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XBP1s repression regulates Kupffer cell polarization leading to immune suppressive effects protecting liver allograft in rats
International Immunopharmacology ( IF 4.8 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.intimp.2020.107294
Weikang Zhang 1 , Ding Cao 2 , Menghao Wang 2 , Yakun Wu 2 , Jianping Gong 2 , Jingzheng Li 2 , Yiming Liu 2
Affiliation  

Background

Polarized kupffer cells (KCs) influence the immune response after liver transplantation. We report an undiscovered immune regulatory role of X-box binding protein 1 (XBP1) on immune function of kupffer cells (KCs).

Methods

Acute rejection model using rats.

Results

We found that suppression of XBP1s in lipopolysaccharide (LPS) -activated KCs could increase the expression of arginase-1 (Arg-1) and CD204 but also decrease the expression levels of MHC-II and CD40 and shift the phenotype markers of KCs toward M2 via the janus kinase (JAK) 3- Signal Transducer And Activator Of Transcription (STAT) 6 pathway, presenting an immunosuppressive function by enhancing anti-inflammatory cytokine secretion and accelerating apoptosis of activated T cells. XBP1s over-expression in KCs shift the phenotype markers on KCs towards M1 via the JAK1-STAT1 pathway and have shown a strong pro-inflammatory property. Down-regulation of XBP1s in KCs changed the phenotype and cytokine secretion profile towards M2 and markedly protected the function and structure of allograft liver, prolonging the recipient’s survival compared with control and normal saline groups in rats.

Conclusions

Our findings reveal a novel regulatory mechanism of XBP1 in an induced immuno-suppressive state to protect rat’s liver allograft via JAK-STAT mediated KCs polarization.



中文翻译:


XBP1s 抑制调节库普弗细胞极化,导致免疫抑制作用,保护大鼠同种异体肝移植物


 背景


极化库普弗细胞(KC)影响肝移植后的免疫反应。我们报告了 X-box 结合蛋白 1 (XBP1) 对库普弗细胞 (KC) 免疫功能的未被发现的免疫调节作用。

 方法


使用大鼠的急性排斥模型。

 结果


我们发现,在脂多糖(LPS)激活的KCs中抑制XBP1可以增加精氨酸酶-1(Arg-1)和CD204的表达,但也会降低MHC-II和CD40的表达水平,并使KCs的表型标记转向M2通过 janus 激酶 (JAK) 3-信号转导和转录激活剂 (STAT) 6 途径,通过增强抗炎细胞因子的分泌和加速活化 T 细胞的凋亡来发挥免疫抑制功能。 XBP1 在 KC 中过度表达,通过 JAK1-STAT1 途径将 KC 上的表型标记物转向 M1,并显示出强烈的促炎特性。 KCs中XBP1的下调将表型和细胞因子分泌谱改变为M2,并显着保护同种异体移植肝脏的功能和结构,与对照组和生理盐水组相比,延长了受体的存活期。

 结论


我们的研究结果揭示了 XBP1 在诱导免疫抑制状态下通过 JAK-STAT 介导的 KC 极化保护大鼠同种异体肝脏移植物的新调节机制。

更新日期:2021-01-02
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