Splenectomy improves liver fibrosis via tumor necrosis factor superfamily 14 (LIGHT) through the JNK/TGF-β1 signaling pathway.
Splenectomy improves liver fibrosis via tumor necrosis factor superfamily 14 (LIGHT) through the JNK/TGF-β1 signaling pathway.
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脾切除通过肿瘤坏死因子超家族 14 (LIGHT) 通过 JNK/TGF-β1 信号通路改善肝纤维化
DOI：
10.1038/s12276-021-00574-2
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发表时间：
2021-03
影响因子：
12.8
通讯作者：
Yin J
中科院分区：
文献类型：
--
作者：
Liang QS;Xie JG;Yu C;Feng Z;Ma J;Zhang Y;Wang D;Lu J;Zhuang R;Yin J
据报道，脾切除术可以改善肝硬变和脾功能亢进患者的肝纤维化。然而，机制仍不清楚。肿瘤坏死因子超家族14(TNFSF14；也称为LIGH)在纤维化的背景下高度表达，并在患有肺和皮肤纤维化等纤维化疾病的患者中促进疾病的进展。在这里，我们确定了脾切除是否控制了光的产生以改善肝纤维化。脾切除降低了伴有脾功能亢进和ConA诱导的肝纤维化小鼠模型的肝硬变患者的血清光水平。遮光导致RAW264.7细胞转化生长因子-β-1表达下调。光处理可通过激活转化生长因子-β信号调节转化生长因子-β-1的表达。小干扰RNA介导的淋巴毒素β受体(LT-βR)沉默导致巨噬细胞纤维化和α-SMA水平显著降低。这些结果表明，光与LTβR结合，并在体外促进肝纤维化。阻断转化生长因子-β-1可在体外阻断光的作用。此外，在脾切除的情况下，给予重组小鼠光蛋白诱导的肝纤维化，而在不切除脾的情况下阻断光，改善了体内的肝纤维化，揭示了脾切除后肝纤维化的减少与光水平的降低直接相关。因此，来自脾和肝巨噬细胞的高水平光激活了JNK信号，并导致肝巨噬细胞产生更多转化生长因子-β1。脾切除通过减少LIGH的表达来减轻肝纤维化。外科手术切除脾阻止了分子信号的释放，从而加剧了肝纤维化，并最终导致了肝硬化的发生。一些研究表明，脾切除可以保护肝硬变患者的肝功能，但这种有益效果的机制尚不清楚。陕西西安空军军医大学第二附属医院的尹继凯、中国和他的同事提出了一种名为光的信号蛋白作为可能的因素。这种蛋白在肝硬变患者和这种疾病的小鼠模型的血清中升高。作者随后确定了由光触发的助长纤维化的分子通路。干扰光功能的治疗可以预防纤维化，就像脾切除后光线水平的急剧下降一样。这些结果突显了一种保护肝硬变患者肝功能的有前景的机制。
Splenectomy has been reported to improve liver fibrosis in patients with cirrhosis and hypersplenism. However, the mechanisms remain unclear. Tumor necrosis factor superfamily 14 (TNFSF14; also known as LIGHT) is highly expressed in the context of fibrosis and promotes disease progression in patients with fibrotic diseases such as pulmonary and skin fibrosis. Here, we determined whether splenectomy controls the production of LIGHT to improve liver fibrosis. Splenectomy reduced serum LIGHT levels in cirrhotic patients with hypersplenism and a ConA-induced liver fibrosis mouse model. Blocking LIGHT resulted in the downregulation of TGF-β1 in RAW264.7 cells. LIGHT treatment of RAW264.7 and JS1 cells in coculture regulated transforming growth factor-β1 (TGF-β1) expression through the activation of JNK signaling. Small interfering RNA-mediated silencing of lymphotoxin β receptor (LTβR) in macrophages resulted in pronounced decreases in the levels of fibrosis and αSMA in JS1 cells. These results indicated that LIGHT bound to LTβR and drove liver fibrosis in vitro. Blocking TGF-β1 abolished the effect of LIGHT in vitro. Furthermore, the administration of recombinant murine LIGHT protein-induced liver fibrosis with splenectomy, while blocking LIGHT without splenectomy improved liver fibrosis in vivo, revealing that the decrease in fibrosis following splenectomy was directly related to reduced levels of LIGHT. Thus, high levels of LIGHT derived from the spleen and hepatic macrophages activate JNK signaling and lead to increased TGF-β1 production in hepatic macrophages. Splenectomy attenuates liver fibrosis by decreasing the expression of LIGHT. Surgical removal of the spleen prevents release of a molecular signal that exacerbates liver fibrosis and ultimately contributes to the onset of cirrhosis. Several studies have indicated that splenectomy may protect liver function in cirrhosis patients, but the mechanism underlying this beneficial effect remains unclear. JiKai Yin of the Second Affiliated Hospital of Air Force Military Medical University, Shaanxi Xi’an, China, and colleagues have proposed a signaling protein called LIGHT as a likely factor. This protein is elevated in serum of patients with cirrhosis and mouse models of this disease. The authors subsequently identified molecular pathways triggered by LIGHT that fuel fibrosis. Treatments that interfere with LIGHT function prevent fibrosis, as does the sharp decrease in LIGHT levels that occurs following splenectomy. These results highlight a promising mechanism for protecting liver function in cirrhosis patients.
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影响因子：
9.3
作者：
Herro R;Croft M
通讯作者：
Croft M
影响因子：
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作者：
Li L;Duan M;Chen W;Jiang A;Li X;Yang J;Li Z
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DOI：
10.1038/jid.2015.110
发表时间：
2015-08
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作者：
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通讯作者：
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DOI：
10.1016/j.jaci.2014.12.1936
发表时间：
2015-09
期刊：
The Journal of allergy and clinical immunology
影响因子：
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作者：
Herro R;Da Silva Antunes R;Aguilera AR;Tamada K;Croft M
通讯作者：
Croft M
影响因子：
5.3
作者：
del Rio, Maria-Luisa;Fernandez-Renedo, Carlos;Rodriguez-Barbosa, Jose-Ignacio
通讯作者：
Rodriguez-Barbosa, Jose-Ignacio