Fra-2 Expression in Osteoblasts Regulates Systemic Inflammation and Lung Injury through Osteopontin
Fra-2 Expression in Osteoblasts Regulates Systemic Inflammation and Lung Injury through Osteopontin
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DOI：
10.1128/mcb.00022-18
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发表时间：
2018-11-01
影响因子：
5.3
通讯作者：
Bozec, Aline
中科院分区：
文献类型：
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作者：
Luo, Yubin;Groetsch, Bettina;Bozec, Aline
炎症反应需要从骨髓动员先天免疫细胞。这个过程的功能取决于骨髓微环境的状态。因此，我们假设成骨细胞（骨髓微环境中必不可少的基质细胞）的分子变化影响炎症反应。在这里，我们表明，成骨细胞特异性表达的AP-1转录因子Fra-2（Fra-2（Ob-tet））诱导全身炎症状态的中性粒细胞和促炎性巨噬细胞浸润到脾脏和肝脏，以及促炎性细胞因子，如白细胞介素-1 β（IL-1 β），IL-6，和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的水平增加。通过在Fra-2（Ob-tet）小鼠体内抑制骨桥蛋白（OPN），我们证明了这一过程依赖于OPN的表达，它介导了骨髓生态位的改变。OPN的表达被Fra-2转录增强，并刺激间充质干细胞（MSC）扩增。此外，在鼠肺损伤模型中，Fra-2（O）（b-tet）小鼠通过对脂多糖（LPS）的增强和持续的炎症反应显示出增加的炎症反应和更严重的疾病特征。我们的研究结果首次证明，成骨细胞的分子变化通过改变先天免疫细胞从骨髓空间的逃避来影响对炎症的易感性。
Inflammatory responses require mobilization of innate immune cells from the bone marrow. The functionality of this process depends on the state of the bone marrow microenvironment. We therefore hypothesized that molecular changes in osteoblasts, which are essential stromal cells of the bone marrow microenvironment, influence the inflammatory response. Here, we show that osteoblast-specific expression of the AP-1 transcription factor Fra-2 (Fra-2(Ob-tet)) induced a systemic inflammatory state with infiltration of neutrophils and proinflammatory macrophages into the spleen and liver as well as increased levels of proinflammatory cytokines, such as interleukin-1 beta (IL-1 beta), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). By in vivo inhibition of osteopontin (OPN) in Fra-2(Ob-tet) mice, we demonstrated that this process was dependent on OPN expression, which mediates alterations of the bone marrow niche. OPN expression was transcriptionally enhanced by Fra-2 and stimulated mesenchymal stem cell (MSC) expansion. Furthermore, in a murine lung injury model, Fra-2(O)(b-tet) mice showed increased inflammatory responses and more severe disease features via an enhanced and sustained inflammatory response to lipopolysaccharide (LPS). Our findings demonstrate for the first time that molecular changes in osteoblasts influence the susceptibility to inflammation by altering evasion of innate immune cells from the bone marrow space.