The HIV protease inhibitor Saquinavir attenuates sepsis-induced acute lung injury and promotes M2 macrophage polarization via targeting matrix metalloproteinase-9.
The HIV protease inhibitor Saquinavir attenuates sepsis-induced acute lung injury and promotes M2 macrophage polarization via targeting matrix metalloproteinase-9.
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HIV 蛋白酶抑制剂沙奎那韦通过靶向基质金属蛋白酶 9 减轻脓毒症引起的急性肺损伤并促进 M2 巨噬细胞极化
DOI：
10.1038/s41419-020-03320-0
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发表时间：
2021-01-11
影响因子：
9
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Tong Y;Yu Z;Chen Z;Zhang R;Ding X;Yang X;Niu X;Li M;Zhang L;Billiar TR;Pitt BR;Li Q
巨噬细胞极化失衡在急性肺损伤（ALI）中起着不可或缺的作用，被视为一个有前景的靶点。基质金属蛋白酶 - 9（MMP - 9）在巨噬细胞中表达，在分泌炎性细胞因子方面具有关键作用。我们曾报道，第一代人类免疫缺陷病毒蛋白酶抑制剂沙奎那韦（SQV）可限制过度的炎症反应。然而，MMP - 9是否能够调节巨噬细胞极化以及是否可被SQV抑制仍不清楚。我们关注巨噬细胞极化在盲肠结扎穿孔（CLP）介导的ALI中的重要作用，并确定SQV通过抑制MMP - 9部分维持M2表型多于M1表型的能力。我们还进行了一项有限的临床研究以确定MMP - 9是否为脓毒症的生物标志物。脂多糖（LPS）增加MMP - 9的表达，重组MMP - 9（rMMP - 9）加剧LPS介导的M1转换。针对MMP - 9的小干扰RNA抑制LPS介导的M1表型，并且rMMP - 9可逆转SQV对这种转换的抑制，这表明MMP - 9在介导LPS诱导的M1表型中具有重要作用。这14名患者外周血单个核细胞中MMP - 9信使RNA水平与其临床评估相关。CLP术后使用SQV，死亡率和ALI呈显著的剂量依赖性降低。SQV在培养的RAW 264.7细胞、原代小鼠骨髓来源的巨噬细胞以及CLP处理小鼠的肺巨噬细胞中显著抑制LPS介导的M1表型并增加M2表型。这项研究支持MMP - 9在巨噬细胞表型转换中的重要作用，并表明SQV介导的对MMP - 9的抑制可能参与在全身性脓毒症期间抑制ALI。
Imbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.
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