肝炎治疗：枯否细胞调节病原体控制和肝细胞再生之间的平

StephenW

Hepatitis therapy: Kupffer cells adjust the balance between pathogen control and hepatocyte regenera
January 17, 2018, Elsevier

Inflammation of the liver can result from different causes. Besides infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), other viruses such as cytomegalovirus (CMV) are able to trigger acute hepatitis. Sometimes hepatitis induces fever and flu-like symptoms, however, it may also damage the liver and might even result in acute liver failure. Yet, currently there is no general agreement on how acute hepatitis should be treated: Should the immune response against the viral pathogen be reinforced or inhibited? Scientists from TWINCORE have now published new insights on the processes involved in liver inflammation in the Journal of Hepatology: Type I interferons, on the one hand, limit viral replication and thereby help the immune cells to control the viral pathogen. On the other hand, type I interferons delay the regeneration of immune cells, which are important to adjust and maintain the immune balance within the liver during acute inflammation.

"So far, it has been assumed that viral replication itself destroys liver cells," says Katharina Borst, scientist at the Institute for Experimental Infection Research, TWINCORE, Hannover, Germany. "Meanwhile we also know that local inflammatory processes can damage the liver." This is critical knowledge, because, if the inflammatory reaction and not the virus accounts for liver damage, one should not enhance the inflammation within the already inflamed organ by treatment with an inflammatory cytokine such as type I interferon. "On the other hand, in clinical practice it is well established that type I interferon is an effective treatment during acute hepatitis and that it protects the liver," argues Dr. Theresa Frenz, also scientist at the Institute for Experimental Infection Research, TWINCORE. At first glance this is a paradoxical situation that needs clarification.

Therefore, the scientists set out to understand the mechanism by which type I interferon works in the liver. To understand the local immune responses, they analyzed Kupffer cells, which are liver-resident scavenger cells within the immune system. The researchers used vaccinia virus to infect livers that either could or could not detect type I interferon, or in which only the Kupffer cells or the hepatocytes, the main cell type of the liver, could or could not detect type I interferon.

"This experiment showed us that hepatocytes do not need type I interferon to combat viral infection, since we could not find differences, regardless of whether we analyzed normal livers or livers in which only hepatocytes did not detect type I interferon," says Katharina Borst. "This is surprising, since hepatocytes are the main target cell for type for infection."

However, type I interferon seems to be important for Kupffer cells, says Dr. Frenz: "We believe, that type I interferon triggers Kupffer cells to take up infected cells and undergo apoptosis (suicide) afterwards, since surprisingly, Kupffer cells disappear after infection." The body replaces those lost Kupffer cells by scavenger cells, which develop from the bone marrow. Such cells are not "real" Kupffer cells, but they still take over similar tasks. Interestingly, this process is accelerated if the bone marrow cells cannot sense type I interferon," says Ms. Borst. "Obviously, type I interferon is very important to adjust the regulation of inflammatory processes."

"We verified that therapeutic treatment of acute viral hepatitis with type I interferon is reasonable, since it activates local immune cells and helps to eliminate the virus," concludes institute director Prof. Ulrich Kalinke. "However, in order to better support the regeneration of the inflamed liver, we need to learn more about the balance of enhancement and modulation of inflammation. This will be the basis to develop new therapeutic interventions for acute hepatitis."

Explore further: Effect of gut bacteria on specific immune cells underlies persistent liver inflammation

More information: Katharina Borst et al, Type I interferon receptor-signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis, Journal of Hepatology (2017). DOI: 10.1016/j.jhep.2017.11.029

StephenW

肝炎治疗：枯否细胞调节病原体控制和肝细胞再生之间的平衡
2018年1月17日，Elsevier

肝脏的炎症可以由不同的原因引起。除乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）感染外，其他病毒如巨细胞病毒（CMV）也能引发急性肝炎。有时肝炎引起发烧和流感样症状，但也可能损害肝脏，甚至可能导致急性肝功能衰竭。然而，目前还没有就如何治疗急性肝炎达成共识：是否应该加强或抑制针对病毒病原体的免疫应答？来自TWINCORE的科学家们现在发表了关于肝脏病学期刊中肝脏炎症过程的新见解：I型干扰素，一方面限制了病毒复制，从而帮助免疫细胞控制病毒病原体。另一方面，I型干扰素延迟免疫细胞的再生，这对于在急性炎症期间调节和维持肝脏内的免疫平衡是重要的。

德国汉诺威TWINCORE实验感染研究所的科学家Katharina Borst说：“到目前为止，人们一直认为病毒复制本身就会破坏肝细胞。 “同时我们也知道局部炎症过程会损伤肝脏。”这是至关重要的知识，因为如果炎性反应而不是病毒造成肝损害，则不应该通过用炎性细胞因子如I型干扰素治疗来增强已经发炎的器官内的炎症。 TWINCORE实验感染研究所的科学家Theresa Frenz博士认为：“另一方面，在临床实践中，I型干扰素在急性肝炎期间是一种有效的治疗方法，并能保护肝脏。乍一看，这是一个矛盾的情况，需要澄清。

因此，科学家开始了解I型干扰素在肝脏中起作用的机制。为了了解局部的免疫反应，他们分析了Kupffer细胞，它们是免疫系统内的肝脏清除细胞。研究人员利用痘苗病毒感染肝脏，可以或不可以检测到I型干扰素，或者只有肝脏的主要细胞类型的枯否细胞或肝细胞能够或不能检测到I型干扰素。

Katharina Borst说：“这个实验告诉我们，肝细胞不需要I型干扰素来对抗病毒感染，因为我们无法分辨出是否有肝细胞正常的肝脏或者肝脏，只有肝细胞没有检测到I型干扰素。 “这是令人惊讶的，因为肝细胞是感染类型的主要靶细胞。”

然而，I型干扰素似乎对Kupffer细胞很重要，Frenz博士说：“我们认为，I型干扰素能诱发Kupffer细胞摄取感染的细胞，之后会发生细胞凋亡（自杀），因为感染后Kupffer细胞会消失“。清除细胞，从骨髓发展，身体取代了这些损失的枯否细胞。这种细胞不是“真正的”库普弗细胞，但它们仍然接管类似的任务。有趣的是，如果骨髓细胞不能感觉到I型干扰素，这个过程就会加速，“Borst女士说，”显然，I型干扰素对于调节炎症过程的调节是非常重要的。

该研究所主任Ulrich Kalinke教授总结说：“我们证实，使用I型干扰素治疗急性病毒性肝炎是合理的，因为它能激活局部免疫细胞并有助于消除病毒。 “但是，为了更好地支持发炎肝脏的再生，我们需要更多地了解炎症增强和调节的平衡，这将是开发新的急性肝炎治疗干预措施的基础。

进一步探索：肠道细菌对特定免疫细胞的影响是持续肝脏炎症的基础

更多信息：Katharina Borst等，I型干扰素受体信号延迟库普弗细胞补给在急性暴发性病毒性肝炎，“肝脏病学杂志”（2017年）。 DOI：10.1016 / j.jhep.2017.11.029