cells. This interaction induces p44/p42 MAPK activation and chemokine release. The data suggest that MIF and its receptor, CD74, may be useful targets to reduce neutrophilic lung inflammation, and acute lung injury.
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