未折叠蛋白反应
骨化三醇受体
促炎细胞因子
内质网
炎症
内分泌学
内科学
肿瘤坏死因子α
巨噬细胞极化
细胞生物学
癌症研究
巨噬细胞
化学
生物
维生素D与神经学
医学
生物化学
体外
作者
Ying Zhou,Bingning Dong,Kang Ho Kim,Sung-Woo Choi,Zhen Sun,Nan Wu,Yifan Wu,Jessica Scott,David D. Moore
出处
期刊:Hepatology
[Wiley]
日期:2020-01-02
卷期号:71 (4): 1453-1466
被引量:29
摘要
Background and Aims Hepatic endoplasmic reticulum (ER) stress, whether triggered by intrinsic or extrinsic factors, can be resolved by the unfolded protein response (UPR). Sustained UPR activation leads to cell death and inflammatory response and contributes to liver disease progression. Hepatic tissue macrophages are key players in orchestrating liver inflammation, and ER stress can enhance macrophage activation. However, it is not well defined how the interplay between ER stress and inflammation is regulated during hepatic stress response. Approach and Results Here we demonstrate that vitamin D receptor (VDR) activation mitigates hepatic ER stress response, whereas VDR knockout mice undergo persistent UPR activation and apoptosis in response to chemical ER stress inducer. Moreover, VDR deficiency promotes hepatic macrophage infiltration and increases gene expression and systematic levels of proinflammatory cytokines, including interleukin (IL)‐1β, IL‐6, and tumor necrosis factor α. VDR expression is induced in hepatic macrophages by ER stress, and VDR plays a dual regulatory role in macrophages by protecting against ER stress and promoting anti‐inflammatory polarization. Co‐culture with VDR‐activated bone marrow–derived macrophages suppresses UPR target genes in primary hepatocytes treated with ER stress inducers. Thus, the immunomodulatory functions of VDR in macrophages are critical in hepatic ER stress resolution in mice. Conclusions VDR signaling in macrophages regulates a shift between proinflammatory and anti‐inflammatory activation during ER stress–induced inflammation to promote hepatic ER stress resolution.
科研通智能强力驱动
Strongly Powered by AbleSci AI