Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity.
Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity.
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DOI：
10.1002/hep.27761
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发表时间：
2015-06
期刊：
影响因子：
13.5
通讯作者：
Grakoui, Arash
中科院分区：
文献类型：
--
作者：
Thapa, Manoj;Chinnadurai, Raghavan;Velazquez, Victoria M.;Tedesco, Dana;Elrod, Elizabeth;Han, Jin-Hwan;Sharma, Prachi;Ibegbu, Chris;Gewirtz, Andrew;Anania, Frank;Pulendran, Bali;Suthar, Mehul S.;Grakoui, Arash
肝星状细胞（HSCs）活化介导的慢性肝病会导致肝纤维化。在此，我们假设HSCs的免疫调节特性可能促进B细胞的促纤维化活性。在四氯化碳（CCl₄）处理的B细胞缺陷型μMT小鼠中，纤维化完全减轻，这表明B细胞是必需的。HSCs产生的视黄酸增加了B细胞的存活、浆细胞标志物CD138的表达以及IgG的产生。添加视黄酸抑制剂LE540后，这些活性被逆转。纤维化肝脏B细胞的转录谱分析显示，与NF - κB活化、促炎细胞因子产生和CD40信号传导相关的基因表达增加，这表明这些B细胞被激活，并且可能作为炎症细胞发挥作用。生物学验证实验还显示激活增加（CD44和CD86表达）、组成性IgG产生以及促炎细胞因子TNF - α、MCP - 1和MIP1 - α的分泌。同样，靶向缺失B细胞内在的MyD88信号传导（一种参与RA信号传导的先天性衔接蛋白），导致迁移性CD11c⁺树突状细胞和Ly6C⁺⁺单核细胞的浸润减少，从而减轻肝脏病变。
我们的研究结果表明，肝纤维化是通过HSC介导的先天性B细胞活性增强机制发生的，并强调B细胞是肝内免疫环境的重要“第一反应者”。
Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) leads to liver fibrosis. Here, we postulated that the immune regulatory properties of HSCs might promote the profibrogenic activity of B cells. Fibrosis is completely attenuated in carbon tetrachloride (CCl4)-treated B cell deficient μMT mice showing that B cells are required. The retinoic acid produced by HSCs augmented B cell survival, plasma cell marker CD138 expression, and IgG production. These activities were reversed following the addition of the retinoic acid inhibitor, LE540. Transcriptional profiling of fibrotic liver B cells revealed an increased expression of genes related to NF-κB activation, proinflammatory cytokine production and CD40 signaling suggesting that these B cells are activated and may be acting as inflammatory cells. Biological validation experiments also revealed increased activation (CD44 and CD86 expressions), constitutive IgG production and secretion of the proinflammatory cytokines TNF-α, MCP-1 and MIP1-α. Likewise targeted deletion of B-cell-intrinsic MyD88 signaling, an innate adaptor with involvement in RA signaling, resulted in reduced infiltration of migratory CD11c+ dendritic cells and Ly6C++ monocytes, and hence reduced liver pathology. Our findings demonstrate that liver fibrosis occurs through a mechanism of HSC-mediated augmentation of innate B cell activity and highlight B cells as an important ‘first responders’ of the intrahepatic immune environment.
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影响因子：
32.4
作者：
Hou B;Saudan P;Ott G;Wheeler ML;Ji M;Kuzmich L;Lee LM;Coffman RL;Bachmann MF;DeFranco AL
通讯作者：
DeFranco AL
影响因子：
6
作者：
Kimura, K;Moriwaki, H;Chisari, FV
通讯作者：
Chisari, FV
影响因子：
4.3
作者：
Gragnani, Laura;Fognani, Elisa;Zignego, Anna Linda
通讯作者：
Zignego, Anna Linda
影响因子：
2.4
作者：
Fujii T;Fuchs BC;Yamada S;Lauwers GY;Kulu Y;Goodwin JM;Lanuti M;Tanabe KK
通讯作者：
Tanabe KK
影响因子：
4.4
作者：
Jagannathan, Madhumita;Hasturk, Hatice;Nikolajczyk, Barbara S.
通讯作者：
Nikolajczyk, Barbara S.