肝胆相照论坛

标题: I型干扰素受体信号延迟急性暴发性病毒性肝炎期间Kupffer细胞 [打印本页]
作者: StephenW    时间: 2018-3-17 21:28     标题: I型干扰素受体信号延迟急性暴发性病毒性肝炎期间Kupffer细胞

Research Article
Type I interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitisAuthor links open overlay panelKatharinaBorst1†TheresaFrenz1†JuliaSpanier1Pia-KatharinaTegtmeyer1ChintanChhatbar1JenniferSkerra1LucaGhita1SukumarNamineni23StefanLienenklaus14MarioKöster5MathiasHeikenwaelder23GerdSutter6UlrichKalinke11Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hanover Medical School and the Helmholtz Centre for Infection Research, Brunswick, Germany2Department Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany3Institute of Virology, Technical University Munich, Munich, Germany4Institute for Laboratory Animal Science, Hanover Medical School, Hanover, Germany5Research Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Brunswick, Germany6Institute for Infectious Diseases and Zoonoses, Ludwig-Maximilians University, Munich, Germany

Received 19 May 2017, Revised 15 September 2017, Accepted 15 November 2017, Available online 21 December 2017.

See Editorial, pages 635–637




https://doi.org/10.1016/j.jhep.2017.11.029Get rights and content
Referred to byWilliam Alazawi, Percy A. Knolle
Interfering with Kupffer cell replenishment: New insights into liver injuryJournal of Hepatology, Volume 68, Issue 4, April 2018, Pages 635-637
Download PDF

Highlights•

During acute viral hepatitis local IFN-I responses modulate liver inflammation.

•

IFNAR triggering of Kupffer cells protects against liver pathology during acute viral hepatitis.

•

Acute viral hepatitis induces Kupffer cell loss independently of direct infection.

•

Hepatitis-induced Kupffer cell loss is reversed by infiltrating blood monocytes.

•

In acute viral hepatitis IFNAR triggering of monocytes delays replenishment of monocyte-derived Kupffer cells.



Background & Aim

Virus-induced fulminant hepatitis is a major cause of acute liver failure. During acute viral hepatitis the impact of type I interferon (IFN-I) on myeloid cells, including liver-resident Kupffer cells (KC), is only partially understood. Herein, we dissected the impact of locally induced IFN-I responses on myeloid cell function and hepatocytes during acute liver inflammation.


Methods

Two different DNA-encoded viruses, vaccinia virus (VACV) and murine cytomegalovirus (MCMV), were studied. In vivo imaging was applied to visualize local IFN-β induction and IFN-I receptor (IFNAR) triggering in VACV-infected reporter mice. Furthermore, mice with a cell type-selective IFNAR ablation were analyzed to dissect the role of IFNAR signaling in myeloid cells and hepatocytes. Experiments with Cx3cr1+/gfp mice revealed the origin of reconstituted KC. Finally, mixed bone marrow chimeric mice were studied to specifically analyze the effect of IFNAR triggering on liver infiltrating monocytes.


Results

VACV infection induced local IFN-β responses, which lead to IFNAR signaling primarily within the liver. IFNAR triggering was needed to control the infection and prevent fulminant hepatitis. The severity of liver inflammation was independent of IFNAR triggering of hepatocytes, whereas IFNAR triggering of myeloid cells protected from excessive inflammation. Upon VACV or MCMV infection KC disappeared, whereas infiltrating monocytes differentiated to KC afterwards. During IFNAR triggering such replenished monocyte-derived KC comprised more IFNAR-deficient than -competent cells in mixed bone marrow chimeric mice, whereas after the decline of IFNAR triggering both subsets showed an even distribution.


Conclusion

Upon VACV infection IFNAR triggering of myeloid cells, but not of hepatocytes, critically modulates acute viral hepatitis. During infection with DNA-encoded viruses IFNAR triggering of liver-infiltrating blood monocytes delays the development of monocyte-derived KC, pointing towards new therapeutic strategies for acute viral hepatitis.


Lay summary

Viral infection can cause fulminant hepatitis, which in turn is a major cause of acute liver failure. Herein, we aimed to study the role of type 1 interferon responses in acute viral hepatitis. We identified that during infection with DNA-encoded viruses, type 1 interferon receptor triggering of blood monocytes delays the development of monocyte-derived Kupffer cells. This points to new therapeutic strategies for acute viral hepatitis.



