Carma3 Protects from Liver Injury by Preserving Mitochondrial Integrity in Liver Sinusoidal Endothelial Cells
Carma3 Protects from Liver Injury by Preserving Mitochondrial Integrity in Liver Sinusoidal Endothelial Cells
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DOI：
10.4049/jimmunol.2101195
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发表时间：
2022-08-01
影响因子：
4.4
通讯作者：
Lin, Xin
中科院分区：
文献类型：
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作者：
Cheng, Liqing;Wei, Zhanqi;Lin, Xin
Carma3是一种细胞内支架蛋白，可与Bcl10和Malt1形成复合物，介导G蛋白偶联受体或生长因子受体诱导的NF-kappa B活化。然而，Carma3在体内的功能尚不清楚。在这里，通过建立Con a诱导的自身免疫性肝炎模型，我们发现Carma3（-/-）小鼠的肝损伤加剧。令人惊讶的是，我们发现Carma3在肝窦内皮细胞（LSECs）中的表达水平高于肝脏中的肝细胞。在Carma3（-/-）小鼠中，Con A治疗诱导更多LSEC损伤，并伴有更严重的凝血。在体外，我们发现Carma3定位于线粒体，Con A处理可以在Carma3缺失的LSECs中引发更多的线粒体损伤和细胞死亡。综上所述，我们的数据揭示了Carma3在维持LSEC完整性方面未被认识到的作用，这些结果可能会扩展新的策略来预防毒性损伤引起的肝损伤。
Carma3 is an intracellular scaffolding protein that can form complex with Bcl10 and Malt1 to mediate G protein-coupled receptor- or growth factor receptor-induced NF-kappa B activation. However, the in vivo function of Carma3 has remained elusive. Here, by establishing a Con A-induced autoimmune hepatitis model, we show that liver injury is exacerbated in Carma3(-/-) mice. Surprisingly, we find that the Carma3 expression level is higher in liver sinusoidal endothelial cells (LSECs) than in hepatocytes in the liver. In Carma3(-/-) mice, Con A treatment induces more LSEC damage, accompanied by severer coagulation. In vitro we find that Carma3 localizes at mitochondria and Con A treatment can trigger more mitochondrial damage and cell death in Carma3-deficient LSECs. Taken together, our data uncover an unrecognized role of Carma3 in maintaining LSEC integrity, and these results may extend novel strategies to prevent liver injury from toxic insults.