ATRA-mediated-crosstalk between stellate cells and Kupffer cells inhibits autophagy and promotes NLRP3 activation in acute liver injury

Zhen Yu; Xiaoyu Xie; Xiaonan Su; Huanran Lv; Shouyang Song; Chenxi Liu; Yajing You; Miaomiao Tian; Lihui Zhu; Le Wang; Jianni Qi; Qiang Zhu

doi:10.1016/j.cellsig.2022.110304

ATRA-mediated-crosstalk between stellate cells and Kupffer cells inhibits autophagy and promotes NLRP3 activation in acute liver injury

Cell Signal. 2022 May:93:110304. doi: 10.1016/j.cellsig.2022.110304. Epub 2022 Mar 10.

Authors

Zhen Yu¹, Xiaoyu Xie², Xiaonan Su³, Huanran Lv⁴, Shouyang Song¹, Chenxi Liu¹, Yajing You¹, Miaomiao Tian⁵, Lihui Zhu¹, Le Wang⁶, Jianni Qi⁷, Qiang Zhu⁸

Affiliations

¹ Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
² Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
³ Department of Gastroenterology, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
⁴ Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
⁵ Department of Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
⁶ Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Geriatric Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
⁷ Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. Electronic address: slqijn@126.com.
⁸ Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. Electronic address: zhuqiang@sdu.edu.cn.

PMID: 35278669
DOI: 10.1016/j.cellsig.2022.110304

Abstract

The crosstalk between hepatic stellate cells (HSCs) and Kupffer cells (KCs) is involved in acute liver injury (ALI). Meanwhile, the change of lipid droplet in HSCs predicts the development of ALI. However, it is not clear whether all trans retinoic acid (ATRA), as one of the important products of lipid droplet metabolism from HSC, regulate the activation of KCs. Firstly, our results confirmed that ATRA release and IL-1β production were significantly increased in a CCl4-induced model of ALI. In addition, we observed that ATRA could induce KCs to produce IL-1β through retinoic acid receptor (RAR) in vitro. Further mechanism studies confirmed that RAR could promote priming of NLRP3 inflammasome through transcriptional activation. ATRA also blocked autophagic flow by activating the AKT/mTOR pathway, leading to an excessive accumulation of ROS, which further activated the NLRP3 inflammasome. Activated NLRP3 inflammasome caused pyroptosis of macrophages and explosive release of IL-1β. In conclusion, we have uncovered a novel crosstalk pattern between HSCs and KCs, and ATRA-mediated-crosstalk between HSCs and KCs inhibits autophagy and promotes NLRP3 activation to aggravate acute liver injury.

Keywords: ATRA; Autophagy; Kupffer cell; NLRP3; Pyroptosis; Stellate cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy
Inflammasomes* / metabolism
Kupffer Cells* / metabolism
Liver / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Tretinoin / metabolism
Tretinoin / pharmacology

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Tretinoin