Graphical abstract


作者: StephenW    时间: 2018-3-17 21:28

I型干扰素受体信号延迟急性暴发性病毒性肝炎期间Kupffer细胞补充
作者链接打开覆盖面板KatharinaBorst1†TheresaFrenz1†JuliaSpanier1Pia-KatharinaTegtmeyer1ChintanChhatbar1JenniferSkerra1LucaGhita1SukumarNamineni23StefanLienenklaus14MarioKöster5MathiasHeikenwaelder23GerdSutter6UlrichKalinke1

1
    TWINCORE实验和临床感染研究中心是汉诺威医学院与德国布伦瑞克亥姆霍兹感染研究中心的合资企业，实验感染研究所

2
    德国海德堡德国癌症研究中心（DKFZ）慢性炎症和癌症部

3
    德国慕尼黑慕尼黑工业大学病毒学研究所

4
    汉诺威医学院实验动物科学研究所，德国汉诺威

五
    研究组感染与免疫模型系统，亥姆霍兹感染研究中心，德国布伦瑞克

6
    德国慕尼黑路德维希马克西米利安大学传染病与人畜共患病研究所

2017年5月19日收到，2017年9月15日修订，2017年11月15日接受，2017年12月21日在线提供。

见编辑，第635-637页
CROSSMARK车标
https://doi.org/10.1016/j.jhep.2017.11.029
获取权利和内容
通过
威廉Alazawi，Percy A. Knolle
干扰Kupffer细胞补给：肝损伤的新见解
Journal of Hepatology，第68卷，第4期，2018年4月，第635-637页
下载PDF
强调

•

    在急性病毒性肝炎期间，局部IFN-I应答调节肝脏炎症。
•

    枯否氏细胞的IFNAR触发可防止急性病毒性肝炎期间的肝脏病理。
•

    急性病毒性肝炎诱导Kupffer细胞丧失独立于直接感染。
•

    浸润血液单核细胞可逆转肝炎诱导的库普弗细胞损失。
•

    在急性病毒性肝炎中，单核细胞的IFNAR触发延迟单核细胞衍生枯否细胞的补充。

背景和目的

病毒诱发的暴发性肝炎是急性肝衰竭的主要原因。在急性病毒性肝炎期间，I型干扰素（IFN-I）对骨髓细胞（包括肝脏驻留Kupffer细胞（KC））的影响仅被部分理解。在此，我们解剖了在急性肝炎期间局部诱导的IFN-I应答对骨髓细胞功能和肝细胞的影响。
方法

研究了两种不同的DNA编码病毒，牛痘病毒（VACV）和鼠巨细胞病毒（MCMV）。应用体内成像来显现VACV感染的报告小鼠中的局部IFN-β诱导和IFN-I受体（IFNAR）触发。此外，分析了具有细胞类型选择性IFNAR消融的小鼠以剖析IFNAR信号传导在骨髓细胞和肝细胞中的作用。用Cx3cr1 + / gfp小鼠进行的实验揭示了重建KC的起源。最后，研究混合骨髓嵌合小鼠以专门分析IFNAR触发对肝浸润单核细胞的影响。
结果

VACV感染诱导局部IFN-β应答，其导致主要在肝脏内的IFNAR信号传导。需要IFNAR触发来控制感染并预防暴发性肝炎。肝脏炎症的严重性独立于肝细胞的IFNAR触发，而IFNAR引发的骨髓细胞免受过度炎症的影响。在VACV或MCMV感染后，KC消失，然后浸润的单核细胞分化成KC。在IFNAR触发期间，这种补充的单核细胞衍生的KC在混合骨髓嵌合小鼠中包含比共感受性细胞更多的IFNAR缺陷，而在IFNAR触发下降后，两种亚型均表现出均匀分布。
结论

在VACV感染后，骨髓细胞（而不是肝细胞）的IFNAR触发严重调节急性病毒性肝炎。在用DNA编码的病毒感染期间，IFNAR触发肝浸润性血液单核细胞会延迟单核细胞衍生的KC的发展，从而指向急性病毒性肝炎的新治疗策略。
总结

病毒感染可引起暴发性肝炎，这又是急性肝衰竭的主要原因。在此，我们旨在研究1型干扰素应答在急性病毒性肝炎中的作用。我们发现在感染DNA编码的病毒的过程中，1型干扰素受体触发血液单核细胞会延迟单核细胞来源的枯否细胞的发育。这指向了急性病毒性肝炎的新治疗策略。



欢迎光临 肝胆相照论坛 (http://hbvhbv.info/forum/) Powered by Discuz! X1.5