Institute of Liver Studies and Cellular Biology of Inflammation, King's College London, London, United Kingdom.
Hepatology. 2012 Aug;56(2):735-46. doi: 10.1002/hep.25657. Epub 2012 Jul 6.
Acetaminophen-induced acute liver failure (AALF) is associated with innate immunity activation, which contributes to the severity of hepatic injury and clinical outcome. A marked increase in hepatic macrophages (h-mφ) is observed in experimental models of AALF, but controversy exists regarding their role, implicating h-mφ in both aggravation and resolution of liver injury. The role of h-mφ in human AALF is virtually unexplored. We sought to investigate the role of chemokine (C-C motif) ligand 2 (CCL2) in the recruitment of circulating monocytes to the inflamed liver and to determine how the h-mφ infiltrate and liver microenvironment may contribute to tissue repair versus inflammation in AALF. We evaluated circulating monocytes, their chemokine (C-C motif) receptor 2 (CCR2) expression, and serum CCL2 levels in patients with AALF. Cell subsets and numbers of circulation-derived (MAC387+) or resident proliferating (CD68/Ki67+) h-mφ in hepatic immune infiltrates were determined by immunohistochemistry. Inflammatory cytokine levels were determined in whole and laser microdissected liver tissue by proteome array. In AALF, circulating monocytes were depleted, with the lowest levels observed in patients with adverse outcomes. CCL2 levels were high in AALF serum and hepatic tissue, and circulating monocyte subsets expressed CCR2, suggesting CCL2-dependent hepatic monocyte recruitment. Significant numbers of both MAC387+ and CD68+ h-mφ were found in AALF compared with control liver tissue with a high proportion expressing the proliferation marker Ki67. Levels of CCL2, CCL3, interleukin (IL)-6, IL-10, and transforming growth factor-β1 were significantly elevated in AALF liver tissue relative to chronic liver disease controls.
In AALF, the h-mφ population is expanded in areas of necrosis, both through proliferation of resident cells and CCL2-dependent recruitment of circulating monocytes. The presence of h-mφ within an anti-inflammatory/regenerative microenvironment indicates that they are implicated in resolution of inflammation/tissue repair processes during AALF.
乙酰氨基酚诱导的急性肝衰竭（AALF）与先天免疫激活有关，这有助于肝损伤的严重程度和临床结果。在 AALF 的实验模型中观察到肝巨噬细胞（h-mφ）明显增加，但关于其作用存在争议，暗示 h-mφ既加重又缓解肝损伤。h-mφ 在人类 AALF 中的作用实际上尚未得到探索。我们试图研究趋化因子（C-C 基序）配体 2（CCL2）在募集循环单核细胞到发炎的肝脏中的作用，并确定 h-mφ 浸润和肝脏微环境如何有助于 AALF 中的组织修复与炎症。我们评估了 AALF 患者的循环单核细胞、它们的趋化因子（C-C 基序）受体 2（CCR2）表达和血清 CCL2 水平。通过免疫组织化学测定肝免疫浸润中循环衍生的（MAC387+）或驻留增殖的（CD68/Ki67+）h-mφ的细胞亚群和数量。通过蛋白质组阵列测定全肝和激光微切割肝组织中的炎症细胞因子水平。在 AALF 中，循环单核细胞被耗尽，在预后不良的患者中观察到最低水平。CCL2 水平在 AALF 血清和肝组织中较高，循环单核细胞亚群表达 CCR2，提示 CCL2 依赖性肝单核细胞募集。与对照肝组织相比，在 AALF 中发现大量的 MAC387+和 CD68+h-mφ，其中很大一部分表达增殖标志物 Ki67。与慢性肝病对照相比，CCL2、CCL3、白细胞介素（IL）-6、IL-10 和转化生长因子-β1 的水平在 AALF 肝组织中显著升高。
在 AALF 中，坏死区域的 h-mφ 群体通过驻留细胞的增殖和 CCL2 依赖性募集循环单核细胞而扩张。在抗炎/再生微环境中存在 h-mφ 表明它们参与 AALF 中炎症/组织修复过程的解决。
