Splenectomy Promotes Macrophage Polarization in a Mouse Model of Concanavalin A- (ConA-) Induced Liver Fibrosis

Wang, Yongjuan; Guo, Xiaopei; Jiao, Guohui; Zhou, Lu; Zhang, Jie; Wang, Bangmao

doi:10.1155/2019/5756189

Cited by 19 publications

(14 citation statements)

References 30 publications

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“…In addition to the alterations in the abundance of liver macrophages, splenectomy may affect their phenotypes. In mouse model of hepatitis and cirrhosis induced by concanavalin A, splenectomy caused polarization of liver macrophages towards M2 phenotype thus alleviating the condition of the liver [24]. We have also noticed a slight tendency towards an increase in the amount of CD206 protein in the liver after splenectomy.…”

Section: Plos Onementioning

confidence: 58%

Molecular mechanisms of splenectomy-induced hepatocyte proliferation

et al. 2020

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Functional and anatomical connection between the liver and the spleen is most clearly manifested in various pathological conditions of the liver (cirrhosis, hepatitis). The mechanisms of the interaction between the two organs are still poorly understood, as there have been practically no studies on the influence exerted by the spleen on the normal liver. Mature male Sprague-Dawley rats of 250-260 g body weight, 3 months old, were splenectomized. The highest numbers of Ki67+ hepatocytes in the liver of splenectomized rats were observed at 24 h after the surgery, simultaneously with the highest index of Ki67-positive hepatocytes. After surgical removal of the spleen, expression of certain genes in the liver tissues increased. A number of genes were upregulated in the liver at a single time point of 24 h, including Ccne1, Egf, Tnfa, Il6, Hgf, Met, Tgfb1r2 and Nos2. The expression of Ccnd1, Tgfb1, Tgfb1r1 and Il10 in the liver was upregulated over the course of 3 days after splenectomy. Monitoring of the liver macrophage populations in splenectomized animals revealed a statistically significant increase in the proportion of CD68-positive cells in the liver (as compared with sham-operated controls) detectable at 24 h and 48 h after the surgery. The difference in the liver content of CD68-positive cells between splenectomized and shamoperated animals evened out by day 3 after the surgery. No alterations in the liver content of CD163-positive cells were observed in the experiments. A decrease in the proportion of CD206-positive liver macrophages was observed at 48 h after splenectomy. The splenectomy-induced hepatocyte proliferation is described by us for the first time. Mechanistically, the effect is apparently induced by the removal of spleen as a major source of Tgfb1 (hepatocyte growth inhibitor) and subsequently supported by activation of proliferation factorencoding genes in the liver.

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Section: Plos Onementioning

confidence: 58%

Molecular mechanisms of splenectomy-induced hepatocyte proliferation

et al. 2020

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“…All mice were subjected to isoflurane anesthesia before splenectomy. Splenectomy was performed as described previously 20 . All mice were euthanized on the first day of the 8th week, and surgical procedures were conducted under completely sterile conditions.…”

Section: Methodsmentioning

confidence: 99%

Splenectomy improves liver fibrosis via tumor necrosis factor superfamily 14 (LIGHT) through the JNK/TGF-β1 signaling pathway

Liang

Xie²,

Yu³

et al. 2021

Exp Mol Med

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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.

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“…MDSCs homing in on the spleen were demonstrated in an in vivo bioimager analysis after intravenous injection of MDSCs isolated from tumour‐bearing mice into wild‐type mice, resulting in the accumulation of MDSCs in the spleen and liver 14 . Moreover, a concanavalin A‐induced liver fibrosis mouse model reported that circulating monocytic MDSCs were increased after splenectomy 15 . Therefore, splenectomy could lead to MDSC accumulation in the blood circulation, and in support of this, increased MDSCs were observed only in splenectomised β‐thalassaemia/HbE patients.…”

Section: Figurementioning

confidence: 99%