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.

References

  1. Cai, J., Zhang, X., Chen, P., Li, Y., Liu, S., Liu, Q., Zhang, H., Wu, Z., Song, K. and Liu, J. (2022) The ER stress sensor inositol-requiring enzyme 1α in Kupffer cells promotes hepatic ischemia-reperfusion injury. J. Biol. Chem. 298, 101532.
  2. de Galarreta, M. R., Navarro, A., Ansorena, E., Garzon, A. G., Modol, T., Lopez-Zabalza, M. J., Martinez-Irujo, J. J. and Iraburu, M. J. (2016) Unfolded protein response induced by Brefeldin A increases collagen type I levels in hepatic stellate cells through an IRE1α, p38 MAPK and Smad-dependent pathway. Biochim. Biophys. Acta. Mol. Cell. Res. 1863, 2115-2123. https://doi.org/10.1016/j.bbamcr.2016.05.002
  3. Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. and Sanyal, A. J. (2018) Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908-922. https://doi.org/10.1038/s41591-018-0104-9
  4. Hamilton, B. J., Nagy, E., Malter, J. S., Arrick, B. A. and Rigby, W. (1993) Association of heterogeneous nuclear ribonucleoprotein A1 and C proteins with reiterated AUUUA sequences. J. Biol. Chem. 268, 8881-8887. https://doi.org/10.1016/S0021-9258(18)52955-0
  5. Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R., Schapira, M. and Ron, D. (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099-1108. https://doi.org/10.1016/S1097-2765(00)00108-8
  6. Heindryckx, F., Binet, F., Ponticos, M., Rombouts, K., Lau, J., Kreuger, J. and Gerwins, P. (2016) Endoplasmic reticulum stress enhances fibrosis through IRE 1α-mediated degradation of miR-150 and XBP-1 splicing. EMBO Mol. Med. 8, 729-744. https://doi.org/10.15252/emmm.201505925
  7. Kawasaki, N., Asada, R., Saito, A., Kanemoto, S. and Imaizumi, K. (2012) Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci. Rep. 2, 799.
  8. Kazankov, K., Jorgensen, S. M. D., Thomsen, K. L., Moller, H. J., Vilstrup, H., George, J., Schuppan, D. and Gronbaek, H. (2019) The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat. Rev. Gastroenterol. Hepatol. 16, 145-159. https://doi.org/10.1038/s41575-018-0082-x
  9. Koo, J. H. and Han, C. Y. (2021) Signaling nodes associated with endoplasmic reticulum stress during NAFLD progression. Biomolecules 11, 242.
  10. Koo, J. H., Lee, H. J., Kim, W. and Kim, S. G. (2016) Endoplasmic reticulum stress in hepatic stellate cells promotes liver fibrosis via PERK-mediated degradation of HNRNPA1 and up-regulation of SMAD2. Gastroenterology 150, 181-193. https://doi.org/10.1053/j.gastro.2015.09.039
  11. Koo, J. H., Lee, W. H., Lee, C. G. and Kim, S. G. (2012) Fyn inhibition by cycloalkane-fused 1, 2-dithiole-3-thiones enhances antioxidant capacity and protects mitochondria from oxidative injury. Mol. Pharmacol. 82, 27-36. https://doi.org/10.1124/mol.111.077149
  12. Kweon, Y.-O., Paik, Y.-H., Schnabl, B., Qian, T., Lemasters, J. J. and Brenner, D. A. (2003) Gliotoxin-mediated apoptosis of activated human hepatic stellate cells. J. Hepatol. 39, 38-46. https://doi.org/10.1016/S0168-8278(03)00178-8
  13. Lebeaupin, C., Proics, E., De Bieville, C., Rousseau, D., Bonnafous, S., Patouraux, S., Adam, G., Lavallard, V., Rovere, C. and Le Thuc, O. (2015) ER stress induces NLRP3 inflammasome activation and hepatocyte death. Cell Death Dis. 6, e1879.
  14. Liao, X., Zhan, W., Li, R., Tian, T., Yu, L. and Yang, Q. (2021) Irisin ameliorates endoplasmic reticulum stress and liver fibrosis through inhibiting PERK-mediated destabilization of HNRNPA1 in hepatic stellate cells. Biol. Chem. 402, 703-715. https://doi.org/10.1515/hsz-2020-0251
  15. Malhi, H., Kropp, E. M., Clavo, V. F., Kobrossi, C. R., Han, J., Mauer, A. S., Yong, J. and Kaufman, R. J. (2013) C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis. J. Biol. Chem. 288, 18624-18642. https://doi.org/10.1074/jbc.M112.442954
  16. Pakos-Zebrucka, K., Koryga, I., Mnich, K., Ljujic, M., Samali, A. and Gorman, A. M. (2016) The integrated stress response. EMBO Rep. 17, 1374-1395. https://doi.org/10.15252/embr.201642195
  17. Papadodima, O., Chatziioannou, A., Patrinou-Georgoula, M., Kolisis, F. N., Pletsa, V. and Guialis, A. (2013) HuR-regulated mRNAs associated with nuclear hnRNP A1-RNP complexes. Int. J. Mol. Sci. 14, 20256-20281. https://doi.org/10.3390/ijms141020256
  18. Roy, R., Huang, Y., Seckl, M. J. and Pardo, O. E. (2017) Emerging roles of hnRNPA1 in modulating malignant transformation. Wiley Interdiscip. Rev. RNA 8, e1431.
  19. Tacke, F. and Zimmermann, H. W. (2014) Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090-1096. https://doi.org/10.1016/j.jhep.2013.12.025
  20. Van Rooijen, N., Sanders, A. and van den Berg, T. K. (1996) Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. J. Immunol. Methods 193, 93-99. https://doi.org/10.1016/0022-1759(96)00056-7
  21. Yamamoto, K., Takahara, K., Oyadomari, S., Okada, T., Sato, T., Harada, A. and Mori, K. (2010) Induction of liver steatosis and lipid droplet formation in ATF6α-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol. Biol. Cell 21, 2975-2986. https://doi.org/10.1091/mbc.e09-02-0133
  22. Yamamoto, Y. and Gaynor, R. B. (2004) IκB kinases: key regulators of the NF-κB pathway. Trends Biochem. Sci. 29, 72-79. https://doi.org/10.1016/j.tibs.2003.12.003
  23. Yang, F., Liu, Y., Ren, H., Zhou, G., Yuan, X. and Shi, X. (2019) ER-stress regulates macrophage polarization through pancreatic EIF2alpha kinase. Cell Immunol. 336, 40-47. https://doi.org/10.1016/j.cellimm.2018.12.008
  24. Yao, S., Miao, C., Tian, H., Sang, H., Yang, N., Jiao, P., Han, J., Zong, C. and Qin, S. (2014) Endoplasmic reticulum stress promotes macrophage-derived foam cell formation by up-regulating cluster of differentiation 36 (CD36) expression. J. Biol. Chem. 289, 4032-4042. https://doi.org/10.1074/jbc.M113.524512
  25. Zhang, G., Wang, X., Rothermel, B. A., Lavandero, S. and Wang, Z. V. (2022) The integrated stress response in ischemic diseases. Cell Death Differ. 29, 750-757. https://doi.org/10.1038/s41418-021-00889-7
  26. Zhang, K., Wang, S., Malhotra, J., Hassler, J. R., Back, S. H., Wang, G., Chang, L., Xu, W., Miao, H. and Leonardi, R. (2011) The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis. EMBO J. 30, 1357-1375. https://doi.org/10.1038/emboj.2011.52