MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis
MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis
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DOI：
10.1189/jlb.1112587
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发表时间：
2014-01-01
影响因子：
5.5
通讯作者：
Manicone, Anne M.
中科院分区：
文献类型：
--
作者：
Gharib, Sina A.;Johnston, Laura K.;Manicone, Anne M.
MMP28促进交替激活的(M2)巨噬细胞功能，并调节肺内的纤维化反应。基质金属蛋白酶家族的成员在先天性免疫的各种过程中发挥作用，特别是在控制白细胞运输和激活的重要步骤方面。MMP28(Epetysin)是这一家族中的一员，我们已经发现MMP28由巨噬细胞表达，并调节它们向肺内的募集。我们假设MMP28调节其他关键的巨噬细胞反应，如巨噬细胞极化。此外，我们假设这些依赖于MMP28的巨噬细胞极化变化将改变肺内的纤维化反应。我们检测了WT和Mmp28-/-BMDM在分别用内毒素或IL-4/IL-13刺激M1和M2细胞后基因表达的变化。我们还收集了暴露于铜绿假单胞菌的WT和Mmp28-/-小鼠肺中的巨噬细胞，以评估巨噬细胞极化的变化。最后，我们评估了WT和Mmp28-/-小鼠在博莱霉素诱导的肺纤维化过程中的巨噬细胞极化表型，并评估了小鼠体重减轻和总胶原水平的差异。我们发现MMP28抑制促炎巨噬细胞的功能，促进M2编程。在这两个活体模型中，我们发现Mmp28-/-小鼠的M2极化存在缺陷。在博莱霉素诱导的肺损伤中，这些变化与减少纤维化有关。MMP28是巨噬细胞极化的重要调节因子，促进M2功能。MMP28的缺失导致M2极化减少，并保护其免受博莱霉素诱导的纤维化的影响。这些发现突出了MMP28在巨噬细胞生物学和肺部疾病中的新作用。
MMP28 promotes alternatively activated (M2) macrophage function, and regulates the fibrotic response in the lung. Members of the MMP family function in various processes of innate immunity, particularly in controlling important steps in leukocyte trafficking and activation. MMP28 (epilysin) is a member of this family of proteinases, and we have found that MMP28 is expressed by macrophages and regulates their recruitment to the lung. We hypothesized that MMP28 regulates other key macrophage responses, such as macrophage polarization. Furthermore, we hypothesized that these MMP28-dependent changes in macrophage polarization would alter fibrotic responses in the lung. We examined the gene expression changes in WT and Mmp28-/- BMDMs, stimulated with LPS or IL-4/IL-13 to promote M1 and M2 cells, respectively. We also collected macrophages from the lungs of Pseudomonas aeruginosa-exposed WT and Mmp28-/- mice to evaluate changes in macrophage polarization. Lastly, we evaluated the macrophage polarization phenotypes during bleomycin-induced pulmonary fibrosis in WT and Mmp28-/- mice and assessed mice for differences in weight loss and total collagen levels. We found that MMP28 dampens proinflammatory macrophage function and promots M2 programming. In both in vivo models, we found deficits in M2 polarization in Mmp28-/- mice. In bleomycin-induced lung injury, these changes were associated with reduced fibrosis. MMP28 is an important regulator of macrophage polarization, promoting M2 function. Loss of MMP28 results in reduced M2 polarization and protection from bleomycin-induced fibrosis. These findings highlight a novel role for MMP28 in macrophage biology and pulmonary disease.