XBP1s 的抑制调节枯否细胞极化，导致免疫抑制作用，从而保护大鼠肝移植中的肝脏。

XBP1s repression regulates Kupffer cell polarization leading to immune suppressive effects protecting liver allograft in rats.

机构信息

Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China.

Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.

出版信息

Int Immunopharmacol. 2021 Feb;91:107294. doi: 10.1016/j.intimp.2020.107294. Epub 2021 Jan 1.

DOI:10.1016/j.intimp.2020.107294

PMID:33395585

Abstract

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.

摘要

背景

极化的枯否细胞（KCs）影响肝移植后的免疫反应。我们报告了 X 盒结合蛋白 1（XBP1）对枯否细胞（KCs）免疫功能的一个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 XBP1s 可以增加精氨酸酶-1（Arg-1）和 CD204 的表达，但也降低 MHC-II 和 CD40 的表达水平，并通过 Janus 激酶（JAK）3-信号转导和转录激活因子（STAT）6 途径将 KCs 的表型标志物向 M2 转移，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。KCs 中的 XBP1s 过表达通过 JAK1-STAT1 途径使 KCs 的表型标志物向 M1 转移，并表现出很强的促炎特性。KCs 中 XBP1s 的下调使表型和细胞因子分泌谱向 M2 转变，并显著保护同种异体肝的功能和结构，与对照组和生理盐水组相比，延长了受体的存活时间。