Conditional depletion of macrophages ameliorates cholestatic liver injury and fibrosis via lncRNA-H19.
Conditional depletion of macrophages ameliorates cholestatic liver injury and fibrosis via lncRNA-H19.
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通过lncRNA-H19条件性清除巨噬细胞可改善胆汁淤积性肝损伤和纤维化
DOI：
10.1038/s41419-021-03931-1
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发表时间：
2021-06-24
影响因子：
9
通讯作者：
Xiao Y
中科院分区：
文献类型：
--
作者：
Tian X;Wang Y;Lu Y;Wang W;Du J;Chen S;Zhou H;Cai W;Xiao Y
虽然巨噬细胞被认为是慢性肝病发病机制中的重要参与者，但其在胆汁淤积性肝纤维化中的作用仍不完全清楚。我们以前报道过，长链非编码RNA H19（lncRNA-H19）有助于胆道闭锁（BA）的胆管细胞增殖和胆汁淤积性肝纤维化。我们在这里发现，单核细胞/巨噬细胞CD 11B mRNA水平显着增加，在BA患者的肝脏，并与肝脏炎症和纤维化的进展呈正相关。巨噬细胞越来越多地浸润并积聚在BA患者肝脏的纤维化龛和胆管周围区域。使用转基因CD 11b-白喉毒素受体（CD 11b-DTR）小鼠选择性清除巨噬细胞可阻止胆管结扎（BDL）诱导的肝损伤和纤维化进展。同时，巨噬细胞耗竭显著降低了BDL诱导的肝lncRNA-H19。使用腺相关病毒血清型9（AAV 9）在肝脏中过表达H19抵消巨噬细胞耗竭对肝纤维化和胆管细胞增殖的影响。此外，H19敲除（H19−/−）和巨噬细胞中H19的条件性缺失（H19Δ CD 11B）均显著抑制巨噬细胞的极化和募集。在THP-1巨噬细胞中过表达的lncRNA-H19增强Rho-GTT CDC 42和RhoA的表达。总之，巨噬细胞的选择性耗竭通过lncRNA-H19抑制胆汁淤积性肝损伤和纤维化，代表了BA患者快速肝纤维化的潜在治疗策略。
Although macrophages are recognized as important players in the pathogenesis of chronic liver diseases, their roles in cholestatic liver fibrosis remain incompletely understood. We previously reported that long noncoding RNA-H19 (lncRNA-H19) contributes to cholangiocyte proliferation and cholestatic liver fibrosis of biliary atresia (BA). We here show that monocyte/macrophage CD11B mRNA levels are increased significantly in livers of BA patients and positively correlated with the progression of liver inflammation and fibrosis. The macrophages increasingly infiltrate and accumulate in the fibrotic niche and peribiliary areas in livers of BA patients. Selective depletion of macrophages using the transgenic CD11b-diphtheria toxin receptor (CD11b-DTR) mice halts bile duct ligation (BDL)-induced progression of liver damage and fibrosis. Meanwhile, macrophage depletion significantly reduces the BDL-induced hepatic lncRNA-H19. Overexpression of H19 in livers using adeno-associated virus serotype 9 (AAV9) counteracts the effects of macrophage depletion on liver fibrosis and cholangiocyte proliferation. Additionally, both H19 knockout (H19−/−) and conditional deletion of H19 in macrophage (H19ΔCD11B) significantly depress the macrophage polarization and recruitment. lncRNA-H19 overexpressed in THP-1 macrophages enhance expression of Rho-GTPase CDC42 and RhoA. In conclusions, selectively depletion of macrophages suppresses cholestatic liver injuries and fibrosis via the lncRNA-H19 and represents a potential therapeutic strategy for rapid liver fibrosis in BA patients.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.8
作者：
BARTOLOMEI, MS;ZEMEL, S;TILGHMAN, SM
通讯作者：
TILGHMAN, SM
影响因子：
6
作者：
Li, Xiaojiaoyang;Liu, Runping;Zhou, Huiping
通讯作者：
Zhou, Huiping
影响因子：
6
作者：
Kitagawa, K;Wada, T;Yokoyama, H
通讯作者：
Yokoyama, H
影响因子：
8
作者：
Cai, Shi-Ying;Ouyang, Xinshou;Boyer, James L.
通讯作者：
Boyer, James L.