State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Hepatology. 2023 Jul 1;78(1):136-149. doi: 10.1097/HEP.0000000000000239. Epub 2023 Jan 13.
The liver has the unique ability of regeneration, which is extremely important for restoring homeostasis after liver injury. Although clinical observations have revealed an association between psychological stress and the liver, whether stress has a causal influence on the liver regeneration remains markedly less defined.
Rearing rodents in an enriched environment (EE) can induce eustress or positive psychological stress. Herein, EE-induced eustress was found to significantly enhance the ability of liver regeneration after partial hepatectomy or carbon tetrachloride-induced liver injury based on the more rapid restoration of liver/body weight ratio and the significantly increased number of proliferating hepatocytes in EE mice. Mechanistically, the cytokine array revealed that IL-22 was markedly increased in the regenerating liver in response to EE. Blockade of IL-22 signaling abrogated the enhanced liver regeneration induced by EE. Group 1 innate lymphoid cells (ILCs), including type 1 ILCs (ILC1s), have been identified as the major sources of IL-22 in the regenerating liver. EE housing led to a rapid accumulation of hepatic ILC1s after partial hepatectomy and the EE-induced enhancement of liver regeneration and elevation of IL-22 was nearly eliminated in ILC1-deficient Tbx21-/- mice. Chemical sympathectomy or blockade of β-adrenergic signaling also abolished the effect of EE on ILC1s and attenuated the enhanced liver regeneration of EE-housed mice.
The study findings support the brain-liver axis and suggest that environment-induced eustress promotes liver regeneration through the sympathetic nerve/ILC1/IL-22 axis.
肝脏具有独特的再生能力，这对于肝损伤后恢复内稳态至关重要。尽管临床观察表明心理压力与肝脏之间存在关联，但压力是否对肝脏再生具有因果影响仍不明确。
在丰富环境（EE）中饲养啮齿动物可诱导良性应激或正性心理应激。本研究发现，EE 诱导的良性应激可显著增强部分肝切除或四氯化碳诱导的肝损伤后肝脏再生的能力，表现为肝/体重比更快恢复，增殖性肝细胞数量明显增加。机制上，细胞因子阵列显示，IL-22 在再生肝脏中明显增加，以响应 EE。阻断 IL-22 信号可消除 EE 诱导的增强的肝脏再生。包括 1 型固有淋巴细胞（ILC1）在内的 ILC1 群已被鉴定为再生肝脏中 IL-22 的主要来源。EE 饲养导致部分肝切除后肝内 ILC1 迅速积聚，而 EE 诱导的肝脏再生增强和 IL-22 升高在 ILC1 缺陷型 Tbx21-/-小鼠中几乎消除。化学交感神经切除术或β-肾上腺素能信号阻断也消除了 EE 对 ILC1 的作用，并减弱了 EE 饲养小鼠增强的肝脏再生。
该研究结果支持脑-肝轴的概念，并表明环境诱导的良性应激通过交感神经/ILC1/IL-22 轴促进肝脏再生。
