Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Endoplasmic Reticulum Stress Activates Hepatic Macrophages through PERK-hnRNPA1 Signaling

  • Ari Kwon (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Yun Seok Kim (Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine) ;
  • Jiyoon Kim (Department of Pharmacology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Ja Hyun Koo (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
  • Received : 2023.10.04
  • Accepted : 2023.10.19
  • Published : 2024.05.01
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Abstract

Endoplasmic reticulum (ER) stress plays a crucial role in liver diseases, affecting various types of hepatic cells. While studies have focused on the link between ER stress and hepatocytes as well as hepatic stellate cells (HSCs), the precise involvement of hepatic macrophages in ER stress-induced liver injury remains poorly understood. Here, we examined the effects of ER stress on hepatic macrophages and their role in liver injury. Acute ER stress led to the accumulation and activation of hepatic macrophages, which preceded hepatocyte apoptosis. Notably, macrophage depletion mitigated liver injury induced by ER stress, underscoring their detrimental role. Mechanistic studies revealed that ER stress stimulates macrophages predominantly via the PERK signaling pathway, regardless of its canonical substrate ATF4. hnRNPA1 has been identified as a crucial mediator of PERK-driven macrophage activation, as the overexpression of hnRNPA1 effectively reduced ER stress and suppressed pro-inflammatory activation. We observed that hnRNPA1 interacts with mRNAs that encode UPR-related proteins, indicating its role in the regulation of ER stress response in macrophages. These findings illuminate the cell type-specific responses to ER stress and the significance of hepatic macrophages in ER stress-induced liver injury. Collectively, the PERK-hnRNPA1 axis has been discovered as a molecular mechanism for macrophage activation, presenting prospective therapeutic targets for inflammatory hepatic diseases such as acute liver injury.

Keywords

Acknowledgement

This work was supported by National Research Foundation of Korea grants funded by the Korea government (MSIT) (2021R1C1C1013323, 2021R1A4A5033289) as well as by the Creative-Pioneering Researchers Program from Seoul National University.

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