Functional role of monocytes and macrophages for the inflammatory response in acute liver injury.
Functional role of monocytes and macrophages for the inflammatory response in acute liver injury.
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DOI：
10.3389/fphys.2012.00056
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发表时间：
2012
影响因子：
4
通讯作者：
Tacke F
中科院分区：
文献类型：
--
作者：
Zimmermann HW;Trautwein C;Tacke F
不同的病因，如药物毒性，急性病毒性肝炎B，或对乙酰氨基酚中毒可导致急性肝损伤，甚至急性肝衰竭（ALF）。已知肝脏中肝细胞的过度细胞死亡会导致强烈的肝脏炎症。肝损伤的实验鼠模型突出了肝巨噬细胞（所谓的枯否细胞）通过释放促炎细胞因子和趋化因子（包括肿瘤坏死因子（TNF）、白细胞介素-6（IL-6）、IL-1 β或单核细胞-趋化蛋白-1（MCP-1、CCL 2））以及激活其他非实质肝细胞（例如，内皮细胞或肝星状细胞。这些促炎介质中的许多可以触发肝细胞死亡途径，例如，通过半胱天冬酶激活，而且还激活保护性信号传导途径，例如，通过核因子κ B（NF-κB）。最近在小鼠中的研究表明，这些巨噬细胞的作用在很大程度上取决于单核细胞进入肝脏的募集，即作为组织巨噬细胞前体的炎性Ly 6c+（Gr 1+）单核细胞亚群。趋化因子受体CCR 2及其配体MCP-1/CCL 2促进肝损伤后单核细胞亚群浸润。相比之下，趋化因子受体CX 3CR 1及其配体fractalkine（CX 3CL 1）是重要的单核细胞浸润的负调节因子，通过控制它们的生存和分化成功能多样的巨噬细胞亚群损伤。因此，最近确定的单核细胞亚群募集，巨噬细胞分化，并与其他肝细胞类型在损伤的肝脏相互作用的细胞和分子途径可能是有趣的新的ALF的未来治疗方法的目标。
Different etiologies such as drug toxicity, acute viral hepatitis B, or acetaminophen poisoning can cause acute liver injury or even acute liver failure (ALF). Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1beta, or monocyte-chemoattractant protein-1 (MCP-1, CCL2) as well as activating other non-parenchymal liver cells, e.g., endothelial or hepatic stellate cells. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g., via caspase activation, but also activate protective signaling pathways, e.g., via nuclear factor kappa B (NF-κB). Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+) monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation, and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF.
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