Tissue-resident Macrophages Protect the Liver From Ischemia Reperfusion Injury via a Heme Oxygenase-1-Dependent Mechanism
Tissue-resident Macrophages Protect the Liver From Ischemia Reperfusion Injury via a Heme Oxygenase-1-Dependent Mechanism
复制标题
DOI：
10.1038/mt.2008.237
复制
发表时间：
2009-01-01
影响因子：
12.4
通讯作者：
Wigmore, Stephen J.
中科院分区：
文献类型：
--
作者：
Devey, Luke;Ferenbach, David;Wigmore, Stephen J.
Kupffer细胞是肝脏中驻留的巨噬细胞群，此前已被认为与肝脏缺血再灌注损伤(IRI)的发病机制有关。Kupffer细胞是肝脏血红素加氧酶-1(HO-1)的主要表达部位，已被证明具有抗炎作用，并保护动物和细胞免受氧化损伤。CD11b DTR小鼠在诱导肝脏缺血前，用氯屈膦酸脂(LC)选择性消融Kupffer细胞和循环单核细胞。Kupffer细胞耗竭导致HO-1表达缺失，增加肝脏IRI的易感性，而去除循环单核细胞并不影响IRI表型。HO-1的靶向缺失使小鼠对肝脏IRI高度敏感。在体内，HO-1缺失导致促炎症Kupffer细胞分化，其特征是Ly6c和MARCO(具有胶原结构的巨噬细胞受体)表达增强，F4/80表达降低，反映为未成熟循环单核细胞的扩张。在体外，在巨噬细胞分化过程中抑制HO-1导致细胞数量增加，并导致促炎症的Ly6c+CD11c-F4/80表型。这些数据支持组织驻留巨噬细胞在缺血损伤后的动态平衡中的关键作用，以及HO-1表达和组织驻留巨噬细胞分化的相互依赖。
Kupffer cells are the resident macrophage population of the liver and have previously been implicated in the pathogenesis of hepatic ischemia-reperfusion injury (IRI). Kupffer cells are the major site of expression of hepatic heme oxygenase-1 (HO-1), which has been shown to have anti-inflammatory actions and to protect animals and cells from oxidative injury. Kupffer cells and circulating monocytes were selectively ablated using liposomal clodronate (LC) in the CD11b DTR mouse before induction of hepatic ischemia. Kupffer cell depletion resulted in loss of HO-1 expression and increased susceptibility to hepatic IRI, whereas ablation of circulating monocytes did not affect IRI phenotype. Targeted deletion of HO-1 rendered mice highly susceptible to hepatic IRI. In vivo, HO-1 deletion resulted in pro-inflammatory Kupffer cell differentiation characterized by enhanced Ly6c and MARCO ( macrophage receptor with collagenous structure) expression as well as decreased F4/80 expression, mirrored by an expansion in immature circulating monocytes. In vitro, HO-1 inhibition throughout macrophage differentiation led to increased cell numbers, and pro-inflammatory Ly6c+ CD11c- F4/80- phenotype. These data support a critical role for tissue-resident macrophages in homeostasis following ischemic injury, and a co-dependence of HO-1 expression and tissue-resident macrophage differentiation.