骨化三醇受体
炎症体
自噬
化学
炎症
p38丝裂原活化蛋白激酶
MAPK/ERK通路
活性氧
激活剂(遗传学)
细胞生物学
激酶
内分泌学
内科学
受体
生物
生物化学
医学
细胞凋亡
作者
Tianfu Wen,Jing Xie,Liman Ma,Zhiqing Hao,Weiwei Zhang,Tingyao Wu,Lihua Li
标识
DOI:10.1016/j.ajpath.2023.11.016
摘要
Macrophage autophagy dysfunction aggravates liver injury by activating inflammasomes, which can cleave pro-IL-1β to its active, secreted form. We investigated whether the vitamin D/vitamin D receptor (VDR) axis could up-regulate macrophage autophagy function to inhibit the activation of inflammasome-dependent IL-1β during cholestasis. Paricalcitol (PAL; VDR agonist) was intraperitoneally injected into bile duct–ligated mice for 5 days. Up-regulation of VDR expression by PAL reduced liver injury by reducing the oxidative stress–induced inflammatory reaction in macrophages. Moreover, PAL inhibited inflammasome-dependent IL-1β generation. Mechanistically, the knockdown of VDR increased IL-1β generation, whereas VDR overexpression exerted the opposite effect following tert-butyl hydroperoxide treatment. The inflammasome antagonist glyburide, the caspase-1–specific inhibitor YVAD, and the reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) blocked the increase in Vdr shRNA-induced IL-1β production. Interestingly, up-regulation of VDR also enhanced macrophage autophagy. Autophagy reduction impaired the up-regulation of VDR-inhibited macrophage inflammasome-generated IL-1β, whereas autophagy induction showed a synergistic effect with VDR overexpression through ROS-p38 mitogen-activated protein kinase (MAPK) pathway. This result was confirmed by p38 MAPK inhibitor, MAPK activator, and ROS inhibitor NAC. Collectively, PAL triggered macrophage autophagy by suppressing activation of the ROS-p38 MAPK pathway, which, in turn, suppressed inflammasome-generated cleaved, active forms of IL-1β, eventually leading to reduced inflammation. Thus, triggering the VDR may be a potential target for the anti-inflammatory treatment of cholestatic liver disease.
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