TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury
TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury
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DOI：
10.1073/pnas.1614935113
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发表时间：
2016-12-13
影响因子：
11.1
通讯作者：
Malik, Asrar B.
中科院分区：
文献类型：
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作者：
Mittal, Manish;Tiruppathi, Chinnaswamy;Malik, Asrar B.
TNF α刺激基因-6 （TSG6）是一种由活化的巨噬细胞产生的30 kda蛋白，可调节炎症；然而，其在巨噬细胞活化中的作用机制尚不完全清楚。我们观察到，与WT （TSG6(+/+)）小鼠相比，lps诱导的TSG6（-/-）小鼠的炎症性肺损伤和死亡率明显增加。气管内灌注TSG6治疗小鼠可预防lps诱导的肺损伤和中性粒细胞隔离，提高小鼠存活率。我们发现TSG6抑制TLR4与MyD88的关联，从而抑制NF-kappa B的激活。TSG6还能抑制巨噬细胞中促炎蛋白（iNOS、IL-6、TNF α、IL-1 β和CXCL1）的表达，同时增加抗炎蛋白（CD206、Chi3l3、IL-4和IL-10）的表达。这种转变与促炎转录因子STAT1和STAT3的抑制激活有关。此外，我们观察到LPS本身上调TSG6（+/+）小鼠中TSG6的表达，提示TSG6在过渡巨噬细胞中的自分泌作用。因此，TSG6的功能是将巨噬细胞从促炎表型转化为抗炎表型，继发于抑制TLR4/NF-kappa B信号和STAT1和STAT3激活。
TNF alpha-stimulated gene-6 (TSG6), a 30-kDa protein generated by activated macrophages, modulates inflammation; however, its mechanism of action and role in the activation of macrophages are not fully understood. Herewe observed markedly augmented LPS-induced inflammatory lung injury and mortality in TSG6(-/-) mice compared with WT (TSG6(+/+)) mice. Treatment of mice with intratracheal instillation of TSG6 prevented LPS-induced lung injury and neutrophil sequestration, and increased survival in mice. We found that TSG6 inhibited the association of TLR4 with MyD88, thereby suppressing NF-kappa B activation. TSG6 also prevented the expression of proinflammatory proteins (iNOS, IL-6, TNF alpha, IL-1 beta, and CXCL1) while increasing the expression of anti-inflammatory proteins (CD206, Chi3l3, IL-4, and IL-10) in macrophages. This shift was associated with suppressed activation of proinflammatory transcription factors STAT1 and STAT3. In addition, we observed that LPS itself up-regulated the expression of TSG6 in TSG6(+/+) mice, suggesting an autocrine role for TSG6 in transitioning macrophages. Thus, TSG6 functions by converting macrophages from a proinflammatory to an anti-inflammatory phenotype secondary to suppression of TLR4/NF-kappa B signaling and STAT1 and STAT3 activation.