Role of TLR signaling and chemokine in liver regeneration, and their application to accelerated regeneration

Toll样受体（TLR）作为先天免疫信号传感器，在宿主防御中发挥重要作用。髓样分化因子（MyD）88是TLR介导的信号传导所需的常见接头分子。当受体被激活时，携带TLR的细胞以MyD 88依赖性方式产生各种促炎细胞因子。部分肝切除术后的肝再生需要天然免疫应答，特别是枯否细胞产生的白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF-α），尽管识别和激活过程仍然未知。我们研究了TLR/MyD 88信号转导是否是诱导PH后天然免疫应答的关键。在PH后的Myd 88-/-小鼠中，诱导参与肝细胞复制的即刻早期基因表达和肝脏中STAT 3的磷酸化，以及Kupffer细胞中TNF-α/IL-6的产生和NF-κB的活化均严重低于正常，并与受损的肝再生相关。然而，识别革兰氏阴性和阳性细菌产物的TLR 2、4和9对PH后NF-κB活化和IL-6产生不是必需的，这排除了TLR 2/TLR 4或TLR 9对MyD 88介导的通路的可能贡献。

Toll-like receptors (TLRs) act as innate immune signal sensors and play central roles in host defense. Myeloid differentiation factor (MyD) 88 is a common adaptor molecule required for signaling mediated by TLRs. When the receptors are activated, cells bearing TLRs produce various proinflammatory cytokines in a MyD88-dependent manner. Liver regeneration following partial hepatectomy (PH) requires innate immune responses, particularly interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) production by Kupffer cells, although the recognition and activation processes are still unknown.We investigated whether TLR/MyD88 signaling is critical for induction of innate immune responses after PH. In Myd88-/- mice after PH, induction of expression of immediate early genes involved in hepatocyte replication and phosphorylation of STAT3 in the liver, and production of TNF-α/IL-6 by and activation of NF-κB in the Kupffer cells were grossly subnormal and were associated with impaired liver regeneration. However, TLR2, 4 and 9, which recognize gram-negative and -positive bacterial products, are not essential for NF-κB activation and IL-6 production after PH, which excludes a possible contribution of TLR2/TLR4 or TLR9 to MyD88-mediated pathways.In conclusion, the TLR/MyD88 pathway is essential for incidental liver restoration, particularly its early phase.