In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α
In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α
复制标题
DOI：
10.1172/jci37581
复制
发表时间：
2009-11-01
影响因子：
15.9
通讯作者：
Miller, George
中科院分区：
文献类型：
--
作者：
Connolly, Michael K.;Bedrosian, Andrea S.;Miller, George
肝纤维化发生在大多数慢性肝病期间，并且由对损伤组织的炎症反应驱动。由于DC是调节肝脏免疫的核心，我们推测DC功能的改变有助于肝纤维化的免疫学变化，并影响纤维化肝脏内的病理性炎症环境。使用小鼠模型，我们确定了DC在纤维化中改变肝脏免疫的贡献，并研究了DC在调节纤维化肝脏内炎症环境中的作用。我们发现DC耗竭完全消除了纤维化肝脏中产生的许多炎症介质的升高水平。DCs约占肝纤维化白细胞的25%，并显示CD 11b（+）CD 8（-）分数升高，B220（+）浆细胞样分数降低，MHC II和CD 40表达增加。此外，在肝损伤后，DC获得了诱导肝星状细胞、NK细胞和T细胞介导炎症、增殖和产生强免疫应答的显著能力。纤维化DC的促炎和免疫原性作用取决于其TNF-α的产生。因此，调节DC功能可能是纤维炎性肝病实验治疗的一种有吸引力的方法。
Hepatic fibrosis occurs during most chronic liver diseases and is driven by inflammatory responses to injured tissue. Because DCs are central to modulating liver immunity, we postulated that altered DC function contributes to immunologic changes in hepatic fibrosis and affects the pathologic inflammatory milieu within the fibrotic liver. Using mouse models, we determined the contribution of DCs to altered hepatic immunity in fibrosis and investigated the role of DCs in modulating the inflammatory environment within the fibrotic liver. We found that DC depletion completely abrogated the elevated levels of many inflammatory mediators that are produced in the fibrotic liver. DCs represented approximately 25% of the fibrotic hepatic leukocytes and showed an elevated CD11b(+)CD8(-) fraction, a lower B220(+) plasmacytoid fraction, and increased expression of MHC II and CD40. Moreover, after liver injury, DCs gained a marked capacity to induce hepatic stellate cells, NK cells, and T cells to mediate inflammation, proliferation, and production of potent immune responses. The proinflammatory and immunogenic effects of fibrotic DCs were contingent on their production of TNF-alpha. Therefore, modulating DC function may be an attractive approach to experimental therapeutics in fibro-inflammatory liver disease.