Kupffer cells regulate liver recovery through induction of chemokine receptor CXCR2 on hepatocytes after acetaminophen overdose in mice.
Kupffer cells regulate liver recovery through induction of chemokine receptor CXCR2 on hepatocytes after acetaminophen overdose in mice.
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DOI：
10.1007/s00204-021-03183-0
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发表时间：
2022-01
影响因子：
6.1
通讯作者：
Jaeschke H
中科院分区：
文献类型：
--
作者：
Nguyen NT;Umbaugh DS;Sanchez-Guerrero G;Ramachandran A;Jaeschke H
对乙酰氨基酚（APAP）是一种广泛使用的镇痛药，也是美国和许多西方国家急性肝损伤的主要原因。APAP肝毒性与中性粒细胞和单核细胞浸润所显示的无菌炎症反应有关。虽然免疫细胞促进肝脏修复的作用已被证实，但巨噬细胞或中性粒细胞与肝细胞之间的直接相互作用，以帮助促进肝细胞增殖和组织修复仍不清楚。本研究的目的是探讨常驻巨噬细胞（Kupffer细胞）与肝细胞之间的关系，重点关注趋化因子受体CXCR2。C57BL/6J小鼠服用过量APAP (300mg/kg)，使用选择性拮抗剂SB225002研究CXCR2对肝细胞的作用。此外，使用氯膦酸脂质体来消耗库普弗细胞以评估CXCR2表达的变化。我们的数据显示，CXCR2主要在肝细胞上表达，并在APAP治疗后24小时特异性诱导坏死区周围的肝细胞表达。使用抑制剂靶向这种受体导致肝脏恢复延迟。Kupffer细胞的缺失明显阻止了CXCR2对肝细胞的诱导。体外和体内实验也表明，Kupffer细胞通过产生IL-10调节存活肝细胞中CXCR2的表达和促再生基因的表达。因此，Kupffer细胞通过CXCR2表达支持坏死区域周围肝细胞向增殖状态的转变。
Acetaminophen (APAP) is a widely used analgesic, but also a main cause of acute liver injury in the United States and many western countries. APAP hepatotoxicity is associated with a sterile inflammatory response as shown by the infiltration of neutrophils and monocytes. While the contribution of the immune cells to promote liver repair have been demonstrated, the direct interactions between macrophages or neutrophils with hepatocytes to help facilitate hepatocyte proliferation and tissue repair remain unclear. The purpose of this study was to investigate the relationship between resident macrophages (Kupffer cells) and hepatocytes with a focus on the chemokine receptor CXCR2. C57BL/6J mice were subjected to an APAP overdose (300mg/kg) and the role of CXCR2 on hepatocytes was investigated using a selective antagonist, SB225002. Additionally, clodronate liposomes were used to deplete Kupffer cells to assess changes in CXCR2 expression. Our data showed that CXCR2 was mainly expressed on hepatocytes and it was induced specifically in hepatocytes around the necrotic area 24 hours after APAP treatment. Targeting this receptor using an inhibitor caused a delayed liver recovery. Depletion of Kupffer cells significantly prevented CXCR2 induction on hepatocytes. In vitro and in vivo experiments also demonstrated that Kupffer cells regulate CXCR2 expression and pro-regenerative gene expression in surviving hepatocytes through production of IL-10. Thus, Kupffer cells support the transition of hepatocytes around the area of necrosis to a proliferative state through CXCR2 expression.
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DOI：
10.1152/ajpgi.00317.2004
发表时间：
2005-05-01
影响因子：
4.5
作者：
Dorman, RB;Gujral, JS;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
3.8
作者：
Gujral, JS;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
15.9
作者：
Eash, Kyle J.;Greenbaum, Adam M.;Link, Daniel C.
通讯作者：
Link, Daniel C.
影响因子：
3.8
作者：
Bajt, ML;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
13.5
作者：
Bourdi, M;Masubuchi, Y;Pohl, LR
通讯作者：
Pohl, LR