Innate immunity and cytokines in liver disease

肝损伤、炎症和修复中的先天免疫和细胞因子 肝脏是天然免疫力较强的器官，在宿主抵御微生物感染和肿瘤转化中发挥着重要作用。新的证据表明，先天性免疫以及由先天性免疫细胞产生的各种细胞因子也参与了急慢性肝病的发病机制。我们实验室一直在积极研究先天免疫及其相关细胞因子在肝脏损伤和修复中的作用。在本财政年度中，我们证明了(1)肝脏和髓系STAT3的相互作用通过缓和天然免疫在促进肝脏再生方面发挥了重要作用；(2)在髓系细胞特异性STAT3基因敲除小鼠中，四氯化碳诱导的肝脏炎症和肝细胞损伤是分离的。 肝脏和髓系STAT3通过调节天然免疫促进肝再生 三分之二的肝部分切除引发的肝再生伴随着肝脏内毒素水平的升高，内毒素有助于再生过程，但肝脏炎症和细胞凋亡仍然矛盾地受到限制。在这里，我们发现信号转导和转录激活因子3(STAT3)是一种重要的抗炎信号，在肝部分切除后髓系细胞中被激活，其有条件的缺失导致炎症反应的增强。令人惊讶的是，伴随着肝脏STAT3活性的增加，再生反应得到改善，而不是受损，这可能有助于增强肝脏再生。事实上，在肝细胞和髓系细胞中有条件地删除STAT3会导致STAT1的激活和肝细胞的凋亡增加，并显著降低部分肝切除后的存活率，而额外的STAT1整体删除可以保护这些效应。结论：髓系细胞和肝脏STAT3信号的相互作用是通过缓和STAT1信号介导的强烈的先天炎症反应来预防肝再生过程中肝功能衰竭所必需的。 四氯化碳诱导的髓系细胞特异性STAT3基因敲除小鼠肝脏炎症和肝细胞损伤之间的关系。 肝损伤与炎症有关，炎症通常被认为会加速肝脏疾病的进展；然而，临床数据表明，在一些患者中，炎症并不总是与肝细胞损伤相关。通过实验动物模型研究这些事件背后的细胞机制，我们发现炎症可以减轻四氯化碳(CCl(4))诱导的髓系特异性信号转导和转录激活因子3(STAT3)基因敲除小鼠的肝坏死。作为一种重要的抗炎信号，CCl(4)注射后，髓系细胞中STAT3的条件性缺失导致肝脏炎症显著增强。然而，这些效应也伴随着肝坏死的减少，这与血清白介素6(IL-6)升高和肝脏STAT3激活有关。在髓系特异性STAT3基因敲除小鼠中，肝细胞中STAT3的额外缺失恢复了肝坏死，但减少了肝脏炎症。结论：炎症介导的STAT3激活减轻了髓系特异性STAT3基因敲除小鼠中CCl(4)诱导的肝细胞损伤，提示炎症与激活肝脏STAT3的肝保护性细胞因子的优势相关，可能减轻而不是加速慢性肝病患者的肝细胞损伤。

Innate immunity and cytokines in liver injury, inflammation, and repair The liver is an organ with strong innate immunity, which plays an important role in host defense against microbial infection and tumor transformation. Emerging evidence suggests that innate immunity as well as a variety of cytokines produced by innate immune cells also contribute to the pathogenesis of acute and chronic liver diseases. Our laboratory has been actively studying the role of innate immunity and its associated cytokines in liver injury and repair. During the fiscal year, we have demonstrated that (1) interplay of hepatic and myeloid STAT3 plays an important role in facilitating liver regeneration via tempering innate immunity; (2) liver inflammation and hepatocellular damage induced by carbon tetrachloride are dissociated in myeloid cell-specific STAT 3 gene knockout mice. Interplay of hepatic and myeloid STAT3 in facilitating liver regeneration via tempering innate immunity Liver regeneration triggered by two-thirds partial hepatectomy is accompanied by elevated hepatic levels of endotoxin, which contributes to the regenerative process, but liver inflammation and apoptosis remain paradoxically limited. Here, we show that signal transducer and activator of transcription 3 (STAT3), an important anti-inflammatory signal, is activated in myeloid cells after partial hepatectomy and its conditional deletion results in an enhanced inflammatory response. Surprisingly, this is accompanied by an improved rather than impaired regenerative response with increased hepatic STAT3 activation, which may contribute to the enhanced liver regeneration. Indeed, conditional deletion of STAT3 in both hepatocytes and myeloid cells results in elevated activation of STAT1 and apoptosis of hepatocytes, and a dramatic reduction in survival after partial hepatectomy, whereas additional global deletion of STAT1 protects against these effects. Conclusion: An interplay of myeloid and hepatic STAT3 signaling is essential to prevent liver failure during liver regeneration through tempering a strong innate inflammatory response mediated by STAT1 signaling. Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific STAT 3 gene knockout mice. Liver injury is associated with inflammation, which is generally believed to accelerate the progression of liver diseases; however, clinical data show that inflammation does not always correlate with hepatocelluar damage in some patients. Investigating the cellular mechanisms underlying these events using an experimental animal model, we show that inflammation may attenuate liver necrosis induced by carbon tetrachloride (CCl(4)) in myeloid-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. As an important anti-inflammatory signal, conditional deletion of STAT3 in myeloid cells results in markedly enhanced liver inflammation after CCl(4) injection. However, these effects are also accompanied by reduced liver necrosis, correlating with elevated serum interleukin-6 (IL-6) and hepatic STAT3 activation. An additional deletion of STAT3 in hepatocytes in myeloid-specific STAT3 knockout mice restored hepatic necrosis but decreased liver inflammation. CONCLUSION: Inflammation-mediated STAT3 activation attenuates hepatocellular injury induced by CCl(4) in myeloid-specific STAT3 knockout mice, suggesting that inflammation associated with a predominance of hepatoprotective cytokines that activate hepatic STAT3 may reduce rather than accelerate hepatocellular damage in patients with chronic liver diseases.